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Paediatric pseudo-obstruction syndrome v0.2 PHOX2B Eleanor Williams reviewed gene: PHOX2B: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 PDCL3 Eleanor Williams reviewed gene: PDCL3: Rating: ; Mode of pathogenicity: ; Publications: 32621347; Phenotypes: Loss-of-function of this protein affects the contractility of smooth muscle tissues; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 NRTN Eleanor Williams reviewed gene: NRTN: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: 1 case reported.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 NKX2-1 Eleanor Williams reviewed gene: NKX2-1: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Megacolon, oesophageal atresia; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 NDUFS1 Eleanor Williams reviewed gene: NDUFS1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 MYLK Eleanor Williams reviewed gene: MYLK: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYLK leads to impaired smooth muscle cell contraction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MYL9 Eleanor Williams reviewed gene: MYL9: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYL9 leads to impaired intestinal smooth muscle contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MYH11 Eleanor Williams reviewed gene: MYH11: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal MYH11 in smooth muscle myosin leads to impaired contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 MPV17 Eleanor Williams reviewed gene: MPV17: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Elevated transaminases, GGT, hyperbilirubinemia, failure to thrive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 LMOD1 Eleanor Williams reviewed gene: LMOD1: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Abnormal LMOD1 leads to impaired intestinal smooth muscle contractility; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 LIG3 Eleanor Williams reviewed gene: LIG3: Rating: ; Mode of pathogenicity: ; Publications: 33855352; Phenotypes: ; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 L1CAM Eleanor Williams reviewed gene: L1CAM: Rating: ; Mode of pathogenicity: ; Publications: 31848803; Phenotypes: Defect in the differentiation of the interstitial cells of Cajal leading to progressive distension and intermittent episodes of obstruction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 KIF26A Eleanor Williams reviewed gene: KIF26A: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: GDNF-Ret in ENS development; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 GFRA1 Eleanor Williams reviewed gene: GFRA1: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Effect on ENS development; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 GDNF Eleanor Williams reviewed gene: GDNF: Rating: ; Mode of pathogenicity: ; Publications: 21858136; Phenotypes: Long segment megacolon, HSCR; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 FOCAD Eleanor Williams reviewed gene: FOCAD: Rating: ; Mode of pathogenicity: ; Publications: 31814461; Phenotypes: familial intestinal degenerative neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 FLNA Eleanor Williams reviewed gene: FLNA: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Cytoskeletal abnormalities and potentially disrupts enteric-neuron structure and function. Seizures and progressive abdominal distension and obstruction; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric pseudo-obstruction syndrome v0.2 ERBB3 Eleanor Williams reviewed gene: ERBB3: Rating: ; Mode of pathogenicity: ; Publications: 33720042; Phenotypes: Aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ERBB2 Eleanor Williams reviewed gene: ERBB2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 EDNRB Eleanor Williams reviewed gene: EDNRB: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 EDN3 Eleanor Williams reviewed gene: EDN3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: monogenic syndrome with a variable predisposition to HSCR; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ECE1 Eleanor Williams reviewed gene: ECE1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Short segment megacolon, craniofacial defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 DLX2 Eleanor Williams reviewed gene: DLX2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: massive proximal bowel distention attributed to abnormal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 DLX1 Eleanor Williams reviewed gene: DLX1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: massive proximal bowel distention attributed to abnormal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 DGUOK Eleanor Williams reviewed gene: DGUOK: Rating: ; Mode of pathogenicity: ; Publications: 23385875; Phenotypes: Elevated serum concentration of tyrosine/phenylalanine, elevation of liver enzymes, increased serum concentration of ferritin, deficiency in complexes I, III, IV; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric pseudo-obstruction syndrome v0.2 DDX3X Eleanor Williams reviewed gene: DDX3X: Rating: ; Mode of pathogenicity: ; Publications: 32896648; Phenotypes: Psychomotor retardation, severe constipation, and a recurrent paralytic ileus.; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 COX15 Eleanor Williams reviewed gene: COX15: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 COX10 Eleanor Williams reviewed gene: COX10: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 CHRNE Eleanor Williams reviewed gene: CHRNE: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Congenital myasthenia, cholinergic receptors; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 C17orf107 Eleanor Williams reviewed gene: C17orf107: Rating: ; Mode of pathogenicity: ; Publications: 30663199; Phenotypes: Congenital myasthenia, cholinergic receptors; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 BCS1L Eleanor Williams reviewed gene: BCS1L: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Psychomotor regression, failure to thrive, hypotonia, dystonia, ataxia, peripheral neuropathy, ophthalmoparesis, nystagmus, optic atrophy; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 BCR Eleanor Williams reviewed gene: BCR: Rating: ; Mode of pathogenicity: ; Publications: 34190380; Phenotypes: Growth retardation and impaired gastrointestinal motility; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.2 ACTG2 Eleanor Williams reviewed gene: ACTG2: Rating: ; Mode of pathogenicity: ; Publications: 33729000, 31848803; Phenotypes: Altered ACTG2 protein in the muscularis propria leads to impaired contractility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Paediatric pseudo-obstruction syndrome v0.2 ACTA2 Eleanor Williams reviewed gene: ACTA2: Rating: ; Mode of pathogenicity: ; Publications: 33729000; Phenotypes: Dysfunction of SMCs throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension.; Mode of inheritance: Unknown
Paediatric pseudo-obstruction syndrome v0.1 ZEB2 Eleanor Williams gene: ZEB2 was added
gene: ZEB2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ZEB2 was set to
Paediatric pseudo-obstruction syndrome v0.1 TYMP Eleanor Williams gene: TYMP was added
gene: TYMP was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TYMP was set to
Paediatric pseudo-obstruction syndrome v0.1 TWNK Eleanor Williams gene: TWNK was added
gene: TWNK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TWNK was set to
Paediatric pseudo-obstruction syndrome v0.1 TTC7A Eleanor Williams gene: TTC7A was added
gene: TTC7A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TTC7A was set to
Paediatric pseudo-obstruction syndrome v0.1 TPM3 Eleanor Williams gene: TPM3 was added
gene: TPM3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TPM3 was set to
Paediatric pseudo-obstruction syndrome v0.1 TK2 Eleanor Williams gene: TK2 was added
gene: TK2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: TK2 was set to
Paediatric pseudo-obstruction syndrome v0.1 SURF1 Eleanor Williams gene: SURF1 was added
gene: SURF1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SURF1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SUCLG1 Eleanor Williams gene: SUCLG1 was added
gene: SUCLG1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SUCLG1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SUCLA2 Eleanor Williams gene: SUCLA2 was added
gene: SUCLA2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SUCLA2 was set to
Paediatric pseudo-obstruction syndrome v0.1 SOX10 Eleanor Williams gene: SOX10 was added
gene: SOX10 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SOX10 was set to
Paediatric pseudo-obstruction syndrome v0.1 SGO1 Eleanor Williams gene: SGO1 was added
gene: SGO1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SGO1 was set to
Paediatric pseudo-obstruction syndrome v0.1 SEMA3F Eleanor Williams gene: SEMA3F was added
gene: SEMA3F was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SEMA3F was set to
Paediatric pseudo-obstruction syndrome v0.1 SDHA Eleanor Williams gene: SDHA was added
gene: SDHA was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SDHA was set to
Paediatric pseudo-obstruction syndrome v0.1 SCN10A Eleanor Williams gene: SCN10A was added
gene: SCN10A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: SCN10A was set to
Paediatric pseudo-obstruction syndrome v0.1 RRM2B Eleanor Williams gene: RRM2B was added
gene: RRM2B was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RRM2B was set to
Paediatric pseudo-obstruction syndrome v0.1 RET Eleanor Williams gene: RET was added
gene: RET was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RET was set to
Paediatric pseudo-obstruction syndrome v0.1 RAD21 Eleanor Williams gene: RAD21 was added
gene: RAD21 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: RAD21 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROKR2 Eleanor Williams gene: PROKR2 was added
gene: PROKR2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROKR2 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROKR1 Eleanor Williams gene: PROKR1 was added
gene: PROKR1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROKR1 was set to
Paediatric pseudo-obstruction syndrome v0.1 PROK1 Eleanor Williams gene: PROK1 was added
gene: PROK1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PROK1 was set to
Paediatric pseudo-obstruction syndrome v0.1 POLG Eleanor Williams gene: POLG was added
gene: POLG was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: POLG was set to
Paediatric pseudo-obstruction syndrome v0.1 PHOX2B Eleanor Williams gene: PHOX2B was added
gene: PHOX2B was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PHOX2B was set to
Paediatric pseudo-obstruction syndrome v0.1 PDCL3 Eleanor Williams gene: PDCL3 was added
gene: PDCL3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: PDCL3 was set to
Paediatric pseudo-obstruction syndrome v0.1 NRTN Eleanor Williams gene: NRTN was added
gene: NRTN was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NRTN was set to
Paediatric pseudo-obstruction syndrome v0.1 NKX2-1 Eleanor Williams gene: NKX2-1 was added
gene: NKX2-1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NKX2-1 was set to
Paediatric pseudo-obstruction syndrome v0.1 NDUFS1 Eleanor Williams gene: NDUFS1 was added
gene: NDUFS1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: NDUFS1 was set to
Paediatric pseudo-obstruction syndrome v0.1 MYLK Eleanor Williams gene: MYLK was added
gene: MYLK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYLK was set to
Paediatric pseudo-obstruction syndrome v0.1 MYL9 Eleanor Williams gene: MYL9 was added
gene: MYL9 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYL9 was set to
Paediatric pseudo-obstruction syndrome v0.1 MYH11 Eleanor Williams gene: MYH11 was added
gene: MYH11 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MYH11 was set to
Paediatric pseudo-obstruction syndrome v0.1 MPV17 Eleanor Williams gene: MPV17 was added
gene: MPV17 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: MPV17 was set to
Paediatric pseudo-obstruction syndrome v0.1 LMOD1 Eleanor Williams gene: LMOD1 was added
gene: LMOD1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: LMOD1 was set to
Paediatric pseudo-obstruction syndrome v0.1 LIG3 Eleanor Williams gene: LIG3 was added
gene: LIG3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: LIG3 was set to
Paediatric pseudo-obstruction syndrome v0.1 L1CAM Eleanor Williams gene: L1CAM was added
gene: L1CAM was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: L1CAM was set to
Paediatric pseudo-obstruction syndrome v0.1 KIF26A Eleanor Williams gene: KIF26A was added
gene: KIF26A was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: KIF26A was set to
Paediatric pseudo-obstruction syndrome v0.1 GFRA1 Eleanor Williams gene: GFRA1 was added
gene: GFRA1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: GFRA1 was set to
Paediatric pseudo-obstruction syndrome v0.1 GDNF Eleanor Williams gene: GDNF was added
gene: GDNF was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: GDNF was set to
Paediatric pseudo-obstruction syndrome v0.1 FOCAD Eleanor Williams gene: FOCAD was added
gene: FOCAD was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: FOCAD was set to
Paediatric pseudo-obstruction syndrome v0.1 FLNA Eleanor Williams gene: FLNA was added
gene: FLNA was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: FLNA was set to
Paediatric pseudo-obstruction syndrome v0.1 ERBB3 Eleanor Williams gene: ERBB3 was added
gene: ERBB3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ERBB3 was set to
Paediatric pseudo-obstruction syndrome v0.1 ERBB2 Eleanor Williams gene: ERBB2 was added
gene: ERBB2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ERBB2 was set to
Paediatric pseudo-obstruction syndrome v0.1 EDNRB Eleanor Williams gene: EDNRB was added
gene: EDNRB was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: EDNRB was set to
Paediatric pseudo-obstruction syndrome v0.1 EDN3 Eleanor Williams gene: EDN3 was added
gene: EDN3 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: EDN3 was set to
Paediatric pseudo-obstruction syndrome v0.1 ECE1 Eleanor Williams gene: ECE1 was added
gene: ECE1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ECE1 was set to
Paediatric pseudo-obstruction syndrome v0.1 DLX2 Eleanor Williams gene: DLX2 was added
gene: DLX2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DLX2 was set to
Paediatric pseudo-obstruction syndrome v0.1 DLX1 Eleanor Williams gene: DLX1 was added
gene: DLX1 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DLX1 was set to
Paediatric pseudo-obstruction syndrome v0.1 DGUOK Eleanor Williams gene: DGUOK was added
gene: DGUOK was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DGUOK was set to
Paediatric pseudo-obstruction syndrome v0.1 DDX3X Eleanor Williams gene: DDX3X was added
gene: DDX3X was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: DDX3X was set to
Paediatric pseudo-obstruction syndrome v0.1 COX15 Eleanor Williams gene: COX15 was added
gene: COX15 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: COX15 was set to
Paediatric pseudo-obstruction syndrome v0.1 COX10 Eleanor Williams gene: COX10 was added
gene: COX10 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: COX10 was set to
Paediatric pseudo-obstruction syndrome v0.1 CHRNE Eleanor Williams gene: CHRNE was added
gene: CHRNE was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: CHRNE was set to
Paediatric pseudo-obstruction syndrome v0.1 C17orf107 Eleanor Williams gene: C17orf107 was added
gene: C17orf107 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: C17orf107 was set to
Paediatric pseudo-obstruction syndrome v0.1 BCS1L Eleanor Williams gene: BCS1L was added
gene: BCS1L was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: BCS1L was set to
Paediatric pseudo-obstruction syndrome v0.1 BCR Eleanor Williams gene: BCR was added
gene: BCR was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: BCR was set to
Paediatric pseudo-obstruction syndrome v0.1 ACTG2 Eleanor Williams gene: ACTG2 was added
gene: ACTG2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ACTG2 was set to
Paediatric pseudo-obstruction syndrome v0.1 ACTA2 Eleanor Williams gene: ACTA2 was added
gene: ACTA2 was added to Paediatric pseudo-obstruction syndrome. Sources: Expert list
Mode of inheritance for gene: ACTA2 was set to
Paediatric pseudo-obstruction syndrome v0.0 Eleanor Williams Added Panel Paediatric pseudo-obstruction syndrome
Congenital myopathy v3.11 FXR1 Arina Puzriakova Publications for gene: FXR1 were set to 30770808
Intellectual disability v4.21 SOX4 Arina Puzriakova Phenotypes for gene: SOX4 were changed from Coffin-Siris syndrome 10, 618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism to Coffin-Siris syndrome 10, OMIM:618506; Syndromic intellectual disability; Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; facial dysmorphism
Intellectual disability v4.20 SOX4 Arina Puzriakova Publications for gene: SOX4 were set to 30661772
Nephrocalcinosis or nephrolithiasis v3.2 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
watchlist tags were added to gene: SLC26A6.
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Likely inborn error of metabolism v3.2 SLC26A6 Arina Puzriakova gene: SLC26A6 was added
gene: SLC26A6 was added to Inborn errors of metabolism. Sources: Literature
watchlist tags were added to gene: SLC26A6.
Mode of inheritance for gene: SLC26A6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC26A6 were set to 35115415
Phenotypes for gene: SLC26A6 were set to Enteric hyperoxaluria and nephrolithiasis
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)

SLC26A6 is currently not associated with any human phenotype in OMIM or G2P.
Sources: Literature
Intellectual disability v4.19 CASK Arina Puzriakova Publications for gene: CASK were set to
Cerebellar hypoplasia v1.71 CASK Arina Puzriakova Publications for gene: CASK were set to
Severe microcephaly v3.3 CASK Arina Puzriakova Publications for gene: CASK were set to
Ataxia and cerebellar anomalies - narrow panel v3.20 CASK Arina Puzriakova Publications for gene: CASK were set to 35149592
Malformations of cortical development v3.3 CASK Arina Puzriakova Publications for gene: CASK were set to 21954287; 20595373; 32700313; 33090494; 33272775
Ataxia and cerebellar anomalies - narrow panel v3.19 CASK Arina Puzriakova Publications for gene: CASK were set to
Intellectual disability v4.18 KLHL20 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: KLHL20.
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Classified gene: KLHL20 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
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Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Early onset or syndromic epilepsy v3.11 KLHL20 Arina Puzriakova Gene: klhl20 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.18 KLHL20 Arina Puzriakova Classified gene: KLHL20 as Amber List (moderate evidence)
Intellectual disability v4.18 KLHL20 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
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Sleyp et al. 2022 (PMID: 36214804) reported on 14 patients with de novo missense variants who all presented with mild to severe ID, seizures, ASD, hyperactivity, and dysmorphic facial features. One variant (c.1069G>A, p.Gly357Arg) was recurrent in 11/14 cases but all variants clustered in the Kelch-type β-propeller domain (substrate binding surface) of the KLHL20 protein. No functional studies were performed but given the overlap in clinical presentation observed in patients with the same recurrent variant but also multiple different variants, its worth including as diagnostic-grade.
Intellectual disability v4.18 KLHL20 Arina Puzriakova Gene: klhl20 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v3.10 KLHL20 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: KLHL20.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.39 TGFBR2 Dmitrijs Rots reviewed gene: TGFBR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v4.2 KCNK3 Arina Puzriakova changed review comment from: Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.; to: Comment on list classification: Given the number of unrelated cases with a comparable phenotype (including arthrogryposis/flexion contractures/foot deformities), all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.
Arthrogryposis v4.2 KCNK3 Arina Puzriakova Entity copied from Intellectual disability v4.17
Arthrogryposis v4.2 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Arthrogryposis. Sources: Literature,Expert Review Amber
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 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 v4.17 KCNK3 Arina Puzriakova Classified gene: KCNK3 as Amber List (moderate evidence)
Intellectual disability v4.17 KCNK3 Arina Puzriakova Added comment: Comment on list classification: Given the number of unrelated cases with a comparable phenotype, all shown to have variants that cluster near the X-gate and cause increased channel activation, this gene should be promoted to Green status at the next GMS panel update.

The overall phenotype is likely most compatible with the Paediatric disorders super panel, and addition to the ID panel will ensure this genes' inclusion.
Intellectual disability v4.17 KCNK3 Arina Puzriakova Gene: kcnk3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.16 KCNK3 Arina Puzriakova gene: KCNK3 was added
gene: KCNK3 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: KCNK3.
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Developmental disorder with sleep apnea
Mode of pathogenicity for gene: KCNK3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Heterozygous variant in the KCNK3 gene already have a well-established link with pulmonary arterial hypertension (OMIM:615344).

However, Sormann et al. 2022 (PMID: 36195757) identified nine unrelated individuals harbouring one of six de novo missense variants in KCNK3 who presented with developmental delay and sleep apnea among other variable features (musculoskeletal and limb anomalies, abnormalities of male genitalia/groin and digestive disturbance). The variants were shown to cause defective X-gating leading to overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways (i.e. GOF), distinct from the PAH mechanism which is caused by LOF variants.
Sources: Literature
Pulmonary arterial hypertension v3.2 KCNK3 Arina Puzriakova Phenotypes for gene: KCNK3 were changed from Idiopathic pulmonary arterial hypertension; IPAH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension; Pulmonary hypertension, primary, 4, 615344 to Pulmonary hypertension, primary, 4, OMIM:615344
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh Tag watchlist was removed from gene: POGLUT1.
Tag Q4_22_promote_green tag was added to gene: POGLUT1.
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh edited their review of gene: POGLUT1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 31897643 reports seven POGLUT1 variants in six families with Muscular dystrophy, limb-girdle, autosomal recessive 21, OMIM:617232. Supportive in vitro and in vivo functional studies were presented in PMID: 31897643.; Changed rating: GREEN
Congenital muscular dystrophy v3.17 POGLUT1 Sarah Leigh Publications for gene: POGLUT1 were set to 27807076; 33861953
Congenital muscular dystrophy v3.16 POGLUT1 Sarah Leigh Phenotypes for gene: POGLUT1 were changed from ?Muscular dystrophy, limb-girdle, autosomal recessive 21, 617232 to Muscular dystrophy, limb-girdle, autosomal recessive 21, OMIM:617232; autosomal recessive limb-girdle muscular dystrophy type 2R1, MONDO:0014977
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Classified gene: POGLUT1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.15 POGLUT1 Sarah Leigh Gene: poglut1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.14 POGLUT1 Sarah Leigh Publications for gene: POGLUT1 were set to 27807076
Congenital muscular dystrophy v3.13 GGPS1 Sarah Leigh Publications for gene: GGPS1 were set to 32403198
Early onset or syndromic epilepsy v3.10 DNM1 Sarah Leigh Publications for gene: DNM1 were set to 25262651; 27066543; 33372033; 34172529
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Tag Q4_22_promote_green tag was added to gene: DPM3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh edited their review of gene: DPM3: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene. At least four variants have been reported in at least five cases, together with supportive functional studies (PMID: 19576565; 31469168).; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Classified gene: DPM3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.3 DPM3 Sarah Leigh Gene: dpm3 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.12 HNRNPA2B1 Sarah Leigh Tag Q4_22_promote_green tag was added to gene: HNRNPA2B1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.2 DPM3 Sarah Leigh Publications for gene: DPM3 were set to 28803818; 19576565
Congenital muscular dystrophy v3.12 DPM3 Sarah Leigh Publications for gene: DPM3 were set to 19576565
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Classified gene: HNRNPA2B1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital muscular dystrophy v3.11 HNRNPA2B1 Sarah Leigh Gene: hnrnpa2b1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.10 HNRNPA2B1 Sarah Leigh Added comment: Comment on phenotypes: The OMIM phenotype for HNRNPA2B1 (?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422) is based on one family. PMID: 35484142 presents further variants associated with an expanded phenotype.
Congenital muscular dystrophy v3.10 HNRNPA2B1 Sarah Leigh Phenotypes for gene: HNRNPA2B1 were changed from ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422; inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, MONDO:0014178 to early-onset oculopharyngeal muscular dystrophy, muscular dystrophy, congenital myopathy
Congenital muscular dystrophy v3.9 HNRNPA2B1 Sarah Leigh edited their review of gene: HNRNPA2B1: Added comment: PMID: 35484142 reports nine heterozygous terminating HNRNPA2B1 variants in ten unrelated cases of early onset severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD); Changed rating: GREEN; Changed publications to: 35484142; Changed phenotypes to: early-onset oculopharyngeal muscular dystrophy
Intellectual disability v4.15 RPL10 Dmitrijs Rots reviewed gene: RPL10: 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: 35876338; Phenotypes: ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v3.18 SPTAN1 Dmitrijs Rots gene: SPTAN1 was added
gene: SPTAN1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 36331550; 35150594
Phenotypes for gene: SPTAN1 were set to Ataxia; hereditary spastic paraplegia
Review for gene: SPTAN1 was set to GREEN
Added comment: Two large cohorts (36331550; 35150594) described >30 cases with hereditary ataxia and a variant in SPTAN1.
Sources: Literature
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v3.9 FRMD5 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 5 unrelated cases with seizures plus supportive fly model.
Early onset or syndromic epilepsy v3.9 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v3.5 ATP2B3 Dmitrijs Rots reviewed gene: ATP2B3: Rating: ; Mode of pathogenicity: None; Publications: 36207321, 28807751, 25953895; Phenotypes: Ataxia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v3.18 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v3.18 FRMD5 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 7 unrelated cases with ataxia plus supportive fly model.
Ataxia and cerebellar anomalies - narrow panel v3.18 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v4.15 FRMD5 Arina Puzriakova Classified gene: FRMD5 as Amber List (moderate evidence)
Intellectual disability v4.15 FRMD5 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 8 unrelated cases plus supportive fly model.
Intellectual disability v4.15 FRMD5 Arina Puzriakova Gene: frmd5 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.9 HNRNPA2B1 Sarah Leigh Phenotypes for gene: HNRNPA2B1 were changed from oculopharyngodistal myopathy, muscular dystrophy, congenital myopathy to ?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, OMIM:615422; inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2, MONDO:0014178
Early onset or syndromic epilepsy v3.8 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Genetic epilepsy syndromes. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v3.17 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Intellectual disability v4.14 FRMD5 Arina Puzriakova gene: FRMD5 was added
gene: FRMD5 was added to Intellectual disability. Sources: Literature
Q4_22_promote_green tags were added to gene: FRMD5.
Mode of inheritance for gene: FRMD5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FRMD5 were set to 36206744
Phenotypes for gene: FRMD5 were set to Neurodevelopmental disorder with eye movement abnormalities and ataxia, OMIM:620094
Review for gene: FRMD5 was set to GREEN
Added comment: Lu et al. 2022 (PMID: 36206744) report 8 unrelated individuals with de novo missense FRMD5 variants who presented with developmental delay (8/8), intellectual disability (7/7), ataxia (7/8), seizures (5/8), and abnormalities of eye movement (8/8). LOF mutant flies exhibited motor impairment, defective responses to light and heat-induced seizures. Fly phenotypes were rescued by expression of the wildtype gene but not by two of the patient missense mutants.

FRMD5 is associated with a relevant phenotype in OMIM (MIM# 620094) but is not yet listed in G2P.
Sources: Literature
Congenital muscular dystrophy v3.8 HNRNPA2B1 Sarah Leigh Publications for gene: HNRNPA2B1 were set to https://www.nmd-journal.com/article/S0960-8966(20)30203-0/fulltext
Ataxia and cerebellar anomalies - narrow panel v3.16 CAPRIN1 Dmitrijs Rots gene: CAPRIN1 was added
gene: CAPRIN1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAPRIN1 were set to 36136249
Phenotypes for gene: CAPRIN1 were set to Infantile-onset ataxia
Penetrance for gene: CAPRIN1 were set to Complete
Mode of pathogenicity for gene: CAPRIN1 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: CAPRIN1 was set to GREEN
Added comment: CAPRIN1 is reported in two indepedent cases with infantile-onset ataxia and cognitive decline (reported 2 de novo in two cases + functional evidence, so enough evidence for green rating).
Sources: Literature
Intellectual disability v4.13 CAPRIN1 Dmitrijs Rots reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36136249; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v3.16 NPTX1 Dmitrijs Rots gene: NPTX1 was added
gene: NPTX1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to Ataxia
Penetrance for gene: NPTX1 were set to unknown
Mode of pathogenicity for gene: NPTX1 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: NPTX1 was set to GREEN
Added comment: Multiple individiuals with de novo or inherited (segregating with the phenotype) NPTX1 reported in the literature with both late and infantile-onset ataxia. Enough evidence for green.

The phenotype is described in 34788392 as:
"The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging."
Sources: Literature
Intellectual disability v4.13 BUB1 Sarah Leigh edited their review of gene: BUB1: Added comment: Not associated with a phenotype in OMIM, but has a moderate association with BUB1-related microcephaly and developmental disorder in Gen2Phen. PMID: 35044816 reports three BUB1 variants in two cases of developmental delay, including microcephaly, together with supportive functional studies.; Changed rating: GREEN
BAP1 associated tumour predisposition syndrome v0.0 Eleanor Williams Added Panel BAP1 associated tumour predisposition syndrome
Set list of related panels to R422
Autoimmune Polyendocrine Syndrome v0.0 Eleanor Williams Added Panel Autoimmune Polyendocrine Syndrome
Set list of related panels to R155
Autoimmune lymphoproliferative syndrome with defective apoptosis v0.0 Eleanor Williams Added Panel Autoimmune lymphoproliferative syndrome with defective apoptosis
Set list of related panels to R19
Ataxia telangiectasia - mutation testing v0.0 Eleanor Williams Added Panel Ataxia telangiectasia - mutation testing
Set list of related panels to R295
APC associated Polyposis v0.0 Eleanor Williams Added Panel APC associated Polyposis
Set list of related panels to R414
Alveolar capillary dysplasia with misalignment of pulmonary veins v0.0 Eleanor Williams Added Panel Alveolar capillary dysplasia with misalignment of pulmonary veins
Set list of related panels to R330
Alstrom syndrome v0.0 Eleanor Williams Added Panel Alstrom syndrome
Set list of related panels to R106
Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis v0.0 Eleanor Williams Added Panel Albright hereditary osteodystrophy, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, acrodysostosis and osteoma cutis
Set list of related panels to R293
Agammaglobulinaemia with absent BTK expression v0.0 Eleanor Williams Added Panel Agammaglobulinaemia with absent BTK expression
Set list of related panels to R233
Acute intermittent porphyria v0.0 Eleanor Williams Added Panel Acute intermittent porphyria
Set list of related panels to R169
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova changed review comment from: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.; to: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei. Both variants were shown to truncate the muscle isoform (termed LAP1B) while the LAP1C isoform remained intact.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Classified gene: SLC35F1 as Red List (low evidence)
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as only a single patient with a heterozygous missense variant has been reported to date (PMID:33821533). Limited information on the SLC35F1 gene is known in general.
Intellectual disability v4.13 SLC35F1 Arina Puzriakova Gene: slc35f1 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v2.1 KBTBD13 Dmitrijs Rots gene: KBTBD13 was added
gene: KBTBD13 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: KBTBD13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KBTBD13 were set to 36335629
Penetrance for gene: KBTBD13 were set to Incomplete
Mode of pathogenicity for gene: KBTBD13 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: KBTBD13 was set to GREEN
Added comment: 3 families with cardiomyopathy and other related cardiac phenotypes reported in 36335629 with mouse model. Enough evidence for green. All cases had p.R408C variant.
Sources: Literature
Malformations of cortical development v3.2 PAFAH1B1 Achchuthan Shanmugasundram Publications for gene: PAFAH1B1 were set to
Malformations of cortical development v3.1 PAFAH1B1 Achchuthan Shanmugasundram reviewed gene: PAFAH1B1: Rating: ; Mode of pathogenicity: None; Publications: 34635911; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v3.7 GPHN Achchuthan Shanmugasundram Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, OMIM:615501 to Molybdenum cofactor deficiency C, OMIM:615501; Developmental and epileptic encephalopathy, MONDO:0100062
Early onset or syndromic epilepsy v3.6 GPHN Achchuthan Shanmugasundram Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070; 23393157
Early onset or syndromic epilepsy v3.5 GPHN Achchuthan Shanmugasundram reviewed gene: GPHN: Rating: GREEN; Mode of pathogenicity: None; Publications: 34617111; Phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062; Mode of inheritance: None
Intellectual disability v4.12 BUB1 Sarah Leigh Tag Q4_22_MOI tag was added to gene: BUB1.
Tag Q4_22_promote_green tag was added to gene: BUB1.
Intellectual disability v4.12 BUB1 Sarah Leigh Classified gene: BUB1 as Amber List (moderate evidence)
Intellectual disability v4.12 BUB1 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 v4.12 BUB1 Sarah Leigh Gene: bub1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.10 KY Sarah Leigh commented on gene: KY: Associated with Myopathy, myofibrillar, 7 (OMIM: 617114) in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants have been reported in unrelated cases. PMID: 30591934 demostrates segregation of KY c.415C>T (p.R139*) in the affected homozygous members of a consanguineous family, where the parents are heterozygotes and the unaffected sister is homozygous for the wild type allele. PMID 27485408 describes the spontaneously generated murine ortholog of variant Ky with postnatally developing kyphoscoliosis, the authors note the similarities between the patient and mouse muscle fibres.
Congenital myopathy v3.10 TNNC2 Sarah Leigh reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Clefting v3.2 MYCN Achchuthan Shanmugasundram gene: MYCN was added
gene: MYCN was added to Clefting. Sources: Literature
Mode of inheritance for gene: MYCN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYCN were set to 34590686
Phenotypes for gene: MYCN were set to Cleft lip with or without cleft palate, MONDO:0016034
Review for gene: MYCN was set to RED
Added comment: Comment on classification of this gene: This gene has been added with a RED rating to this panel, as identified from one case and supported by functional studies with mouse model.

Out of the 104 multiplex families with Mendelian non-syndromic cleft lip with or without cleft palate (NSCL/P), a novel pathogenic variant (c.703G>C/ p.A235P) has been identified in MYCN gene from one family. This variant was found in the proband and his affected mother and absent in the unaffected sister, showing co-segregation with phenotype in this family.

In addition, experimental evidence from conditional knockout mouse model showed that these mice displayed cleft palate, microglossia and micrognathia, resembling the Pierre Robin sequence (PRS) in humans.

This gene has not yet been associated with clefting either in OMIM or in Gene2Phenotype.
Sources: Literature
Congenital myopathy v3.10 UNC45B Sarah Leigh Tag Q4_22_promote_green tag was added to gene: UNC45B.
Tag Q4_22_expert_review tag was added to gene: UNC45B.
Tag Q4_22_NHS_review tag was added to gene: UNC45B.
Congenital myopathy v3.10 UNC45B Sarah Leigh commented on gene: UNC45B: Associated with relevant Myofibrillar myopathy 11 in OMIM and as strong Gen2Phen gene for UNC45B-associated Progressive Myopathy with Eccentric Cores. At least 7 variants have been reported in at least 10 unrelated families. SEgregation has been observed and functional studies suggest that reduced expression of UNC45B is associated with Myofibrillar myopathy 11. This review represents further information from subsequent case reports and the update of OMIM to allow OMIM asign a phenotype tp this gene.
Congenital myopathy v3.10 UNC45B Sarah Leigh Phenotypes for gene: UNC45B were changed from Progressive Myopathy with Eccentric Cores to Myofibrillar myopathy 11, OMIM:619178; myofibrillar myopathy 11, MONDO:0030927
Congenital myopathy v3.9 UNC45B Sarah Leigh Publications for gene: UNC45B were set to 33217308
Early onset or syndromic epilepsy v3.5 SNIP1 Sarah Leigh Publications for gene: SNIP1 were set to 22279524; 34570759
Mitochondrial disorders v3.2 TARS2 Achchuthan Shanmugasundram Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21, OMIM:615918 to Combined oxidative phosphorylation deficiency 21, OMIM:615918, MONDO:0014398
Mitochondrial disorders v3.1 TARS2 Achchuthan Shanmugasundram reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21, MIM# 615918, MONDO:0014398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v2.3 PDGFRB Achchuthan Shanmugasundram edited their review of gene: PDGFRB: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
White matter disorders and cerebral calcification - narrow panel v2.3 PDGFRB Achchuthan Shanmugasundram Publications for gene: PDGFRB were set to 23255827 - original family report and sproadic case report; 24796542 - an additional case report of a idiopathic basal ganglia calcification patient with the p.R695C mutation, which resulted in partial loss of autophosphorylation; 25292412 - functional studies; 26599395 - mouse models and functional studies; 26129893
White matter disorders and cerebral calcification - narrow panel v2.2 PDGFRB Achchuthan Shanmugasundram reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 34494111; Phenotypes: Basal ganglia calcification, idiopathic, 4, MIM# 615007, MONDO:0014004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v3.2 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Microcephaly, MONDO:0001149
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to microcephaly is based on biallelic variants identified from a report of two siblings.

Two siblings harbouring variants c.6625C>T/ p.Arg2209Ter (identified in heterozygous state in both siblings and father) and c.2610 + 5G > A (identified in heterozygous state in both siblings and mother) were reported with ataxia, microcephaly and severe intellectual disability. The occipitofrontal circumference (OFC) was at 3rd centile for individual 1 and at 10th centile for individual 2 and dropped to below 1st centile at eight months and five months respectively.

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

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v3.16 TPR Achchuthan Shanmugasundram edited their review of gene: TPR: Changed rating: RED
Ataxia and cerebellar anomalies - narrow panel v3.16 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Cerebellar ataxia, MONDO:0000437
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to ataxia is based on biallelic variants identified from a report of two siblings.

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

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

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability v4.11 TPR Achchuthan Shanmugasundram gene: TPR was added
gene: TPR was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TPR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPR were set to 34494102
Phenotypes for gene: TPR were set to Intellectual disability, MONDO:0001071
Review for gene: TPR was set to RED
Added comment: Comment on classification of this gene: This gene should be added with a RED rating as the association of TPR to intellectual disability is based on biallelic variants identified from a report of two siblings.

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

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

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Neurofibromatosis Type 1 v1.32 NF1 Achchuthan Shanmugasundram reviewed gene: NF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34476477; Phenotypes: Neurofibromatosis, type 1, MIM# 162200, MONDO:0018975, Renovascular hypertension, MONDO:0006947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Renal ciliopathies v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 15138899; 22982934; 15689444
Renal ciliopathies v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Retinal disorders v3.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Retinal disorders v3.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: ; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Unexplained young onset end-stage renal disease v2.3 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 266900; 34415307
Unexplained young onset end-stage renal disease v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to 266900
Unexplained young onset end-stage renal disease v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Unexplained kidney failure in young people v1.116 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Cystic kidney disease v3.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Cystic kidney disease v3.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Tubulointerstitial kidney disease v2.2 NPHP1 Achchuthan Shanmugasundram Publications for gene: NPHP1 were set to
Tubulointerstitial kidney disease v2.1 NPHP1 Achchuthan Shanmugasundram reviewed gene: NPHP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34415307; Phenotypes: ; Mode of inheritance: None
Congenital muscular dystrophy v3.7 GOSR2 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: GOSR2.
Congenital muscular dystrophy v3.7 GOSR2 Achchuthan Shanmugasundram Publications for gene: GOSR2 were set to 29855340
Congenital muscular dystrophy v3.6 GOSR2 Achchuthan Shanmugasundram Classified gene: GOSR2 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.6 GOSR2 Achchuthan Shanmugasundram Gene: gosr2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.5 GOSR2 Achchuthan Shanmugasundram reviewed gene: GOSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29855340, 33639315, 34167170; Phenotypes: Congenital muscular dystrophy, MONDO:0019950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.4 BET1 Achchuthan Shanmugasundram Phenotypes for gene: BET1 were changed from Epilepsy; congenical musculara dystrophy to Epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v3.3 BET1 Achchuthan Shanmugasundram Publications for gene: BET1 were set to PMID: 34779586
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Red List (low evidence)
Early onset or syndromic epilepsy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v3.1 BET1 Achchuthan Shanmugasundram reviewed gene: BET1: Rating: RED; Mode of pathogenicity: None; Publications: 34779586; Phenotypes: Epilepsy, MONDO:0005027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v3.5 BET1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: BET1.
Congenital muscular dystrophy v3.5 BET1 Achchuthan Shanmugasundram Phenotypes for gene: BET1 were changed from Congenital muscular dystrophy with epilepsy to Congenital muscular dystrophy, MONDO:0019950
Congenital muscular dystrophy v3.4 BET1 Achchuthan Shanmugasundram Publications for gene: BET1 were set to
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.3 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Classified gene: BET1 as Amber List (moderate evidence)
Congenital muscular dystrophy v3.2 BET1 Achchuthan Shanmugasundram Gene: bet1 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v3.1 BET1 Achchuthan Shanmugasundram reviewed gene: BET1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34779586; Phenotypes: Congenital muscular dystrophy, MONDO:0019950; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.10 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed phenotypes to: Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed phenotypes to: Kury-Isidor syndrome, OMIM:619762
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes edited their review of gene: BAP1: Changed rating: GREEN
Early onset or syndromic epilepsy v3.1 BAP1 Mafalda Gomes gene: BAP1 was added
gene: BAP1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BAP1 were set to 35051358
Added comment: Küry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance.
Sources: Literature
Intellectual disability v4.10 BAP1 Mafalda Gomes reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35051358; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v3.4 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Limb disorders v3.4 SUFU Arina Puzriakova Added comment: Comment on list classification: Recessive phenotype fits the scope of this panel; however only two cases have been reported to date in a single paper. Monoallelic form does not appear to feature skeletal abnormalities but rather is dominated by neurological phenotypes. Therefore maintaining Amber rating and biallelic MOI on this panel but adding a watchlist tag.
Limb disorders v3.4 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Limb disorders v3.3 SUFU Arina Puzriakova Tag watchlist tag was added to gene: SUFU.
Limb disorders v3.3 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: AMBER; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on list classification: Recessive phenotype fits the scope of this panel; however only two cases have been reported to date in a single paper. Monoallelic form does not appear to feature skeletal abnormalities but rather is dominated by neurological phenotypes. Therefore maintaining Amber rating and biallelic MOI on this panel but adding a watchlist tag.
Skeletal ciliopathies v2.3 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v2.2 SUFU Arina Puzriakova Tag watchlist tag was added to gene: SUFU.
Skeletal ciliopathies v2.2 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: AMBER; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Rare multisystem ciliopathy disorders v1.168 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Classified gene: SUFU as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Added comment: Comment on list classification: Upgraded from Amber to Green under a monoallelic MOI - sufficient unrelated cases with heterozygous variants and a comparable phenotype within the Joubert spectrum.
Rare multisystem ciliopathy disorders v1.167 SUFU Arina Puzriakova Gene: sufu has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.166 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Rare multisystem ciliopathy disorders v1.166 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova Tag watchlist was removed from gene: SUFU.
Tag watchlist_moi tag was added to gene: SUFU.
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.15 SUFU Arina Puzriakova Entity copied from Neurological ciliopathies v2.4
Ataxia and cerebellar anomalies - narrow panel v3.15 SUFU Arina Puzriakova gene: SUFU was added
gene: SUFU was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list,Expert Review Amber
watchlist_moi, Q4_22_MOI, Q4_22_promote_green tags were added to gene: SUFU.
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUFU were set to 21289193; 28965847; 33024317; 34675124
Phenotypes for gene: SUFU were set to Joubert syndrome 32, OMIM:617757
Ophthalmological ciliopathies v2.4 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Ophthalmological ciliopathies v2.3 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v2.2 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Ophthalmological ciliopathies v2.2 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ophthalmological ciliopathies v2.1 SUFU Arina Puzriakova Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_MOI tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Ophthalmological ciliopathies v2.1 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Neurological ciliopathies v2.4 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v2.3 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Neurological ciliopathies v2.3 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurological ciliopathies v2.2 SUFU Arina Puzriakova Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_MOI tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Neurological ciliopathies v2.2 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v4.10 SUFU Arina Puzriakova edited their review of gene: SUFU: Changed publications to: 21289193, 28965847, 33024317, 34675124
Intellectual disability v4.10 SUFU Arina Puzriakova Penetrance for gene SUFU was set from to None
Intellectual disability v4.9 SUFU Arina Puzriakova Classified gene: SUFU as Amber List (moderate evidence)
Intellectual disability v4.9 SUFU Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update under a MONOALLELIC inheritance pattern only, unless the NHS GMS working group disagree and feel the MOI should include both mono- and biallelic variants based on the current evidence.
Intellectual disability v4.9 SUFU Arina Puzriakova Gene: sufu has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v2.2 SUFU Arina Puzriakova Publications for gene: SUFU were set to
Intellectual disability v4.8 SUFU Arina Puzriakova Publications for gene: SUFU were set to 21289193; 28965847; 33024317, 34675124
Intellectual disability v4.7 SUFU Arina Puzriakova Added comment: Comment on mode of inheritance: Following consultation with Helen Brittain (Genomics England Clinical team) it was decided that based on the current evidence the MOI should be set to 'monoallelic' only for now but with a 'watchlist' tag to monitor for additional biallelic cases relating to a Joubert-like presentation.
Intellectual disability v4.7 SUFU Arina Puzriakova Mode of inheritance for gene: SUFU was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v4.6 SUFU Arina Puzriakova Publications for gene: SUFU were set to 28965847; 30914295
Intellectual disability v4.5 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Intellectual disability v4.4 SUFU Arina Puzriakova Tag Q4_22_MOI tag was added to gene: SUFU.
Intellectual disability v4.4 SUFU Arina Puzriakova Tag watchlist was removed from gene: SUFU.
Tag watchlist_moi tag was added to gene: SUFU.
Tag Q4_22_promote_green tag was added to gene: SUFU.
Intellectual disability v4.4 SUFU Arina Puzriakova edited their review of gene: SUFU: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v4.4 SUFU Arina Puzriakova reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: 21289193, 28965847, 33024317, 34675124; Phenotypes: Joubert syndrome 32, OMIM:617757; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v2.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Rhabdomyolysis and metabolic muscle disorders v2.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 34581780; 34935254; 35672413; 35915960; 35942668
Phenotypes for gene: MLIP were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Review for gene: MLIP was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in rhabdomyolysis, as identified from biallelic variants from four unrelated cases from multiple ethnicities.

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis (reported in five individuals from four families), and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years (PMID:34581780). However, patients carrying biallelic variants in MLIP gene were not reported with rhabdomyolysis in other studies (PMID:34935254; PMID:35672413; PMID:35915960).

The association of MLIP to rhabdomyolysis has now been documented in OMIM (#620138).
Sources: Literature
Cardiac arrhythmias - additional genes v2.3 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138, Arrhythmia, HP:0011675
Cardiac arrhythmias - additional genes v2.3 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Arrhythmia, HP:0011675 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Arrhythmia, HP:0011675
Congenital myopathy v3.8 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.4 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Acute rhabdomyolysis v1.4 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138 to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Acute rhabdomyolysis v1.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Acute rhabdomyolysis v1.2 MLIP Achchuthan Shanmugasundram edited their review of gene: MLIP: Changed phenotypes to: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138
Acute rhabdomyolysis v1.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Acute rhabdomyolysis. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 34581780; 34935254; 35672413; 35915960; 35942668
Phenotypes for gene: MLIP were set to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138
Review for gene: MLIP was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in rhabdomyolysis, as identified from biallelic variants from four unrelated cases from multiple ethnicities.

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis (reported in five individuals from four families), and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years (PMID:34581780). However, patients carrying biallelic variants in MLIP gene were not reported with rhabdomyolysis in other studies (PMID:34935254; PMID:35672413; PMID:35915960).

The association of MLIP to rhabdomyolysis has now been documented in OMIM (#620138).
Sources: Literature
Cardiac arrhythmias - additional genes v2.2 MLIP Achchuthan Shanmugasundram gene: MLIP was added
gene: MLIP was added to Cardiac arrhythmias - additional genes. Sources: Literature
Mode of inheritance for gene: MLIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254
Phenotypes for gene: MLIP were set to Arrhythmia, HP:0011675
Review for gene: MLIP was set to RED
Added comment: Comment on classification of this gene: The rating for this gene should be added as RED, as the implication of this gene in cardiac arrhythmias was identified from biallelic variants from only one family (despite a mild ventricular dysfunction in another unrelated individual). However, this is well supported by results from functional studies from human tissue samples and mouse models.

Five individuals from two different pedigrees carrying two different novel homozygous nonsense variants were reported with myopathy characterized by hyperCKemia and with absence of rhabdomyolysis. The age of onset of symptoms for the single patient from family 1 is 2.5 years. All four individuals (age ranges from 24 to 37) from family 2 (Amish ancestry) were reported either with Sinus arrhythmia or Sinus bradycardia and one of these individuals displayed left ventricular hypertrophy. It was also found that there is founder effect for this allele in the Amish population in the resident county of these individuals (PMID:34935254).

Seven patients from six families carrying six different biallelic (either homozygous or compound heterozygous) variants in MLIP gene were presented with a consistent phenotype including mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase (CK) levels. The age of onset of symptoms ranged from 8 months to 7 years. However, mild left ventricular dysfunction was reported only in one patient, despite the presence of mild structural abnormalities in two other patients (PMID:34581780).

The expression of MLIP was identified to be reduced in patients with dilated cardiomyopathy, as studied from LV samples from patients with terminal-stage heart failure. In addition, deletion of MLIP gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models and overexpression prevented pathologic remodelling and preserved cardiac function (PMID:26436652). MLIP has also been identified as a regulator of myoblast differentiation (PMID:33802236) and myonuclear positioning (PMID:32719146).
Sources: Literature
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: MLIP.
Congenital myopathy v3.7 MLIP Achchuthan Shanmugasundram Phenotypes for gene: MLIP were changed from MLIP-related myopathy with rhabdomyolysis to Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis; MIM# 620138
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.6 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 26436652; 32719146; 33802236; 34581780; 34935254; 35672413; 35915960; 35942668
Congenital myopathy v3.5 MLIP Achchuthan Shanmugasundram Publications for gene: MLIP were set to 34581780
Congenital myopathy v3.4 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Congenital myopathy v3.4 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.3 MLIP Achchuthan Shanmugasundram Classified gene: MLIP as Amber List (moderate evidence)
Congenital myopathy v3.3 MLIP Achchuthan Shanmugasundram Gene: mlip has been classified as Amber List (Moderate Evidence).
Congenital myopathy v3.2 MLIP Achchuthan Shanmugasundram reviewed gene: MLIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 26436652, 32719146, 33802236, 34581780, 34935254, 35672413, 35915960, 35942668; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis, MIM# 620138; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_MOI tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_expert_review tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Tag Q4_22_demote_amber tag was added to gene: CCDC78.
Congenital myopathy v3.2 CCDC78 Achchuthan Shanmugasundram Publications for gene: CCDC78 were set to 22818856
Congenital myopathy v3.1 CCDC78 Achchuthan Shanmugasundram reviewed gene: CCDC78: Rating: AMBER; Mode of pathogenicity: None; Publications: 22818856, 25635128; Phenotypes: centronuclear myopathy-4, MIM# 614807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v3.5 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, 614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Optic atrophy, MONDO:0003608
Optic neuropathy v3.4 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 23243084; 22864630
Optic neuropathy v3.3 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Optic atrophy, MONDO:0003608; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v3.3 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, OMIM:614707 to Brown-Vialetto-Van Laere syndrome 2, OMIM:614707, MONDO:0013867; Sensorineural hearing loss disorder, MONDO:0020678
Monogenic hearing loss v3.2 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 22740598; 22864630; 23243084; 24253200
Monogenic hearing loss v3.1 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.7 SLC52A2 Achchuthan Shanmugasundram Tag treatable tag was added to gene: SLC52A2.
Hereditary neuropathy or pain disorder v2.7 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364
Hereditary neuropathy or pain disorder v2.6 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to BVVL; Brown-Vialetto-Van Laere syndrome 2
Hereditary neuropathy or pain disorder v2.5 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Hereditary sensory and autonomic neuropathy, MONDO:0015364, Progressive bulbar palsy, MONDO:0008890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.14 SLC52A2 Achchuthan Shanmugasundram Tag treatable tag was added to gene: SLC52A2.
Tag Q4_22_promote_green tag was added to gene: SLC52A2.
Paediatric motor neuronopathies v2.3 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 23243084; 22864630
Paediatric motor neuronopathies v2.2 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, OMIM:614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Hereditary sensory and autonomic neuropathy, MONDO:0015364
Paediatric motor neuronopathies v2.1 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Hereditary sensory and autonomic neuropathy, MONDO:0015364, Progressive bulbar palsy, MONDO:0008890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.14 SLC52A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC52A2 were changed from Brown-Vialetto-Van Laere syndrome 2, MIM# 614707 to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867; Cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - narrow panel v3.13 SLC52A2 Achchuthan Shanmugasundram Publications for gene: SLC52A2 were set to 30377535
Ataxia and cerebellar anomalies - narrow panel v3.12 SLC52A2 Achchuthan Shanmugasundram Classified gene: SLC52A2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v3.12 SLC52A2 Achchuthan Shanmugasundram Gene: slc52a2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v3.11 SLC52A2 Achchuthan Shanmugasundram reviewed gene: SLC52A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22740598, 22864630, 23243084, 24253200, 30343981, 30377535, 31868069, 32909658, 35608644, 36186484; Phenotypes: Brown-Vialetto-Van Laere syndrome 2, MIM# 614707, MONDO:0013867, Cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.5 SLC25A46 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SLC25A46.
Hereditary neuropathy or pain disorder v2.5 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, 616505; Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260
Hereditary neuropathy or pain disorder v2.4 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to 26168012
Hereditary neuropathy or pain disorder v2.3 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28376086, 28934388, 30178502; Phenotypes: Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v3.3 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB 616505 to Optic atrophy, MONDO:0003608; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260
Optic neuropathy v3.2 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to 26168012; 28369803
Optic neuropathy v3.1 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28369803, 28376086, 28558379, 28934388, 30178502, 33816684; Phenotypes: Optic atrophy, MONDO:0003608, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v3.5 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Hereditary motor and sensory neuropathy type VIB, 616505 to Cerebellar ataxia, MONDO:0000437; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Hereditary ataxia with onset in adulthood v3.4 SLC25A46 Achchuthan Shanmugasundram Publications for gene: SLC25A46 were set to
Hereditary ataxia with onset in adulthood v3.3 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 28376086, 28558379, 28934388; Phenotypes: Adult-onset ataxia, Cerebellar ataxia, MONDO:0000437, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.11 SLC25A46 Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in ataxia, as identified from biallelic loss-of-function variants from at least 8 unrelated individuals/ families from multiple ethnicities and supported by results from animal models.

Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653).

A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012).

A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684).

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM.; to: Comment on classification of this gene:

The rating for this gene should be GREEN, as this gene has been identified to be implicated in cerebellar ataxia (MONDO:0000437) from biallelic loss-of-function variants from at least 8 unrelated individuals/ families and in pontocerebellar hypoplasia, type 1E (MIM# 619303) from biallelic loss-of-function variants from at least 6 unrelated individuals/ families. These cases were from multiple ethnicities and were supported by results from animal models.

In addition, this gene has also been identified to be implicated in cerebellar hypoplasia from monoallelic loss-of-function variants from a family of three siblings. As we currently do not have three unrelated cases for monoallelic inheritance, this gene is assigned only to biallelic MOI.

Cerebellar ataxia:

Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653).

A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012).

A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684).

Cerebellar hypoplasia:

Four infants from two different families with homozygous variants (family 1: c.1022T>C/ p.Leu341Pro; family 2: deletion of exon 1) were reported to have died soon after birth with a profound neurodevelopmental disorder associated with congenital pontocerebellar hypoplasia (PMID:27543974). The phenotypes are similar to a female infant from the United States with pontocerebellar atrophy who died at age 15 weeks. This infant reported by Abram et al (2015) exhibited compound heterozygous variants (c.882_885dupTTAC/ p.Asn296fs*297 & c.998C>T/ p.Pro333Leu) (PMID:26168012).

Four infants from two unrelated families of German and Italian descent were reported with PCH1E. All died in the first days or weeks of life. The German infants were identified with homozygous variant c.736A>T (p.Arg246Ter) and the Italian infants were identified with compound heterozygous variants c.42C>G (p.Tyr14Ter) & 462+ 1G>A (PMID:28653766).

Two siblings with bi-allelic compound heterozygous variants (a splicing variant - c.385-1G > A and a deletion) had a fulminant neonatal course. The mother of these siblings exhibited a heterozygous c.385-1G > A allele and the father had an 80-kb deletion spanning SLC25A46 and TMEM232 genes. Pontocerebellar hypoplasia was reported by postmortem brain CT imaging in one of the siblings (PMID:35012485).

Barth (1993) reported a Dutch family in which three siblings died within the first day of life due to lack of spontaneous respiration and profound muscle weakness (PMID:8147499). Although these infants displayed similarities to the clinical indications described by Wan et al, 2016 (PMID:27543974), they were identified to possess heterozygous variant leading to a premature stop codon (c.691C>T/ p.Arg231Ter) in exon 8 of the SLC25A46 gene (PMID:28637197).

Functional studies:

Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production.

Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012).

SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM.
Ataxia and cerebellar anomalies - narrow panel v3.11 SLC25A46 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SLC25A46.
Ataxia and cerebellar anomalies - narrow panel v3.11 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505 to Cerebellar ataxia, MONDO:0000437; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260; Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Ataxia and cerebellar anomalies - narrow panel v3.10 SLC25A46 Achchuthan Shanmugasundram Classified gene: SLC25A46 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v3.10 SLC25A46 Achchuthan Shanmugasundram Gene: slc25a46 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v3.9 SLC25A46 Achchuthan Shanmugasundram reviewed gene: SLC25A46: Rating: GREEN; Mode of pathogenicity: None; Publications: 26168012, 27430653, 28376086, 28558379, 28934388, 30178502, 33816684; Phenotypes: Cerebellar ataxia, MONDO:0000437, Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260, Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.9 SCN2A Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SCN2A.
Ataxia and cerebellar anomalies - narrow panel v3.9 SCN2A Achchuthan Shanmugasundram Phenotypes for gene: SCN2A were changed from Epileptic encephalopathy, early infantile, 11, MIM# 613721 to Episodic ataxia, type 9, MIM# 618924, MONDO:0030064; Developmental and epileptic encephalopathy 11, MIM# 613721, MONDO:0013388
Ataxia and cerebellar anomalies - narrow panel v3.8 SCN2A Achchuthan Shanmugasundram Publications for gene: SCN2A were set to 31924505; 32893078; 31904126
Ataxia and cerebellar anomalies - narrow panel v3.7 SCN2A Achchuthan Shanmugasundram Mode of pathogenicity for gene: SCN2A 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
Ataxia and cerebellar anomalies - narrow panel v3.6 SCN2A Achchuthan Shanmugasundram Classified gene: SCN2A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v3.6 SCN2A Achchuthan Shanmugasundram Gene: scn2a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v3.5 SCN2A Achchuthan Shanmugasundram reviewed gene: SCN2A: 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: 20956790, 26291284, 26645390, 27159988, 27328862, 28065826, 30165711, 30741786, 30813219, 30928199, 32893078, 35219921; Phenotypes: Episodic ataxia, type 9, MIM# 618924, MONDO:0030064, Developmental and epileptic encephalopathy 11, MIM# 613721, MONDO:0013388; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult onset hereditary spastic paraplegia v2.3 COQ4 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: COQ4.
Adult onset hereditary spastic paraplegia v2.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Adult onset hereditary spastic paraplegia v2.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Adult onset hereditary spastic paraplegia v2.2 COQ4 Achchuthan Shanmugasundram gene: COQ4 was added
gene: COQ4 was added to Hereditary spastic paraplegia - adult onset. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36047608
Phenotypes for gene: COQ4 were set to Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Review for gene: COQ4 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in adult onset hereditary spastic paraplegia, as identified from biallelic variants from three unrelated individuals.

Six patients from four families with bi-allelic variants were reported with adult-Onset ataxia-spasticity spectrum phenotype. Out of these, three patients (c.305G>A & c.473G>A, c.434G>A & c.437T>G, c.376G>A & c.473G>A) were identified with hereditary spastic paraparesis and their age of onset ranged from 15 to 24 (PMID:36047608).

COQ4 was not associated with hereditary spastic paraparesis in OMIM or Gene2Phenotype. However, functional studies performed in patient-derived fibroblasts, yeasts and zebrafish larvae confirms the role of COQ4 in brain development. The coq4 F0 CRISPR zebrafish line particularly showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum (PMID:33704555).
Sources: Literature
Hereditary ataxia with onset in adulthood v3.3 COQ4 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: COQ4.
Hereditary ataxia with onset in adulthood v3.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v3.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v3.2 COQ4 Achchuthan Shanmugasundram gene: COQ4 was added
gene: COQ4 was added to Hereditary ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36047608
Phenotypes for gene: COQ4 were set to Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Review for gene: COQ4 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in adult-onset ataxia, as identified from biallelic variants from three unrelated individuals/ families.

Six patients from four families with bi-allelic variants were reported with adult-Onset ataxia-spasticity spectrum phenotype. Out of these, five patients from three families with bi-allelic variants (c.305G>A & c.473G>A, c.434G>A & c.437T>G, c.202+4A>C & c.202+4A>C) were identified with gait and/or limb ataxia. The severity of the phenotype ranged from mild (c.305G>A & c.473G>A) to more severe (c.202+4A>C & c.202+4A>C ) and the age of onset ranged from 15 to 34 (PMID:36047608).

COQ4 was not associated with adult-onset ataxia-spasticity spectrum disease in OMIM or Gene2Phenotype. However, functional studies performed in patient-derived fibroblasts, yeasts and zebrafish larvae confirms the role of COQ4 in brain development. The coq4 F0 CRISPR zebrafish line particularly showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum (PMID:33704555).
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v3.5 COQ4 Achchuthan Shanmugasundram Tag treatable tag was added to gene: COQ4.
Tag Q4_22_promote_green tag was added to gene: COQ4.
Ataxia and cerebellar anomalies - narrow panel v3.5 COQ4 Achchuthan Shanmugasundram Phenotypes for gene: COQ4 were changed from Childhood onset ataxia to Childhood-onset spinocerebellar ataxia; Adult-onset ataxia-spasticity spectrum disease; Hereditary spastic paraparesis, MONDO:0019064; Cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - narrow panel v3.4 COQ4 Achchuthan Shanmugasundram Publications for gene: COQ4 were set to PMID: 30225196; 33704555; 30847826
Ataxia and cerebellar anomalies - narrow panel v3.3 COQ4 Achchuthan Shanmugasundram Classified gene: COQ4 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v3.3 COQ4 Achchuthan Shanmugasundram Gene: coq4 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v3.2 COQ4 Achchuthan Shanmugasundram reviewed gene: COQ4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30225196, 30847826, 33215859, 33704555, 36047608; Phenotypes: Childhood-onset spinocerebellar ataxia, Adult-onset ataxia-spasticity spectrum disease, Hereditary spastic paraparesis, MONDO:0019064, Cerebellar ataxia, MONDO:0000437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SREBF1.
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Classified gene: SREBF1 as Amber List (moderate evidence)
Ectodermal dysplasia v2.3 SREBF1 Achchuthan Shanmugasundram Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v2.2 SREBF1 Achchuthan Shanmugasundram gene: SREBF1 was added
gene: SREBF1 was added to Ectodermal dysplasia. Sources: Literature
Mode of inheritance for gene: SREBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF1 were set to 31790666; 32497488; 32902915; 33253727; 33742461
Phenotypes for gene: SREBF1 were set to Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221; Mucoepithelial dysplasia, hereditary, MIM# 158310, MONDO:0008017
Review for gene: SREBF1 was set to GREEN
Added comment: Comment on classification of this gene: The rating for this gene should be added as GREEN, as this gene has been implicated in both hereditary hair and skin conditions, as identified from monoallelic variants from at least 18 unrelated individuals/ families from multiple ethnicities, and supported by results from in vitro functional studies.

As reviewed by Zornitza Stark, heterozygous variants in 11 unrelated, ethnically diverse individuals has resulted in IFAP syndrome (MIM# 619016), which is characterised generally by moderate or severe hypotrichosis or atrichia (hair), ichthyosis follicularis (skin), and photophobia, Meibomian gland dysfunction, keratitis and/or cataract (eye) (PMID:32497488). Similarly, autosomal-dominant IFAP syndrome was also observed in another report of a Japanese woman and her daughter displaying heterozygous variant c.1669C>T (p.Arg557Cys) in SREBF1 gene (PMID:33253727).

Seven patients from four families displaying heterozygous variants of SREBF1 gene (c.1669C>T (p.Arg557Cys) and c.1670G>A (p.Arg557His)) were reported with HMD (MIM# 158310), which is characterised by chronic keratitis, non-scarring alopecia, mucosal erythema, keratosis pilaris, perineal erythematous intertrigo, psoriatic-like perineal plaques, and involvement of the conjunctival mucosa (PMID:31790666). There are also two other reports of patients with c.1669C>T (p.Arg557Cys) variant displaying autosomal-dominant HMD (PMID:32902915, PMID:33742461). The clinical indications of IFAP and HMD suggests that these two diseases share a common clinical spectrum.

The association of both IFAP and HMD to SREBF1 has been documented in OMIM. In addition, results from in vitro investigation of SREBP1 variants confirms the essential role of SREBF1 in epidermal differentiation, skin barrier formation, hair growth, and eye function (PMID:32497488).
Sources: Literature
Ichthyosis and erythrokeratoderma v2.10 SREBF1 Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: SREBF1.
Ichthyosis and erythrokeratoderma v2.10 SREBF1 Achchuthan Shanmugasundram Phenotypes for gene: SREBF1 were changed from IFAP (ichthyosis follicularis, atrichia, and photophobia) syndrome to Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221; Hereditary mucoepithelial dysplasia, MIM# 158310, MONDO:0008017
Ichthyosis and erythrokeratoderma v2.9 SREBF1 Achchuthan Shanmugasundram Publications for gene: SREBF1 were set to 32497488
Ichthyosis and erythrokeratoderma v2.8 SREBF1 Achchuthan Shanmugasundram Classified gene: SREBF1 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v2.8 SREBF1 Achchuthan Shanmugasundram Gene: srebf1 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v2.7 SREBF1 Achchuthan Shanmugasundram reviewed gene: SREBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31790666, 32497488, 32902915, 33253727, 33742461; Phenotypes: Ichthyosis, follicular, with atrichia and photophobia syndrome 2, MIM# 619016, MONDO:0100221, Hereditary mucoepithelial dysplasia, MIM# 158310, MONDO:0008017; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratodermas v2.4 PERP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: PERP.
Palmoplantar keratodermas v2.4 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Dominant and Recessive Keratoderma to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; Ichthyosis, MONDO:0019269
Palmoplantar keratodermas v2.3 PERP Achchuthan Shanmugasundram Publications for gene: PERP were set to 30321533
Palmoplantar keratodermas v2.2 PERP Achchuthan Shanmugasundram Classified gene: PERP as Amber List (moderate evidence)
Palmoplantar keratodermas v2.2 PERP Achchuthan Shanmugasundram Gene: perp has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v2.1 PERP Achchuthan Shanmugasundram reviewed gene: PERP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898316, 30321533, 31361044, 34265120, 34863005, 32593191; Phenotypes: Olmsted syndrome-2, MIM# 619208, MONDO:003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941, Ichthyosis, MONDO:0019269, Alopecia universalis, Congenital hypotrichosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v2.7 PERP Achchuthan Shanmugasundram edited their review of gene: PERP: Changed phenotypes to: Olmsted syndrome-2, MIM# 619208, MONDO:003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941, Ichthyosis, MONDO:0019269, Alopecia universalis, congenital hypotrichosis
Ichthyosis and erythrokeratoderma v2.7 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; ichthyosis, MONDO:0019269 to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; Ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v2.6 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Olmsted syndrome-2, MIM# 619208, MONDO_003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941; ichthyosis, MONDO:0019269 to Olmsted syndrome-2, MIM# 619208, MONDO:003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO:0030941; ichthyosis, MONDO:0019269
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Classified gene: CADM3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). To date only one paper reports three families with the same missense variant in CADM3. A separate report and/or another variant causing disease would help corroborate this association and so rating Amber for now with a 'watchlist' tag.
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Gene: cadm3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v2.2 CADM3 Arina Puzriakova Tag watchlist tag was added to gene: CADM3.
Ichthyosis and erythrokeratoderma v2.5 PERP Achchuthan Shanmugasundram Tag Q4_22_promote_green tag was added to gene: PERP.
Ichthyosis and erythrokeratoderma v2.5 PERP Achchuthan Shanmugasundram Phenotypes for gene: PERP were changed from Erythrokeratoderma, no OMIM # yet to Olmsted syndrome-2, MIM# 619208, MONDO_003091; Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941; ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v2.4 PERP Achchuthan Shanmugasundram Publications for gene: PERP were set to 31898316
Ichthyosis and erythrokeratoderma v2.3 PERP Achchuthan Shanmugasundram Mode of inheritance for gene: PERP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma v2.2 PERP Achchuthan Shanmugasundram Classified gene: PERP as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v2.2 PERP Achchuthan Shanmugasundram Gene: perp has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v2.1 PERP Achchuthan Shanmugasundram reviewed gene: PERP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898316, 30321533, 31361044, 34265120, 34863005, 32593191; Phenotypes: Olmsted syndrome-2, MIM# 619208, MONDO_003091, Erythrokeratodermia variabilis et progressiva-7, MIM# 619209, MONDO_0030941, ichthyosis, MONDO:0019269, Alopecia universalis, congenital hypotrichosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.2 CADM3 Arina Puzriakova Phenotypes for gene: CADM3 were changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, axonal, type 2FF, OMIM:619519
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.; to: At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.
Paediatric disorders - additional genes v2.3 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v2.3 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v2.2 TOR1AIP1 Arina Puzriakova gene: TOR1AIP1 was added
gene: TOR1AIP1 was added to Paediatric disorders - additional genes. Sources: Expert list
Q4_22_promote_green tags were added to gene: TOR1AIP1.
Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOR1AIP1 were set to 24856141; 25425325; 27342937; 30723199; 31299614; 32055997; 33215087; 34164833
Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, OMIM:617072
Review for gene: TOR1AIP1 was set to GREEN
Added comment: Gene was initially added to the Cardiomyopathy panel; however, after NHS GMS review it was determined that R27 (congenital malformation/syndromic) panel is more appropriate. Therefore adding here with the recommendation of upgrading to Green status at the next review.
-----
Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 15 affected individuals from 10 families with biallelic variants in this gene. Of these, 7 individuals (5 families) reported in PMID:30723199 harbour the same founder variant presenting a very similar phenotype, and are therefore considered collectively here. Patients present a severe multisystem phenotype with muscular dystrophy being the prominent feature observed in at least one case in each family, but additional common features also include joint contractures (4 fam), dilated cardiomyopathy (4 fam), developmental delay (4 fam), and cataracts (3 fam).

Note that one additional homozygous case has been reported with what is thought to be a discrete phenotype characterised by progressive dystonia, cerebellar atrophy, and dilated cardiomyopathy (PMID: 25425325). Biallelic variants have also been linked to a congenital myasthenic syndrome in two unrelated families (PMID: 33215087; 34164833).
Sources: Expert list
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Classified gene: TOR1AIP1 as Amber List (moderate evidence)
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Added comment: Comment on list classification: At least two unrelated multiplex families reported with muscle fatigability, limb girdle weakness and impaired transmission at the neuromuscular synapse. Given the strong functional support including a concordant mouse model, this gene can be promoted to Green status on this panel at the next GMS panel update.
Congenital myaesthenic syndrome v3.3 TOR1AIP1 Arina Puzriakova Gene: tor1aip1 has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v3.2 TOR1AIP1 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: TOR1AIP1.
Congenital myaesthenic syndrome v3.2 TOR1AIP1 Arina Puzriakova Publications for gene: TOR1AIP1 were set to 24856141; 31299614
Congenital myaesthenic syndrome v3.1 TOR1AIP1 Arina Puzriakova edited their review of gene: TOR1AIP1: Changed publications to: 33215087, 34164833
Congenital myaesthenic syndrome v3.1 TOR1AIP1 Arina Puzriakova reviewed gene: TOR1AIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24856141, 27342937, 30723199, 31299614, 32055997; Phenotypes: Congenital myasthenic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis imperfecta v3.3 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX was changed from to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v2.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from LANGER MESOMELIC DYSPLASIA; LERI-WEILL DYSCHONDROSTEOSIS to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
IUGR and IGF abnormalities v1.55 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
Osteogenesis imperfecta v3.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Short stature, idiopathic familial, 300582; Leri-Weill dyschondrosteosis, 127300; Langer mesomelic dysplasia, 249700; Proportionate Short Stature/Small for Gestational Age; Disproportionate Short Stature to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Skeletal dysplasia v3.2 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia 249700; Short stature, idiopathic familial 300582; Leri-Weill dyschondrosteosis 127300 to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Intellectual disability v4.4 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from SHOX deficiency (with Intellectual disability) to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
Radial dysplasia v1.23 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Leri-Weill dyschondrosteosis, 127300; bowing of the radius; radioulnar shortening; Langer mesomelic dysplasia, 249700; curved radius; dorsolateral bowed, short radii to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Limb disorders v3.3 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia, 249700; dorsolateral bowed, short radii; bowing of the radius; curved radius; radioulnar shortening; Leri-Weill dyschondrosteosis, 127300 to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening
Limb disorders v3.2 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX 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 v4.3 SHOX Arina Puzriakova Mode of inheritance for gene: SHOX was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early onset or syndromic epilepsy v3.1 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: 14 cases with mostly recurrent missense variant in this gene is reported.
Sources: Literature
Intellectual disability v4.2 KLHL20 Dmitrijs Rots gene: KLHL20 was added
gene: KLHL20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KLHL20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLHL20 were set to 36214804
Phenotypes for gene: KLHL20 were set to developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder
Penetrance for gene: KLHL20 were set to unknown
Mode of pathogenicity for gene: KLHL20 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: KLHL20 was set to GREEN
Added comment: More 14 individuals with mostly recurrent missense variant reported in KLHL20
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v3.1 TBX1 Ronnie Wright reviewed gene: TBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v3.1 POGLUT1 Katherine Schon reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31897643; Phenotypes: limb girdle weakness, thigh weakness, muscle MRI abnormality; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v2.1 GRM1 Zornitza Stark reviewed gene: GRM1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 13 MIM#614831; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.2 PAX6 Tracy Lester reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v4.2 RARB Zornitza Stark reviewed gene: RARB: Rating: GREEN; Mode of pathogenicity: None; Publications: 30880327, 30281527, 24075189, 27120018, 25457163, 17506106; Phenotypes: Microphthalmia, syndromic 12, MIM# 615524, Neurodevelopmental disorder; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dilated Cardiomyopathy and conduction defects v1.81 PRDM16 Zornitza Stark reviewed gene: PRDM16: Rating: GREEN; Mode of pathogenicity: None; Publications: 29367541, 29447731, 30847666, 33082984, 32183154, 33500567, 34540771, 34350506, 34935411, 35862303, 32083975; Phenotypes: Cardiomyopathy, dilated, 1LL MIM#615373, Left ventricular noncompaction 8 MIM#615373; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v4.2 BLM Zornitza Stark reviewed gene: BLM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bloom syndrome, MIM# 210900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v4.2 PRSS12 Sarah Leigh Publications for gene: PRSS12 were set to
Adult onset neurodegenerative disorder v3.2 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Adult onset neurodegenerative disorder v3.2 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.313 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Hereditary ataxia v1.313 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.2 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v3.1 COG5 Arina Puzriakova Tag watchlist_moi tag was added to gene: COG5.
Unexplained kidney failure in young people v1.116 FAN1 Yu Leng Phua reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35931300; Phenotypes: interstitial nephritis, chronic kidney disease, Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v2.1 FAN1 Yu Leng Phua reviewed gene: FAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35931300; Phenotypes: interstitial nephritis, chronic kidney disease, Interstitial nephritis, karyomegalic 614817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v2.1 LEF1 Yu Leng Phua reviewed gene: LEF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35583550; Phenotypes: Radial ray defects, polydactyly, split hand/foot, ectodermal dysplasia; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hypotonic infant v18.2 Arina Puzriakova Panel version 18.1 has been signed off on 2022-11-30
Cardiac arrhythmias v11.2 Eleanor Williams Panel version 11.1 has been signed off on 2022-11-30
Childhood onset leukodystrophy v10.3 Arina Puzriakova Panel version 10.2 has been signed off on 2022-11-30
Sudden unexplained death or survivors of a cardiac event v17.4 Eleanor Williams Panel version 17.3 has been signed off on 2022-11-30
Other rare neuromuscular disorders v12.2 Arina Puzriakova Panel version 12.1 has been signed off on 2022-11-30
Rare multisystem ciliopathy Super panel v8.3 Arina Puzriakova Panel version 8.2 has been signed off on 2022-11-30
Sudden unexplained death or survivors of a cardiac event v17.3 Eleanor Williams List of related panels changed from Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; 425 to Molecular autopsy; Sudden cardiac death; Sudden cardiac death PILOT; R138; R425
Hypogonadotropic hypogonadism (GMS) v2.3 Achchuthan Shanmugasundram Panel version 2.2 has been signed off on 2022-11-30
Cerebral malformation v8.3 Eleanor Williams Panel version 8.2 has been signed off on 2022-11-30
Hypogonadotropic hypogonadism (GMS) v2.2 Achchuthan Shanmugasundram Panel signed off version 2.0 has been removed
Paediatric disorders v24.3 Arina Puzriakova Panel version 24.2 has been signed off on 2022-11-30
Cystic renal disease v5.2 Eleanor Williams Panel version 5.1 has been signed off on 2022-11-30
Pulmonary fibrosis familial v1.4 Achchuthan Shanmugasundram Panel types changed to GMS Rare Disease; GMS signed-off
Panel version 1.3 has been signed off on 2022-11-30
Pulmonary fibrosis familial v1.3 Achchuthan Shanmugasundram Panel signed off version 1.0 has been removed
Pulmonary fibrosis familial v1.2 Achchuthan Shanmugasundram Panel signed off version 1.1 has been removed
Hereditary ataxia and cerebellar anomalies - childhood onset v9.2 Arina Puzriakova Panel version 9.1 has been signed off on 2022-11-30
Fetal anomalies v2.1 Eleanor Williams Panel version 2.0 has been signed off on 2022-11-30
Fetal anomalies v2.0 Eleanor Williams promoted panel to version 2.0
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.3 Eleanor Williams List of related panels changed from Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151; R152 to Familial hyperparathyroidism; Hypocalciuric hypercalcaemia; R151
Panel version 3.2 has been signed off on 2022-11-30
Familial hyperparathyroidism or hypocalciuric hypercalcaemia v3.2 Eleanor Williams Panel signed off version 3.0 has been removed
Auditory Neuropathy Spectrum Disorde v1.9 ATP11A Barbara Vona gene: ATP11A was added
gene: ATP11A was added to Auditory Neuropathy Spectrum Disorder. Sources: Literature
Mode of inheritance for gene: ATP11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP11A were set to PMID: 36300302; 28601886
Phenotypes for gene: ATP11A were set to Auditory synaptopathy/neuropathy; AUNA2
Penetrance for gene: ATP11A were set to Complete
Mode of pathogenicity for gene: ATP11A was set to Other
Review for gene: ATP11A was set to RED
gene: ATP11A was marked as current diagnostic
Added comment: A large German family with auditory synaptopathy/neuropathy that originally mapped the AUNA2 locus to either chromosome 12q24 or 13q34 underwent genome sequencing. Affected individuals showed symmetrical, slowly progressive postlingual hearing loss starting late in the first decade that eventually advanced to to severe hearing impairment in the fifth decade. Auditory brainstem response thresholds were worse than otoacoustic emissions, suggesting a deficit in neural sound encoding. A 5.5 kb deletion encompassing the last coding exon of both RefSeq annotated ATP11A isoforms was found to segregate with the phenotype. RNA studies from an affected individual confirmed stable expression and both a deletion and activation of a cryptic splice acceptor that leads to inclusion of a pseudoexon and novel 38 amino acids at the C-terminus. ATP11A flippase activity was disrupted in mutant cells, compatible with a loss-of-function mechanism, although a gain of function of dominant negative effect could not be excluded. ATP11A is expressed in the mouse inner ear. Its function was explored in depth using a conditional knockout mouse that showed a progressive dysfunction or loss of spiral ganglion neurons. Additional families are needed to replicate an auditory synaptopathy/neuropathy phenotype.
Sources: Literature
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Intestinal failure or congenital diarrhoea v2.0 Arina Puzriakova promoted panel to version 2.0
Primary immunodeficiency or monogenic inflammatory bowel disease v3.1 Eleanor Williams Panel version 3.0 has been signed off on 2022-11-30
Intestinal failure or congenital diarrhoea v1.51 Arina Puzriakova Panel name changed from Intestinal failure to Intestinal failure or congenital diarrhoea
List of related panels changed from R331 to R331; Intestinal failure
Long QT syndrome v3.0 Achchuthan Shanmugasundram promoted panel to version 3.0
Primary immunodeficiency or monogenic inflammatory bowel disease v3.0 Eleanor Williams promoted panel to version 3.0
Primary immunodeficiency or monogenic inflammatory bowel disease v2.583 Eleanor Williams Panel name changed from Primary immunodeficiency to Primary immunodeficiency or monogenic inflammatory bowel disease
List of related panels changed from Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; R15 to Primary immunodeficiency disorders; A- or hypo-gammaglobulinaemia; Congenital neutropaenia; Agranulocytosis; Combined B and T cell defect; Inherited complement deficiency; SCID; Primary immune disorder; Primary immunodeficiency; A-gammaglobulinaemia; Agammaglobulinaemia; hypo-gammaglobulinaemia; hypogammaglobulinemia; immune deficiency syndromes; Severe combined immunodeficiency; Congenital neutopenia; Familial haemophagocytic lymphohistiocytic disorders; Familial hemophagocytic lymphohistiocytic disorders; PID; Sepsis; Disseminated non-tuberculous mycobacterial infection; Primary immunodeficiency; R15
Intellectual disability v3.1771 RARB Dmitrijs Rots reviewed gene: RARB: 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: 27120018; Phenotypes: Intellectual Disability with Progressive Motor Impairment; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 IRF7 Dmitrijs Rots edited their review of gene: IRF7: Added comment: 7 families in total reported. Enough evidence for green classification.; Changed rating: GREEN; Changed publications to: 35986347, 35670811
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 KCNA5 Inga Nartisa gene: KCNA5 was added
gene: KCNA5 was added to Primary immunodeficiency. Sources: Literature,Expert Review
Mode of inheritance for gene: KCNA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNA5 were set to PMID: 35748970; PMID: 34536415
Phenotypes for gene: KCNA5 were set to autoimmunity; autoinflammation
Review for gene: KCNA5 was set to GREEN
Added comment: Sources: Literature, Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 DIAPH1 Inga Nartisa gene: DIAPH1 was added
gene: DIAPH1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: DIAPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DIAPH1 were set to PMID: 35748970; PMID: 33662367
Phenotypes for gene: DIAPH1 were set to microcephaly; epilepsy; cortical blindness; poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells.
Review for gene: DIAPH1 was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 CHUK Inga Nartisa gene: CHUK was added
gene: CHUK was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: CHUK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHUK were set to PMID: 35748970; PMID: 34533979
Phenotypes for gene: CHUK were set to recurrent infections; skeletal abnormalities; absent secondary lymphoid structures; reduced B cell numbers; hypogammaglobulinemia; lymphocytic infiltration of intestine and liver
Review for gene: CHUK was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 COPG1 Inga Nartisa gene: COPG1 was added
gene: COPG1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: COPG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPG1 were set to PMID: 35748970; PMID: 33529166
Phenotypes for gene: COPG1 were set to persistent bacterial infection; persistent viral infections; defective humoral and cellular immunity
Review for gene: COPG1 was set to GREEN
Added comment: Sources: Expert Review, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 MAN2B2 Inga Nartisa gene: MAN2B2 was added
gene: MAN2B2 was added to Primary immunodeficiency. Sources: Other
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to PMID: 31775018
Review for gene: MAN2B2 was set to GREEN
Added comment: Sources: Other
Ataxia and cerebellar anomalies - narrow panel v2.318 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.317 COG5 Arina Puzriakova Added comment: Comment on mode of inheritance: All cases reported to date have been associated with recessive inheritance with the exception of one family with "one potential heterozygous mutation" reported in 2017 (PMID: 28960046). As no further monoallelic cases have been reported since, updating the MOI from 'both mono- and biallelic' to 'biallelic' only until further evidence emerges supporting pathogenicity of heterozygous variants in this gene.
Ataxia and cerebellar anomalies - narrow panel v2.317 COG5 Arina Puzriakova Mode of inheritance for gene: COG5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1771 FBXW7 Arina Puzriakova Phenotypes for gene: FBXW7 were changed from Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate to Developmental delay, hypotonia, and impaired language, OMIM:620012
Intellectual disability v3.1770 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from Congenital heart defects, nonsyndromic, 2, 614980 to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Paediatric or syndromic cardiomyopathy v1.83 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Fetal anomalies v1.992 TAB2 Arina Puzriakova Phenotypes for gene: TAB2 were changed from CONGENITAL HEART DISEASE, NONSYNDROMIC, 2 to Congenital heart defects, nonsyndromic, 2, OMIM:614980
Hereditary neuropathy or pain disorder v1.105 ARHGEF10 Dmitrijs Rots reviewed gene: ARHGEF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy v1.457 ARHGEF10 Dmitrijs Rots reviewed gene: ARHGEF10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Retinal disorders v2.301 AIPL1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: AIPL1.
Retinal disorders v2.301 AIPL1 Arina Puzriakova edited their review of gene: AIPL1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Retinal disorders v2.301 AIPL1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): Achromatopsia, Cone, and Cone-rod Dystrophy; Cone-rod dystrophy (AD); Leber congenital amaurosis 4 (AR); Retinitis pigmentosa, juvenile (AD); Leber Congenital Amaurosis; Leber congenital amaurosis; Leber congenital amaurosis 4, 604393; Retinitis pigmentosa, juvenile, 604393; Cone-rod dystrophy, 604393; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa
Retinal disorders v2.301 AIPL1 Arina Puzriakova Phenotypes for gene: AIPL1 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Cone-rod dystrophy (AD); Leber congenital amaurosis 4 (AR); Retinitis pigmentosa, juvenile (AD); Leber Congenital Amaurosis; Leber congenital amaurosis; Leber congenital amaurosis 4, 604393; Retinitis pigmentosa, juvenile, 604393; Cone-rod dystrophy, 604393; Eye Disorders; Retinitis Pigmentosa, Dominant; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa to Cone-rod dystrophy, OMIM:604393; Retinitis pigmentosa, juvenile, OMIM:604393; Leber congenital amaurosis 4, OMIM:604393
Retinal disorders v2.300 AIPL1 Arina Puzriakova Publications for gene: AIPL1 were set to
Retinal disorders v2.299 AIPL1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'biallelic' to 'both mono- and biallelic (but biallelic mutations cause a more SEVERE disease form) at the next GMS panel update.

This gene is typically associated with recessive inheritance of a Leber congenital amaurosis (LCA) phenotype. However, some patients with heterozygous variants have also been identified, usually presenting less severe phenotypes within the retinal dystrophy spectrum such as retinitis pigmentosa and rod-cone dystrophy/dysfunction - although heterozygous variants act with reduced penetrance (PMID: 10873396; 15249368; 21900377; 33067476)

Both MOIs are also listed in OMIM.
Retinal disorders v2.299 AIPL1 Arina Puzriakova Mode of inheritance for gene: AIPL1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams changed review comment from: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; to: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Added comment: Comment on mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.28 CFH Eleanor Williams Mode of inheritance for gene: CFH was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Added comment: Comment on mode of inheritance: Changing the MOI to BIALLELIC, autosomal or pseudoautosomal as per the signed off version 2.13 (Oct 2020) and as agreed with NHSE.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.27 DGKE Eleanor Williams Mode of inheritance for gene: DGKE was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.316 PITRM1 Eleanor Williams Tag gene-checked tag was added to gene: PITRM1.
Nephrocalcinosis or nephrolithiasis v2.40 WDR72 Detlef Bockenhauer gene: WDR72 was added
gene: WDR72 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to PMID: 30028003; 30779877; 31959358; 33033857
Phenotypes for gene: WDR72 were set to distal renal tubular acidosis; amelogenesis imperfecta
Penetrance for gene: WDR72 were set to Complete
Review for gene: WDR72 was set to GREEN
Added comment: Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 SASH3 Eleanor Williams commented on gene: SASH3
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 SASH3 Eleanor Williams Tag gene-checked was removed from gene: SASH3.
Severe microcephaly v2.322 PRIM1 Eleanor Williams commented on gene: PRIM1
Severe microcephaly v2.322 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Severe microcephaly v2.321 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 PRIM1 Eleanor Williams commented on gene: PRIM1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.582 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Primary immunodeficiency or monogenic inflammatory bowel disease v2.581 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Fetal anomalies v1.991 PRIM1 Eleanor Williams commented on gene: PRIM1
Fetal anomalies v1.991 PRIM1 Eleanor Williams Phenotypes for gene: PRIM1 were changed from Microcephalic primordial dwarfism, MONDO:0017950 to Microcephalic primordial dwarfism, MONDO:0017950; Primordial dwarfism-immunodeficiency-lipodystrophy syndrome, OMIM:620005
Fetal anomalies v1.990 PRIM1 Eleanor Williams Tag gene-checked was removed from gene: PRIM1.
Intellectual disability v3.1769 JARID2 Eleanor Williams commented on gene: JARID2
Intellectual disability v3.1769 JARID2 Eleanor Williams Phenotypes for gene: JARID2 were changed from Intellectual disability; Neurodevelopmental syndrome to Intellectual disability; Neurodevelopmental syndrome; Developmental delay with variable intellectual disability and dysmorphic facies, OMIM:620098
Intellectual disability v3.1768 JARID2 Eleanor Williams Tag gene-checked was removed from gene: JARID2.
Intellectual disability v3.1768 HNRNPR Eleanor Williams commented on gene: HNRNPR
Intellectual disability v3.1768 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
Intellectual disability v3.1767 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams commented on gene: HNRNPR
Early onset or syndromic epilepsy v2.607 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly; Short digit; Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
Early onset or syndromic epilepsy v2.606 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
DDG2P v2.84 HNRNPR Eleanor Williams commented on gene: HNRNPR
DDG2P v2.84 HNRNPR Eleanor Williams Phenotypes for gene: HNRNPR were changed from INTELLECTUAL DISABILITY 616579 to Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, OMIM:620073
DDG2P v2.83 HNRNPR Eleanor Williams Tag gene-checked was removed from gene: HNRNPR.
Childhood onset dystonia, chorea or related movement disorder v1.265 HNRNPH1 Eleanor Williams commented on gene: HNRNPH1
Childhood onset dystonia, chorea or related movement disorder v1.265 HNRNPH1 Eleanor Williams Phenotypes for gene: HNRNPH1 were changed from HNRNPH1-related neurodevelopmental disorder to HNRNPH1-related neurodevelopmental disorder; Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, OMIM:620083
Childhood onset dystonia, chorea or related movement disorder v1.264 HNRNPH1 Eleanor Williams Tag gene-checked was removed from gene: HNRNPH1.
Intellectual disability v3.1767 HNRNPH1 Eleanor Williams commented on gene: HNRNPH1
Intellectual disability v3.1767 HNRNPH1 Eleanor Williams Phenotypes for gene: HNRNPH1 were changed from HNRNPH1‐related syndromic intellectual disability to HNRNPH1‐related syndromic intellectual disability; Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, OMIM:620083
Intellectual disability v3.1766 HNRNPH1 Eleanor Williams Tag gene-checked was removed from gene: HNRNPH1.
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams commented on gene: HID1
Early onset or syndromic epilepsy v2.606 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Early onset or syndromic epilepsy v2.605 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Pituitary hormone deficiency v2.103 HID1 Eleanor Williams commented on gene: HID1
Pituitary hormone deficiency v2.103 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Pituitary hormone deficiency v2.102 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Intellectual disability v3.1766 HID1 Eleanor Williams commented on gene: HID1
Intellectual disability v3.1766 HID1 Eleanor Williams Phenotypes for gene: HID1 were changed from Syndromic infantile encephalopathy; Hypopituitarism to Syndromic infantile encephalopathy; Hypopituitarism; Developmental and epileptic encephalopathy 105 with hypopituitarism, OMIM:619983
Intellectual disability v3.1765 HID1 Eleanor Williams Tag gene-checked was removed from gene: HID1.
Childhood solid tumours cancer susceptibility v1.23 GPR161 Eleanor Williams commented on gene: GPR161
Childhood solid tumours cancer susceptibility v1.23 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from Predisposition to paediatric medulloblastoma to {Medulloblastoma predisposition syndrome}, OMIM:155255
Childhood solid tumours cancer susceptibility v1.22 GPR161 Eleanor Williams Tag gene-checked was removed from gene: GPR161.
Childhood solid tumours v2.38 GPR161 Eleanor Williams commented on gene: GPR161
Childhood solid tumours v2.38 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from Medulloblastoma predisposition to {Medulloblastoma predisposition syndrome}, OMIM:155255
Childhood solid tumours v2.37 GPR161 Eleanor Williams Tag gene-checked was removed from gene: GPR161.
Intellectual disability v3.1765 CACNA1I Eleanor Williams commented on gene: CACNA1I
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams commented on gene: CACNA1I
Early onset or syndromic epilepsy v2.605 CACNA1I Eleanor Williams Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with speech impairment and with or without seizures, OMIM:620114
Early onset or syndromic epilepsy v2.604 CACNA1I Eleanor Williams Tag gene-checked was removed from gene: CACNA1I.
Intellectual disability v3.1765 CACNA1I Eleanor Williams Phenotypes for gene: CACNA1I were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with speech impairment and with or without seizures, OMIM:620114
Intellectual disability v3.1764 CACNA1I Eleanor Williams Tag gene-checked was removed from gene: CACNA1I.
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Intellectual disability v3.1764 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams commented on gene: ARFGEF1
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Tag gene-checked was removed from gene: ARFGEF1.
Early onset or syndromic epilepsy v2.604 ARFGEF1 Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964
Structural eye disease v1.152 DDX58 Eleanor Williams commented on gene: DDX58
Structural eye disease v1.152 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Intellectual disability v3.1763 DDX58 Eleanor Williams commented on gene: DDX58
Intellectual disability v3.1763 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
DDG2P v2.83 DDX58 Eleanor Williams commented on gene: DDX58
DDG2P v2.83 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
COVID-19 research v1.134 DDX58 Eleanor Williams commented on gene: DDX58
COVID-19 research v1.134 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Glaucoma (developmental) v1.42 DDX58 Eleanor Williams commented on gene: DDX58
Glaucoma (developmental) v1.42 DDX58 Eleanor Williams Tag new-gene-name tag was added to gene: DDX58.
Hereditary neuropathy or pain disorder v1.105 FAM126A Eleanor Williams commented on gene: FAM126A
Hereditary neuropathy or pain disorder v1.105 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Structural eye disease v1.152 FAM126A Eleanor Williams commented on gene: FAM126A
Structural eye disease v1.152 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Hereditary neuropathy v1.457 FAM126A Eleanor Williams commented on gene: FAM126A
Hereditary neuropathy v1.457 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
DDG2P v2.83 FAM126A Eleanor Williams commented on gene: FAM126A
DDG2P v2.83 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Inherited white matter disorders v1.163 FAM126A Eleanor Williams commented on gene: FAM126A
Inherited white matter disorders v1.163 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Bilateral congenital or childhood onset cataracts v2.111 FAM126A Eleanor Williams commented on gene: FAM126A
Bilateral congenital or childhood onset cataracts v2.111 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Fetal anomalies v1.990 FAM126A Eleanor Williams commented on gene: FAM126A
Fetal anomalies v1.990 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Intellectual disability v3.1763 FAM126A Eleanor Williams commented on gene: FAM126A
Intellectual disability v3.1763 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
White matter disorders and cerebral calcification - narrow panel v1.246 FAM126A Eleanor Williams commented on gene: FAM126A
White matter disorders and cerebral calcification - narrow panel v1.246 FAM126A Eleanor Williams Tag new-gene-name tag was added to gene: FAM126A.
Familial melanoma v1.14 TERT Arina Puzriakova Publications for gene: TERT were set to 23348503
Familial melanoma v1.13 TERT Arina Puzriakova Tag watchlist tag was added to gene: TERT.
Familial melanoma v1.13 TERT Arina Puzriakova reviewed gene: TERT: Rating: ; Mode of pathogenicity: None; Publications: 23348503, 23348506, 35912549; Phenotypes: {Melanoma, cutaneous malignant, 9}, OMIM:615134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia with onset in adulthood v2.169 TERT Arina Puzriakova Publications for gene: TERT were set to
Hereditary ataxia with onset in adulthood v2.168 TERT Arina Puzriakova Classified gene: TERT as Green List (high evidence)
Hereditary ataxia with onset in adulthood v2.168 TERT Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update as there is no link with adult-onset ataxia associated with this gene.

Cerebellar hypoplasia (but without ataxia) has been identified in 2/5 unrelated AR cases to date, who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115). Furthermore, literature search only revealed a single adult patient (31 years old) who did not present any signs of ataxia (PMID: 18042801).
Hereditary ataxia with onset in adulthood v2.168 TERT Arina Puzriakova Gene: tert has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.316 TERT Arina Puzriakova changed review comment from: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.; to: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases to date, who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.
Hereditary ataxia with onset in adulthood v2.167 TERT Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: TERT.
Cerebellar hypoplasia v1.70 TERT Arina Puzriakova Publications for gene: TERT were set to 17785587; 16247010
Cerebellar hypoplasia v1.69 TERT Arina Puzriakova reviewed gene: TERT: Rating: AMBER; Mode of pathogenicity: None; Publications: 17785587, 34890115; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.316 TERT Arina Puzriakova changed review comment from: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases displaying a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.; to: Cerebellar hypoplasia (without ataxia) has been identified in 2/5 unrelated AR cases who displayed a phenotype of Hoyeraal-Hreidarsson syndrome, a severe variant of DKC (PMIDs: 17785587; 34890115).

There is no link with AD form and given the various other non-relevant phenotypes linked to heterozygous variants, AR inheritance is appropriate for this panel.
Ataxia and cerebellar anomalies - narrow panel v2.316 TERT Arina Puzriakova Tag watchlist tag was added to gene: TERT.
Ataxia and cerebellar anomalies - narrow panel v2.316 TERT Arina Puzriakova Classified gene: TERT as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.316 TERT Arina Puzriakova Gene: tert has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.315 TERT Arina Puzriakova reviewed gene: TERT: Rating: AMBER; Mode of pathogenicity: None; Publications: 17785587, 34890115; Phenotypes: Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.167 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, 613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Ataxia and cerebellar anomalies - narrow panel v2.315 TERT Arina Puzriakova Deleted their review
Ataxia and cerebellar anomalies - narrow panel v2.315 TERT Arina Puzriakova Deleted their comment
Ataxia and cerebellar anomalies - narrow panel v2.315 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Ataxia and cerebellar anomalies - narrow panel v2.314 TERT Arina Puzriakova Mode of inheritance for gene: TERT was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.69 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Intellectual disability v3.1763 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal recessive 4 to Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Adult solid tumours cancer susceptibility v2.24 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Cerebellar hypoplasia v1.68 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from dyskeratosis congenita-2 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Skeletal dysplasia v2.228 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dyskeratosis congenita, autosomal dominant 2 and autosomal recessive 4 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Childhood solid tumours cancer susceptibility v1.22 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Dynkeratosis Congenita to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Primary immunodeficiency or monogenic inflammatory bowel disease v2.581 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay; Bone marrow failure to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Pigmentary skin disorders v1.54 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 2; DKCA2, DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 4, INCLUDED; Melanoma; Dyskeratosis congenita; DKCB4, INCLUDED to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Familial melanoma v1.13 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from to {Melanoma, cutaneous malignant, 9}, OMIM:615134
COVID-19 research v1.134 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Childhood solid tumours v2.37 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742; {Leukemia, acute myeloid}, OMIM:601626; {Melanoma, cutaneous malignant, 9}, OMIM:615134
Ataxia and cerebellar anomalies - narrow panel v2.313 TERT Arina Puzriakova Classified gene: TERT as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.313 TERT Arina Puzriakova Added comment: Comment on list classification: Couldn't find any evidence linking TERT with ataxia and therefore demoting from Amber to Red.
Ataxia and cerebellar anomalies - narrow panel v2.313 TERT Arina Puzriakova Gene: tert has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.312 TERT Arina Puzriakova Mode of inheritance for gene: TERT was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.311 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from dyskeratosis congenita-2 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Familial pulmonary fibrosis v1.30 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}, 614742; Familial Pulmonary Fibrosis; Pulmonary Fibrosis and Hermansky-Pudlak Syndrome; Pulmonary Disease to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Cytopenia - NOT Fanconi anaemia v1.73 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Pulmonary fibrosis, telomere-related, 1}, 614742; {Dyskeratosis congenita, autosomal dominant 2}, 613989; Coronary artery disease; {Melanoma, cutaneous malignant, 9}, 615134; 614742 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1; Aplastic Anemia; 614742 {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}; {Leukemia, acute myeloid}, 601626; 613989 Dyskeratosis congenita; {Dyskeratosis congenita, autosomal recessive 4}, 613989 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Inherited predisposition to acute myeloid leukaemia (AML) v1.25 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Haematological malignancies for rare disease v1.16 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Haematological malignancies cancer susceptibility v2.39 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Bone marrow failure, macrocytosis; Skin, head and neck, and anogenital squamous cell cancers, Oral and GI squamous cell carcinoma to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742
Cytopenias and congenital anaemias v1.111 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Aplastic Anemia; Coronary artery disease; {Dyskeratosis congenita, autosomal recessive 4}, 613989; {Dyskeratosis congenita, autosomal dominant 2}, 613989; {Pulmonary fibrosis, telomere-related, 1}, 614742; {Leukemia, acute myeloid}, 601626; {Melanoma, cutaneous malignant, 9}, 615134 to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1, OMIM:614742 (AD)
Haematological malignancies for rare disease v1.15 TERT Arina Puzriakova Phenotypes for gene: TERT were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Bone marrow failure, macrocytosis; Skin, head and neck, and anogenital squamous cell cancers, Oral and GI squamous cell carcinoma to {Leukemia, acute myeloid}, OMIM:601626; Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989
Haematological malignancies cancer susceptibility v2.38 MBD4 Arina Puzriakova changed review comment from: Re-tagging on this panel following a separate Green expert review on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.; to: Re-tagging on this panel following a new Green expert review by Dr Claire Palles on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.
Haematological malignancies cancer susceptibility v2.38 RAD21 Arina Puzriakova Tag missense tag was added to gene: RAD21.
Haematological malignancies cancer susceptibility v2.38 RAD21 Arina Puzriakova Mode of pathogenicity for gene: RAD21 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
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: RAD21.
Tag Q4_22_expert_review tag was added to gene: RAD21.
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Added comment: Comment on list classification: RAD21 will be flagged for expert review at the next GMS panel update to determine whether there is enough evidence to classify this gene as Green.

Somatic variants have been found in multiple AML cohorts (PMID: 34157074); however, only one recurrent germline variant (c.892C>T/G, p.P298S/A) was found in three unrelated children with lymphoblastic leukemia or lymphoma (PMID:35563565). The same variant was also found in an adult patient with a solid tumour (malignant peripheral nerve sheath tumour).
Functional studies showed the variant disrupted RAD21 gene expression and DNA damage response but did not perturb formation of the cohesin complex. Notably 2/3 patients harboured known pathogenic somatic KRAS hot-spot variants.

Heterozygous variants in the RAD21 gene are also associated with Cornelia-de-Lange syndrome (MIM# 614701) which is not known to confer cancer predisposition.
Haematological malignancies cancer susceptibility v2.37 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Catecholaminergic polymorphic VT v2.21 CALM2 Sarah Leigh Phenotypes for gene: CALM2 were changed from catecholaminergic polymorphic ventricular tachycardia, MONDO:0017990 to Long QT syndrome 15, OMIM:616249; long QT syndrome 15, MONDO:0014550
Long QT syndrome v2.34 CALM2 Sarah Leigh Phenotypes for gene: CALM2 were changed from Long QT syndrome 15 to Long QT syndrome 15, OMIM:616249; long QT syndrome 15, MONDO:0014550
Catecholaminergic polymorphic VT v2.20 CALM2 Sarah Leigh Publications for gene: CALM2 were set to 27114410; 27100291; 24917665
Long QT syndrome v2.33 CALM2 Sarah Leigh Publications for gene: CALM2 were set to
Clefting v2.73 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Clefting v2.73 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Clefting v2.72 RAD21 Arina Puzriakova gene: RAD21 was added
gene: RAD21 was added to Clefting. Sources: Literature
Q4_22_promote_green tags were added to gene: RAD21.
Mode of inheritance for gene: RAD21 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD21 were set to 22633399; 27882533; 31334757; 32193685
Phenotypes for gene: RAD21 were set to Cornelia de Lange syndrome 4, OMIM:614701
Review for gene: RAD21 was set to GREEN
Added comment: At least 33 unrelated families published with RAD21 alterations. Of these, 6 cases presented with cleft palate or submucous cleft palate. Although only displayed by a subset of patients, clefting is a congenital anomaly that may aid earlier diagnosis if other features such as ID have not yet become apparent. Therefore there would be value in including RAD21 on this panel with a Green rating.
Sources: Literature
Intellectual disability v3.1762 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to
Skeletal dysplasia v2.227 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 30716475; 24378232; 27882533; 27620904
Intellectual disability v3.1761 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4, 614701; COHESINOPATHY to Cornelia de Lange syndrome 4, OMIM:614701
Radial dysplasia v1.22 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Radial dysplasia v1.22 RAD21 Arina Puzriakova Added comment: Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now.

Krab et al. 2020 (PMID: 32193685) collated details on 33 unrelated families (previously and newly published) with RAD21 alterations. In the 22 families with sufficient clinical data available, authors noted that major limb malformations are generally not present. However, minor skeletal anomalies such as clinodactyly of fifth finger (13), camptodactyly (3), scoliosis (2), hip dislocation/dysplasia (2) are reported.
Radial dysplasia v1.22 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Radial dysplasia v1.21 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 31334757; 32193685
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Added comment: Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now.
Skeletal dysplasia v2.226 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.225 RAD21 Arina Puzriakova reviewed gene: RAD21: Rating: ; Mode of pathogenicity: None; Publications: 32193685; Phenotypes: Cornelia de Lange syndrome 4, OMIM:614701; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Radial dysplasia v1.20 RAD21 Arina Puzriakova Tag watchlist was removed from gene: RAD21.
Radial dysplasia v1.20 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 22633399; 31334757
Skeletal dysplasia v2.225 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4 614701 to Cornelia de Lange syndrome 4, OMIM:614701
Radial dysplasia v1.19 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Cornelia de Lange syndrome 4, 614701 to Cornelia de Lange syndrome 4, OMIM:614701
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Classified gene: FOXI3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
A recent study (highlighted by GEL Clinical Team) provides corroborating evidence linking FOXI3 with microtia with or without atresia. Sufficient unrelated cases and supported by concordant animal models.
Paediatric disorders - additional genes v1.108 FOXI3 Arina Puzriakova Gene: foxi3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.107 FOXI3 Arina Puzriakova gene: FOXI3 was added
gene: FOXI3 was added to Paediatric disorders - additional genes. Sources: Expert Review
Q4_22_promote_green tags were added to gene: FOXI3.
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 36260083; 25655429; 18787161; 24650709
Phenotypes for gene: FOXI3 were set to Bilateral Microtia; Congenital aural atresia
Review for gene: FOXI3 was set to GREEN
Added comment: Quiat et al. 2022 (PMID: 36260083) reported 4 unrelated families affected by microtia with or without atresia and different predicted deleterious heterozygous variants in the FOXI3 gene. Variants segregated with disease, including in multiplex families, albeit with reduced penetrance. In vitro studies showed that patient variants conferred abnormal FOXI3 nuclear and cytoplasmic localization.

Tassano et al. 2015 (PMID: 25655429) also identified a patient with microtia, aural atresia, and ipsilateral agenesis of the carotid artery who harboured a 2.5 Mb deletion overlapping the FOXI3 gene.

Congenital ear malformations with variable penetrance have been described in a Foxi3 knockout mouse model and haploinsufficient canine breeds supporting a role of FOXI3 in the human phenotype (PMID: 18787161; 24650709)
Sources: Expert Review
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Classified gene: FOXI3 as Green List (high evidence)
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Added comment: Comment on list classification: Promoting from Red to Green as a recent study (highlighted by GEL Clinical Team) provides corroborating evidence linking FOXI3 with microtia with or without atresia. Sufficient unrelated cases and supported by concordant animal models.
Deafness and congenital structural abnormalities v1.22 FOXI3 Arina Puzriakova Gene: foxi3 has been classified as Green List (High Evidence).
Deafness and congenital structural abnormalities v1.21 FOXI3 Arina Puzriakova Publications for gene: FOXI3 were set to
Deafness and congenital structural abnormalities v1.20 FOXI3 Arina Puzriakova Mode of inheritance for gene: FOXI3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Deafness and congenital structural abnormalities v1.19 FOXI3 Arina Puzriakova reviewed gene: FOXI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36260083, 25655429, 18787161, 24650709; Phenotypes: Microtia with or without atresia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.990 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from MENTAL RETARDATION SYNDROMIC X-LINKED JARID1C-RELATED to Mental retardation, X-linked, syndromic, Claes-Jensen type, OMIM:300534
Fetal anomalies v1.989 KDM5C Arina Puzriakova Publications for gene: KDM5C were set to
Fetal anomalies v1.988 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304) showing that females can be symptomatic.

Therefore, the MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update. This also reflects the current MOI on all other relevant panels.
Fetal anomalies v1.988 KDM5C Arina Puzriakova Mode of inheritance for gene: KDM5C 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 v1.987 KDM5C Arina Puzriakova Tag Q4_22_MOI tag was added to gene: KDM5C.
Adult onset neurodegenerative disorder v2.296 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Adult onset hereditary spastic paraplegia v1.104 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Childhood onset hereditary spastic paraplegia v2.153 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Hereditary spastic paraplegia v1.297 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Classified gene: CNGB3 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (sufficient number of cases, already green on other panels, phenotypic relevance confirmed by clinician).
Albinism or congenital nystagmus v1.27 CNGB3 Arina Puzriakova Gene: cngb3 has been classified as Amber List (Moderate Evidence).
Albinism or congenital nystagmus v1.26 CNGB3 Arina Puzriakova gene: CNGB3 was added
gene: CNGB3 was added to Albinism or congenital nystagmus. Sources: Expert Review
Q4_22_promote_green tags were added to gene: CNGB3.
Mode of inheritance for gene: CNGB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNGB3 were set to 10888875; 10958649; 35332618
Phenotypes for gene: CNGB3 were set to Achromatopsia 3, OMIM:262300
Review for gene: CNGB3 was set to GREEN
Added comment: Added to this panel following suggestion from Dr Helen Brittain (Genomics England Clinical Team) who highlighted a patient who would have benefitted from inclusion of CNGB3 on R39 Albinism or congenital nystagmus. Biallelic variants cause achromatopsia, featuring total colour blindness, photophobia, reduced visual acuity and nystagmus.
Sources: Expert Review
Retinal disorders v2.298 CNGB3 Arina Puzriakova Phenotypes for gene: CNGB3 were changed from Achromatopsia; Macular degeneration, juvenile; Achromatopsia-3, 262300; Macular degeneration, juvenile, 248200 -3; Stargardt Disease, Recessive; Macular Dystrophy/Degeneration/Stargardt Disease; Achromatopsia-3; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy to Achromatopsia 3, OMIM:262300; Macular degeneration, juvenile
Early onset or syndromic epilepsy v2.603 CUX2 Tracy Lester edited their review of gene: CUX2: Added comment: Almost all cases reported to date have a de novo E590K variant, there is currently no evidence supporting this gene being imprinted or for LOF variants being pathogenic. I suggest the inheritance model should be updated to be monoallelic, NOT imprinted.; Changed mode of pathogenicity: Other; Changed publications to: 29795476, 29630738
Intellectual disability v3.1760 FMR1 Arina Puzriakova Publications for gene: FMR1 were set to
Intellectual disability v3.1759 FMR1 Arina Puzriakova reviewed gene: FMR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 21267007, 25171808, 28176767, 29178241; 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)
Ataxia and cerebellar anomalies - narrow panel v2.310 FMR1 Arina Puzriakova Classified gene: FMR1 as Green List (high evidence)
Ataxia and cerebellar anomalies - narrow panel v2.310 FMR1 Arina Puzriakova Added comment: Comment on list classification: FMR1 should be demoted from Green to Red at the next GMS panel update as the disease mechanism for FXTAS (includes ataxia) is repeat expansions and SNVs are not relevant. Furthermore, the FMR1_CGG STR entity will not be added as FXTAS is a late-onset condition and this panel feeds into the childhood-onset ataxia super panel (R55). The STR is already Green on the R45 Hereditary ataxia - adult onset (v2.13) panel.
Ataxia and cerebellar anomalies - narrow panel v2.310 FMR1 Arina Puzriakova Gene: fmr1 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.309 FMR1 Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: FMR1.
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Classified gene: FMR1 as Red List (low evidence)
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Green to Red as the disease mechanism is repeat expansion and SNVs are not relevant to FXTAS.
Hereditary ataxia v1.312 FMR1 Arina Puzriakova Gene: fmr1 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.603 SNIP1 Helen Lord reviewed gene: SNIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34570759, 2279524, 31589614; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 CLPB Helen Lord reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 25597510, 25597511, 26916670; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary ciliary disorders v1.40 OFD1 Amelia Shoemark reviewed gene: OFD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31373179 31366608; Phenotypes: ciliopathies, primary ciliary dyskinesia, joubert; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v2.603 ASH1L Helen Lord reviewed gene: ASH1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 34373061, 25961944, 34782621, 32469098; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital muscular dystrophy v2.31 POGLUT1 Anna Sarkozy changed review comment from: in addition to adult-onset LGMD R21 (OMIM# 617232), biallelic variants in POGLUT1 gene have been reported in one patient with congenital muscular dystrophy and in two further patients with onset before 3 years of age. The presenting symptom were hypotonia with lower limb proximal weakness after gait acquisition, and further progression with mild weakness, wasting and contractures of the upper limbs, mild facial weakness, ptosis, and nasal voice. weakness was more severe and had faster progression compared to later onset patients. Muscle biopsies shows evidence of α-dystroglycan hypoglycosylation. POGLUT1 activity is critical for the Notch signaling pathway, as JAG2. Inview of these evidences, this gene should be considered green for CMD panel as well, in addition to LGMD panel.; to: in addition to adult-onset LGMD R21 (OMIM# 617232), biallelic variants in POGLUT1 gene have been reported in one patient with congenital muscular dystrophy and in two further patients with onset before 3 years of age. The presenting symptom were hypotonia with lower limb proximal weakness after gait acquisition, and further progression with mild weakness, wasting and contractures of the upper limbs, mild facial weakness, ptosis, and nasal voice. weakness was more severe and had faster progression compared to later onset patients. Muscle biopsies show evidence of α-dystroglycan hypoglycosylation. POGLUT1 activity is critical for the Notch signalling pathway, as JAG2. In view of these evidences, this gene should be considered green for CMD panel as well, in addition to LGMD panel.
Congenital muscular dystrophy v2.31 POGLUT1 Anna Sarkozy reviewed gene: POGLUT1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33861953; Phenotypes: muscular dystrophy, secondary alpha-dystroglycanopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.31 JAG2 Anna Sarkozy reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: Other; Publications: 33861953; Phenotypes: muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.93 KY Anna Sarkozy edited their review of gene: KY: Added comment: Two brothers reported with homozygous c405 C > A (pY135*) nonsense mutation in the KY (Kyphoscoliosis peptidase) gene encoding the KY protein. the phenotype is myopathic, with prenatal onset, progressive muscle weakness and atrophy in limbs, face and tongue, contractures and rigid spine. CK is elevated. Muscle biopsy showed Cores and absence of the mutant protein.; Changed mode of pathogenicity: Other
Congenital myopathy v2.93 TNNC2 Anna Sarkozy reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Arrhythmogenic right ventricular cardiomyopathy v2.18 RYR2 Matthew Edwards Deleted their review
Congenital muscular dystrophy v2.31 HNRNPA2B1 Anna Sarkozy edited their review of gene: HNRNPA2B1: Added comment: ten independent families reported with a severe, progressive muscular dystrophy with early onset, and de novo frameshift variants in this gene. phenotype is caractherised by symptoms onset before 2 years of age with severe respiratory insufficiency, delayed motor milestones, ptosis and ophthalmoplegia, axial weakness, progressive proximal and distal weakness. Creatine kinase levels were elevated. Disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and alter the nucleocytoplasmic transport dynamics. in view of this evidence this gene should be upgraded to green; Changed publications to: 35484142; Changed phenotypes to: early-onset oculopharyngeal muscular dystrophy, muscular dystrophy, congenital myopathy
Congenital muscular dystrophy v2.31 GGPS1 Anna Sarkozy reviewed gene: GGPS1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35869884, 32403198; Phenotypes: GGPS1-associated muscular dystrophy with and without hearing loss.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.31 DPM3 Anna Sarkozy reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 19576565, 35932216, 33200426, 31266720; Phenotypes: Congenital muscular dystrophy, secondary alpha-dystroglycanopathy, limb girdle muscular dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.93 UNC45B Anna Sarkozy reviewed gene: UNC45B: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33217308, 31852522, 35292251; Phenotypes: congenital myopathy, progressive myopathy with eccentric cores, core myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Classified gene: RPS6KB1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update (5 unrelated cases plus functional data)
Hypertrophic cardiomyopathy v2.44 RPS6KB1 Arina Puzriakova Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy v2.43 RPS6KB1 Arina Puzriakova gene: RPS6KB1 was added
gene: RPS6KB1 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
Q4_22_promote_green tags were added to gene: RPS6KB1.
Mode of inheritance for gene: RPS6KB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPS6KB1 were set to 34916228
Phenotypes for gene: RPS6KB1 were set to Hypertrophic cardiomyopathy
Review for gene: RPS6KB1 was set to GREEN
Added comment: Jain et al. 2022 (PMID: 34916228) reported on two unrelated HCM families with the same heterozygous missense RPS6KB1 variant (p.G47W), and subsequently three further unrelated probands with HCM harbouring distinct heterozygous variants (p.Q49K, p.Y62H, respectively). Variants segregated with disease, were predicted pathogenic by silico analyses and were ultrarare or absent in population databases. Functional studies in the HL-1 (mouse cardiomyocytes) cells showed that the patient-specific RPS6KB1 mutant significantly increased cell size and activated rpS6 and ERK1/2 signalling cascades. The relationship between RPS6KB1 and cardiac hypertrophy has also been explored in feline and mice models (PMID: 15226426; 17976640)
Sources: Literature
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Classified gene: ARSK as Amber List (moderate evidence)
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Added comment: Comment on list classification: Rating Amber awaiting further cases.
Likely inborn error of metabolism v2.329 ARSK Arina Puzriakova Gene: arsk has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Classified gene: ARSK as Amber List (moderate evidence)
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Added comment: Comment on list classification: Rating Amber awaiting further cases.
Skeletal dysplasia v2.224 ARSK Arina Puzriakova Gene: arsk has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.223 ARSK Arina Puzriakova gene: ARSK was added
gene: ARSK was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSK were set to 34916232
Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex
Review for gene: ARSK was set to AMBER
Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities.
Sources: Literature
Likely inborn error of metabolism v2.328 ARSK Arina Puzriakova gene: ARSK was added
gene: ARSK was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSK were set to 34916232
Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex
Review for gene: ARSK was set to AMBER
Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities.
Sources: Literature
Skeletal ciliopathies v1.19 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Childhood onset dystonia, chorea or related movement disorder v1.264 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Neurological ciliopathies v1.33 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Ophthalmological ciliopathies v1.32 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Rare multisystem ciliopathy disorders v1.165 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757 to Joubert syndrome 32, OMIM:617757
Limb disorders v2.84 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Joubert syndrome 32, 617757; Joubert Syndrome with Cranio-facial and Skeletal Defects to Joubert syndrome 32, OMIM:617757
Holoprosencephaly v2.31 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Basal cell nevus syndrome, 109400 to Basal cell nevus syndrome, OMIM:109400
Genodermatoses with malignancies v1.9 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours for rare disease v1.36 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial Tumours Syndromes of the central & peripheral Nervous system v1.14 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174 to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours cancer susceptibility v2.23 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Childhood solid tumours cancer susceptibility v1.21 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Childhood solid tumours v2.36 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Medulloblastoma, desmoplastic, 155255; Basal cell nevus syndrome, 109400; SUFU associated Medulloblastoma to Basal cell nevus syndrome, OMIM:109400; {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Adult solid tumours for rare disease v1.35 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from SUFU associated Medulloblastoma to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Familial Tumours Syndromes of the central & peripheral Nervous system v1.13 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Brain, CNS, and PNS Cancer to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Genodermatoses with malignancies v1.8 SUFU Arina Puzriakova Phenotypes for gene: SUFU were changed from Medulloblastoma; Medulloblastoma, desmoplastic; {Meningioma, familial, susceptibility to}; (originally on Gorlin syndrome gene panel) to {Medulloblastoma}, OMIM:155255; {Meningioma, familial, susceptibility to}, OMIM:607174
Intellectual disability v3.1759 FOXP4 Ian Berry reviewed gene: FOXP4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33110267; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1759 AGO1 Arina Puzriakova Publications for gene: AGO1 were set to 26350204; 30213762; 22495306; 23020937; 25363768; 25356899; 27620904; 29346770; 28135719
Pulmonary arterial hypertension v2.24 ATP13A3 Arina Puzriakova Publications for gene: ATP13A3 were set to 29650961; 30545973
Intellectual disability v3.1758 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to
Severe microcephaly v2.321 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to 25326669; 26968164
Childhood onset hereditary spastic paraplegia v2.152 CTNNB1 Arina Puzriakova Classified gene: CTNNB1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.152 CTNNB1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.152 CTNNB1 Arina Puzriakova Gene: ctnnb1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.151 CTNNB1 Arina Puzriakova gene: CTNNB1 was added
gene: CTNNB1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q4_22_promote_green tags were added to gene: CTNNB1.
Mode of inheritance for gene: CTNNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNNB1 were set to 23033978; 24614104; 25326669; 26968164; 27915094; 34321325
Phenotypes for gene: CTNNB1 were set to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Review for gene: CTNNB1 was set to GREEN
Added comment: Childhood-onset spasticity is a key feature of the neurodevelopmental phenotype caused by pathogenic monoallelic variants in the CTNNB1 gene. Over 15 unrelated cases reported in literature, almost all of which developed spasticity which significantly affected ability to walk.
Sources: Literature
Intellectual disability v3.1757 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Mental retardation, autosomal dominant 19, 615075Colorectal cancer, somatic, 114500Pilomatricoma, somatic, 132600Ovarian cancer, somatic, 167000Hepatocellular carcinoma, somatic, 114550; MENTAL RETARDATION, AUTOSOMAL DOMINANT 19 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Severe microcephaly v2.320 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from primary microcephaly; Mental retardation, autosomal dominant 19, 615075 to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Retinal disorders v2.297 CTNNB1 Arina Puzriakova Phenotypes for gene: CTNNB1 were changed from Exudative vitreoretinopathy 7 617572 to Exudative vitreoretinopathy 7, OMIM:617572
Familial diabetes v1.67 HNF1A Arina Puzriakova Phenotypes for gene: HNF1A were changed from MODY, type III, 600496{Diabetes mellitus, noninsulin-dependent, 2}, 125853{Diabetes mellitus, insulin-dependent}, 222100Hepatic adenoma, somatic, 142330Renal cell carcinoma, 144700Diabetes mellitus, insulin-dependent, 20, 612520; Maturity Onset Diabetes of the Young to Diabetes mellitus, insulin-dependent, 20, OMIM:612520; {Diabetes mellitus, noninsulin-dependent, 2}, OMIM:125853; MODY, type III, OMIM:600496
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.67 HNF1A Arina Puzriakova Phenotypes for gene: HNF1A were changed from MODY, type III, 600496; {Diabetes mellitus, noninsulin-dependent, 2}, 125853; {Diabetes mellitus, insulin-dependent}, 222100; Hepatic adenoma, somatic, 142330; Renal cell carcinoma, 144700; Diabetes mellitus, insulin-dependent, 20, 612520; Maturity Onset Diabetes of the Young; Maturity-onset diabetes of the young (MODY); Maturity-Onset Diabetes Of The Young; MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3; MODY3 to Diabetes mellitus, insulin-dependent, 20, OMIM:612520; {Diabetes mellitus, noninsulin-dependent, 2}, OMIM:125853; MODY, type III, OMIM:600496
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Tag watchlist_moi tag was added to gene: HNF1A.
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous loss-of-function germline variants are thought to be embryonically lethal, however one family including three insulin-treated family members diagnosed with diabetes before 20 years of age was identified by Misra et al. 2020 (PMID: 32001615) with a homozygous hypomorphic variant in the HNF1A gene. This is not yet sufficient to update the MOI but should be noted if further recessive cases are reported in the future.
Monogenic diabetes v2.51 HNF1A Arina Puzriakova Mode of inheritance for gene: HNF1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v2.78 HK1 Arina Puzriakova Classified gene: HK1 as Amber List (moderate evidence)
Optic neuropathy v2.78 HK1 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Optic atrophy identified in 5/7 patients reported to date with HK1-related neurodevelopmental disorder (AD inheritance).
Optic neuropathy v2.78 HK1 Arina Puzriakova Gene: hk1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.77 HK1 Arina Puzriakova Added comment: Comment on mode of inheritance: Setting to 'monoallelic' as this is the appropriate MOI for this panel (MIM# 618547). Incorrect biallelic MOI was copied from ID panel which will be rectified following GMS approval (Q3_22).
Optic neuropathy v2.77 HK1 Arina Puzriakova Mode of inheritance for gene: HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v2.76 HK1 Arina Puzriakova Tag missense was removed from gene: HK1.
Tag Q3_22_MOI was removed from gene: HK1.
Tag Q3_22_NHS_review was removed from gene: HK1.
Tag Q4_22_promote_green tag was added to gene: HK1.
Optic neuropathy v2.76 HK1 Arina Puzriakova Entity copied from Intellectual disability v3.1756
Optic neuropathy v2.76 HK1 Arina Puzriakova gene: HK1 was added
gene: HK1 was added to Optic neuropathy. Sources: Expert Review Green,BRIDGE study SPEED NEURO Tier1 Gene
missense, Q3_22_MOI, Q3_22_NHS_review tags were added to gene: HK1.
Mode of inheritance for gene: HK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HK1 were set to 30778173; 28135719
Phenotypes for gene: HK1 were set to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Penetrance for gene: HK1 were set to Complete
Mode of pathogenicity for gene: HK1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Retinal disorders v2.296 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79, OMIM:617460; retinitis pigmentosa 79,MONDO:0044320 to Retinitis pigmentosa 79, OMIM:617460; Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Intellectual disability v3.1756 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807 to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Hereditary neuropathy or pain disorder v1.105 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neuropathy, hereditary motor and sensory, Russe type, 605285; Hemolytic anemia due to hexokinase deficiency, 235700 to Neuropathy, hereditary motor and sensory, Russe type, OMIM:605285
Hereditary neuropathy v1.457 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neuropathy, hereditary motor and sensory, Russe type, 605285; Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285 to Neuropathy, hereditary motor and sensory, Russe type, OMIM:605285
Rare anaemia v1.46 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from 235700 Hemolytic anemia due to hexokinase deficiency; Hemolytic anemia due to hexokinase deficiency, 235700; 235700 Enzyme Disorder; Hemolytic anemia due to hexokinase deficiency; Enzyme Disorder to Hemolytic anemia due to hexokinase deficiency, OMIM:235700; Enzyme disorder
Cytopenias and congenital anaemias v1.110 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Enzyme Disorder; Hemolytic anemia due to hexokinase deficiency, 235700 to Hemolytic anemia due to hexokinase deficiency, OMIM:235700
Paediatric or syndromic cardiomyopathy v1.82 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from DCM; Iron overload, liver disease, diabetes, hypogonadism; Hypertrophic-hypocontractile cardiomyopathy; Hereditary haemochromatosis Type 1 (Disorder of iron metabolism); Haemochromatosis; Hemochromatosis, 235200; Hemochromatosis; HCM to Hemochromatosis, OMIM:235200; Iron overload, liver disease, diabetes, hypogonadism; Hypertrophic-hypocontractile cardiomyopathy
Undiagnosed metabolic disorders v1.569 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hereditary haemochromatosis Type 1 (Disorder of iron metabolism); Hemochromatosis, 235200 to Hemochromatosis, OMIM:235200; Disorder of iron metabolism
Hypogonadotropic hypogonadism v1.36 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hemochromatosis, 235200 to Hemochromatosis, OMIM:235200
Likely inborn error of metabolism v2.327 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from Hemochromatosis, 235200; Hereditary haemochromatosis Type 1 (Disorder of iron metabolism) to Hemochromatosis, OMIM:235200
Iron metabolism disorders - NOT common HFE mutations v1.36 HFE Arina Puzriakova Phenotypes for gene: HFE were changed from 235200 HEMOCHROMATOSIS, TYPE 1; HFE1; 235200 Hemochromatosis; 235200HEMOCHROMATOSIS, TYPE 1 to Hemochromatosis, OMIM:235200
Fetal anomalies v1.987 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Fetal hydrops; Thalassemia, alpha-, 604131 to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Fetal hydrops v1.57 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from HYDROPS FETALIS, NONIMMUNE, 236750; NIHF; HYDROPS FETALIS, ALPHA-THALASSEMIA-RELATED, INCLUDED; Hemoglobin H disease, nondeletional, 613978; HEMOGLOBIN H HYDROPS FETALIS SYNDROME; Thalassemia, alpha-, 604131; Alpha thalassaemia; Hb H disease to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Rare anaemia v1.45 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Hypochromic microcytic anemia; Heinz body anemia,140700; Globin Disorder; Erythrocytosis; Thalassemia, alpha-, 604131; 604131 Alpha thalassaemia; 60413 Thalassemia, alpha; Hemoglobin H disease, nondeletional, 613978 to Erythrocytosis 7, OMIM:617981; Heinz body anemia, OMIM:140700; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Thalassemia, alpha-, OMIM:604131
Cytopenias and congenital anaemias v1.109 HBA2 Arina Puzriakova Phenotypes for gene: HBA2 were changed from Globin Disorder; Erythrocytosis; Heinz body anemia,140700; Hemoglobin H disease, nondeletional, 613978; Hypochromic microcytic anemia; Thalassemia, alpha-, 60413 to Erythrocytosis 7, OMIM:617981; Heinz body anemia, OMIM:140700; Hemoglobin H disease, deletional and nondeletional, OMIM:613978; Thalassemia, alpha-, OMIM:604131
Rare anaemia v1.44 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from 604131 Thalassemias, alpha; Erythremias, alpha-; Globin Disorder; Methemoglobinemias, alpha-; Heinz body anemias, alpha-, 140700; 604131 Alpha thalassaemia; Hemoglobin H disease, nondeletional, 613978; Thalassemias, alpha-, 604131 to Erythrocytosis 7, OMIM:617981; Heinz body anemias, alpha-, OMIM:140700; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Thalassemias, alpha-, OMIM:604131
Cytopenias and congenital anaemias v1.108 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from Globin Disorder; Erythremias, alpha-; Heinz body anemias, alpha-, 140700; Hemoglobin H disease, nondeletional, 613978; Methemoglobinemias, alpha-; Thalassemias, alpha-, 604131 to Erythrocytosis 7, OMIM:617981; Heinz body anemias, alpha-, OMIM:140700; Hemoglobin H disease, nondeletional, OMIM:613978; Methemoglobinemia, alpha type, OMIM:617973; Thalassemias, alpha-, OMIM:604131
Fetal anomalies v1.986 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from Fetal hydrops; Thalassemia, alpha-, 604131 to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Fetal hydrops v1.56 HBA1 Arina Puzriakova Phenotypes for gene: HBA1 were changed from HYDROPS FETALIS, NONIMMUNE, 236750; NIHF; HYDROPS FETALIS, ALPHA-THALASSEMIA-RELATED, INCLUDED; Hemoglobin H disease, nondeletional, 613978; Hb H disease; HEMOGLOBIN H HYDROPS FETALIS SYNDROME; Thalassemia, alpha-, 604131; Alpha thalassaemia; alpha thalassaemia major; Hb Bart's to Thalassemias, alpha-, OMIM:604131; Fatal hydrops fetalis; Hb Bart syndrome
Hereditary ataxia with onset in adulthood v2.166 GRN Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Multiple cases reported with variable ages of onset but mostly in adulthood. Cerebellar ataxia with cerebellar atrophy on brain MRI is a prominent feature detected in almost all cases with homozygous pathogenic variants in this gene.
Ataxia and cerebellar anomalies - narrow panel v2.309 GRN Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update. Multiple cases reported with variable ages of onset. Cerebellar ataxia with cerebellar atrophy on brain MRI is a prominent feature detected in almost all cases with homozygous pathogenic variants in this gene.
Hereditary ataxia with onset in adulthood v2.166 GRN Arina Puzriakova Entity copied from Neuronal ceroid lipofuscinosis v1.25
Hereditary ataxia with onset in adulthood v2.166 GRN Arina Puzriakova gene: GRN was added
gene: GRN was added to Hereditary ataxia - adult onset. Sources: London North GLH,NHS GMS,Expert Review Amber
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Ataxia and cerebellar anomalies - narrow panel v2.309 GRN Arina Puzriakova Entity copied from Neuronal ceroid lipofuscinosis v1.25
Ataxia and cerebellar anomalies - narrow panel v2.309 GRN Arina Puzriakova gene: GRN was added
gene: GRN was added to Ataxia and cerebellar anomalies - narrow panel. Sources: London North GLH,NHS GMS,Expert Review Amber
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Retinal disorders v2.295 GRN Arina Puzriakova Added comment: Comment on mode of inheritance: Only found evidence of infraclinical lesions of retinal lipofuscinosis detected in heterozygous carriers (PMID: 28404863) and therefore the MOI of 'biallelic' on this panel is correct.
Retinal disorders v2.295 GRN Arina Puzriakova Mode of inheritance for gene: GRN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.295 GRN Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.
Adult onset neurodegenerative disorder v2.295 GRN Arina Puzriakova Mode of inheritance for gene: GRN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset neurodegenerative disorder v2.294 GRN Arina Puzriakova Phenotypes for gene: GRN were changed from Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485 to Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485; Aphasia, primary progressive, OMIM:607485; Ceroid lipofuscinosis, neuronal, 11, OMIM:614706
Adult onset neurodegenerative disorder v2.293 GRN Arina Puzriakova Publications for gene: GRN were set to 20301545; 17923627
Adult onset neurodegenerative disorder v2.292 GRN Arina Puzriakova Tag Q4_22_MOI tag was added to gene: GRN.
Adult onset neurodegenerative disorder v2.292 GRN Arina Puzriakova reviewed gene: GRN: Rating: ; Mode of pathogenicity: None; Publications: 27021778, 28000352, 31855245; Phenotypes: Frontotemporal lobar degeneration with ubiquitin-positive inclusions, OMIM:607485, Aphasia, primary progressive, OMIM:607485, Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Classified gene: GRN as Amber List (moderate evidence)
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Neuronal ceroid lipofuscinosis v1.25 GRN Arina Puzriakova Gene: grn has been classified as Amber List (Moderate Evidence).
Neuronal ceroid lipofuscinosis v1.24 GRN Arina Puzriakova Publications for gene: GRN were set to
Neuronal ceroid lipofuscinosis v1.23 GRN Arina Puzriakova Tag Q4_22_promote_green tag was added to gene: GRN.
Neuronal ceroid lipofuscinosis v1.23 GRN Arina Puzriakova reviewed gene: GRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 22608501, 27021778, 28000352, 28404863, 30922528, 31855245; Phenotypes: Ceroid lipofuscinosis, neuronal, 11, OMIM:614706; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.152 GRN Arina Puzriakova Phenotypes for gene: GRN were changed from CEROID LIPOFUSCINOSIS, NEURONAL, 11, 614706; Eye Disorders to Ceroid lipofuscinosis, neuronal, 11, OMIM:614706
Fetal anomalies v1.985 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Adult onset neurodegenerative disorder v2.292 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Adult onset neurodegenerative disorder v2.291 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691
Ataxia and cerebellar anomalies - narrow panel v2.308 GRM1 Arina Puzriakova commented on gene: GRM1
Intellectual disability v3.1755 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13, 614831; CONGENITAL CEREBELLAR ATAXIA to Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Ataxia and cerebellar anomalies - narrow panel v2.308 GRM1 Arina Puzriakova Tag watchlist_moi tag was added to gene: GRM1.
Hereditary ataxia v1.311 GRM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'biallelic' to 'both mono- and biallelic'. At least two unrelated cases in literature characterised by AD adult-onset ataxia and supported by functional data, plus additional patients mentioned in Tracy Lester patient cohort.
Hereditary ataxia v1.311 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.310 GRM1 Arina Puzriakova reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223, 36140834, 28886343; Phenotypes: Spinocerebellar ataxia 44, OMIM:617691, Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.165 GRM1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel review. At least two unrelated cases in literature characterised by AD adult-onset ataxia and supported by functional data, plus additional patients mentioned in Tracy Lester patient cohort.
Hereditary ataxia with onset in adulthood v2.165 GRM1 Arina Puzriakova Mode of inheritance for gene: GRM1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1754 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia v1.310 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Ataxia and cerebellar anomalies - narrow panel v2.308 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Ataxia and cerebellar anomalies - narrow panel v2.307 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia with onset in adulthood v2.164 GRM1 Arina Puzriakova Publications for gene: GRM1 were set to
Hereditary ataxia with onset in adulthood v2.163 GRM1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: GRM1.
Hereditary ataxia with onset in adulthood v2.163 GRM1 Arina Puzriakova reviewed gene: GRM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22901947, 26308914, 31319223, 36140834, 28886343; Phenotypes: Spinocerebellar ataxia 44, OMIM:617691, Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital adrenal hypoplasia v2.11 CYP11B2 Abhijit Dixit gene: CYP11B2 was added
gene: CYP11B2 was added to Congenital adrenal hypoplasia. Sources: Literature
Mode of inheritance for gene: CYP11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP11B2 were set to 1594605; 8439335; 9360501; 12788848
Phenotypes for gene: CYP11B2 were set to Hypoaldosteronism; Hyponatremia; Hyperkalemia; Increased serum renin; Dehydration; Failure to thrive
Penetrance for gene: CYP11B2 were set to Complete
Review for gene: CYP11B2 was set to GREEN
Added comment: There are numerous reports of aldosterone deficiency as a consequence of biallelic CYP11B2 variants in literature from 1990s onwards. Miao et al. reviewed 45 published cases in 2019 - see PubMed 31302112.
Sources: Literature
Hereditary ataxia v1.309 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Hereditary ataxia with onset in adulthood v2.163 GRM1 Arina Puzriakova Phenotypes for gene: GRM1 were changed from Spinocerebellar ataxia, autosomal recessive 13; Spinocerebellar ataxia 44, 617691, autosomal recessive spinocerebellar ataxia type 13, 614831 to Spinocerebellar ataxia 44, OMIM:617691; Spinocerebellar ataxia, autosomal recessive 13, OMIM:614831
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh commented on gene: STX16: When the copy number coordinates have been established by ClinGen for STX16, this information will be added to the Familial hypoparathyroidism panel
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: STX16.
Tag cnv tag was added to gene: STX16.
Intellectual disability v3.1753 GPHN Arina Puzriakova Publications for gene: GPHN were set to
Likely inborn error of metabolism v2.326 GPHN Arina Puzriakova Publications for gene: GPHN were set to 27604308
Undiagnosed metabolic disorders v1.568 GPHN Arina Puzriakova Publications for gene: GPHN were set to 27604308
Intellectual disability v3.1752 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C to Molybdenum cofactor deficiency C, OMIM:615501
Intellectual disability v3.1751 GPHN Arina Puzriakova Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.603 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C, 615501 to Molybdenum cofactor deficiency C, OMIM:615501
Likely inborn error of metabolism v2.325 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Molybdenum cofactor deficiency C 615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism); epileptic encephalopathy to Molybdenum cofactor deficiency C, OMIM:615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism)
Undiagnosed metabolic disorders v1.567 GPHN Arina Puzriakova Phenotypes for gene: GPHN were changed from Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism); epileptic encephalopathy; Molybdenum cofactor deficiency C 615501 to Molybdenum cofactor deficiency C, OMIM:615501; Mo cofactor deficiency, complementation group C (Disorders of molybdenum cofactor metabolism)
Paediatric disorders - additional genes v1.106 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Right atrial isomerism (Ivemark), 208530; Congenital heart defects, multiple types, 6, 613854 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Fetal anomalies v1.984 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Congenital heart defects, multiple types; Right atrial isomerism (Ivemark) to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Laterality disorders and isomerism v1.54 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Right atrial isomerism, 208530 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530
Familial non syndromic congenital heart disease v1.79 GDF1 Arina Puzriakova Phenotypes for gene: GDF1 were changed from Tetralogy of Fallot; Double-outlet right ventricle, 217095; Right atrial isomerism, 208530; Visceral Heterotaxy, Transposition Of The Great Arteries, Dextro-Looped 3 to Congenital heart defects, multiple types, 6, OMIM:613854; Right atrial isomerism (Ivemark), OMIM:208530; Tetralogy of Fallot; Double-outlet right ventricle; Right atrial isomerism; Visceral Heterotaxy, Transposition Of The Great Arteries
Familial non syndromic congenital heart disease v1.78 GDF1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'monoallelic' only to 'both mono- and biallelic' to maintain consistency with other panels (including GMS) where is was determined that the evidence is sufficient, albeit limited, to justify this MOI.
Familial non syndromic congenital heart disease v1.78 GDF1 Arina Puzriakova Mode of inheritance for gene: GDF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.566 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Arginine:glycine amidinotransferase deficiency (Mitochondrial respiratory chain disorders (caused by nuclear variants only), disorders of creatinine metabolism); Cerebral creatine deficiency syndrome 3, 612718; arginine:glycine amidinotransferase deficiency to Cerebral creatine deficiency syndrome 3, OMIM:612718; Arginine:glycine amidinotransferase deficiency; Mitochondrial respiratory chain disorders (caused by nuclear variants only); Disorders of creatinine metabolism
Fetal anomalies v1.983 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY to Cerebral creatine deficiency syndrome 3, OMIM:612718
Early onset or syndromic epilepsy v2.602 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718 to Cerebral creatine deficiency syndrome 3, OMIM:612718
Intellectual disability v3.1750 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718; ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY (AGAT DEFICIENCY) to Cerebral creatine deficiency syndrome 3, OMIM:612718
Mitochondrial disorders v2.178 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718; arginine:glycine amidinotransferase deficiency to Cerebral creatine deficiency syndrome 3, OMIM:612718
Possible mitochondrial disorder - nuclear genes v1.161 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Cerebral creatine deficiency syndrome 3, 612718 to Cerebral creatine deficiency syndrome 3, OMIM:612718
Renal tubulopathies v2.63 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure (no MIM number); Cerebral creatine deficiency syndrome 3, 612718 (AR) to Fanconi renotubular syndrome 1, OMIM:134600
Unexplained young onset end-stage renal disease v1.42 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure to Fanconi renotubular syndrome 1, OMIM:134600
Tubulointerstitial kidney disease v1.23 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure to Fanconi renotubular syndrome 1, OMIM:134600
Retinal disorders v2.294 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from Macular Degeneration to Macular degeneration, age-related, 3, OMIM:608895; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 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 according to the recommendations from Helen Brittain (Genomics England, Clinical Fellow).
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Helen Brittain (Genomics England, Clinical Fellow) agreed that DAW1 should be green on this panel.
Sources: Literature
Laterality disorders and isomerism v1.53 DAW1 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, according to the recommendations from Helen Brittain (Genomics England, Clinical Fellow).
Hereditary neuropathy or pain disorder v1.104 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to Charcot-Marie-Tooth disease, demyelinating, type 1H, OMIM:619764; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Hereditary neuropathy v1.456 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to Charcot-Marie-Tooth disease, demyelinating, type 1H, OMIM:619764; Neuropathy, hereditary, with or without age-related macular degeneration, OMIM:608895
Fetal anomalies v1.982 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from Cutis laxa 614434; Cutis laxa 219100 to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Rare genetic inflammatory skin disorders v1.55 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Classified gene: FBLN5 as Green List (high evidence)
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Added comment: Comment on list classification: Updating rating from Red to Green to match the rating on the GMS Thoracic aortic aneurysm and dissection (v1.2) panel.
Thoracic aortic aneurysm or dissection v1.126 FBLN5 Arina Puzriakova Gene: fbln5 has been classified as Green List (High Evidence).
Thoracic aortic aneurysm or dissection v1.125 FBLN5 Arina Puzriakova Publications for gene: FBLN5 were set to
Thoracic aortic aneurysm or dissection (GMS) v1.29 FBLN5 Arina Puzriakova Publications for gene: FBLN5 were set to 12189163; 27089918
Thoracic aortic aneurysm or dissection v1.124 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Thoracic aortic aneurysm or dissection (GMS) v1.28 FBLN5 Arina Puzriakova Phenotypes for gene: FBLN5 were changed from to ?Cutis laxa, autosomal dominant 2, OMIM:614434; Cutis laxa, autosomal recessive, type IA, OMIM:219100
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Respiratory ciliopathies including non-CF bronchiectasis v1.61 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.60 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.60 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.59 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Supportive functional studies and a mouse model were also reported in PMID: 36074124.
Sources: Literature
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh Classified gene: DAW1 as Green List (high evidence)
Non-CF bronchiectasis v1.29 DAW1 Sarah Leigh Gene: daw1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.28 DAW1 Sarah Leigh Tag Q4_22_MOI was removed from gene: DAW1.
Tag Q4_22_promote_green was removed from gene: DAW1.
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Classified gene: DAW1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Laterality disorders and isomerism v1.53 DAW1 Sarah Leigh Gene: daw1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.52 DAW1 Sarah Leigh changed review comment from: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature; to: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder. Supportive functional studies and a mouse model were also reported in PMID: 36074124.
Sources: Literature
Non-CF bronchiectasis v1.28 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Non-CF bronchiectasis. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.59 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Laterality disorders and isomerism v1.52 DAW1 Sarah Leigh gene: DAW1 was added
gene: DAW1 was added to Laterality disorders and isomerism. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: DAW1.
Mode of inheritance for gene: DAW1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAW1 were set to 36074124; 28991257
Phenotypes for gene: DAW1 were set to motile ciliopathy laterality disorder
Review for gene: DAW1 was set to GREEN
Added comment: DAW1 is not in OMIM, Gen2Phen or MONDO. PMID: 36074124 reports five variants in four unrelated cases with a motile ciliopathy / laterality disorder.
Sources: Literature
Adult onset leukodystrophy v1.49 ADAR Arina Puzriakova Classified gene: ADAR as Green List (high evidence)
Adult onset leukodystrophy v1.49 ADAR Arina Puzriakova Added comment: Comment on list classification: Could not find any evidence of adult-onset disease in literature. Even in atypically late-onset cases of AGS, symptoms typically begin with the first 5 years of life.
Adult onset leukodystrophy v1.49 ADAR Arina Puzriakova Gene: adar has been classified as Green List (High Evidence).
Adult onset leukodystrophy v1.48 ADAR Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: ADAR.
Intellectual disability v3.1749 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Dyschromatosis symmetrica hereditaria, 127400Aicardi-Goutieres syndrome 6, 615010; DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Childhood onset dystonia, chorea or related movement disorder v1.263 ADAR Arina Puzriakova Tag Q4_22_MOI tag was added to gene: ADAR.
Early onset dystonia v1.130 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Early onset dystonia v1.129 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic only to both mono- and biallelic.

Dystonia is an established feature of AGS6 (MIM# 615010) associated with AR variants in this gene. Overall the AD condition (dyschromatosis symmetrica hereditaria, MIM# 127400) often presents with changes in skin pigmentation as the only sign of disease. However, there have also been reports of neurologic deficits including ID, developmental regression, brain calcification, seizures and dystonia in some affected individuals, particularly with the Gly1007Arg variant (PMID: 16225627; 16817193; 19017046). Although the penetrance of extracutaneous features is reduced, there is value in testing heterozygous ADAR variants on these panels to ensure syndromic cases are not missed if not tested in the context of the skin phenotype.
Early onset dystonia v1.129 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.263 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from biallelic only to both mono- and biallelic at the next GMS panel update.

Dystonia is an established feature of AGS6 (MIM# 615010) associated with AR variants in this gene. Overall the AD condition (dyschromatosis symmetrica hereditaria, MIM# 127400) often presents with changes in skin pigmentation as the only sign of disease. However, there have also been reports of neurologic deficits including ID, developmental regression, brain calcification, seizures and dystonia in some affected individuals, particularly with the Gly1007Arg variant (PMID: 16225627; 16817193; 19017046). Although the penetrance of extracutaneous features is reduced, there is value in testing heterozygous ADAR variants on these panels to ensure syndromic cases are not missed if not tested in the context of the skin phenotype.
Childhood onset dystonia, chorea or related movement disorder v1.263 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1748 ADAR Arina Puzriakova reviewed gene: ADAR: Rating: ; Mode of pathogenicity: None; Publications: 16225627, 16817193, 19017046; Phenotypes: Aicardi-Goutieres syndrome 6, OMIM:615010, Dyschromatosis symmetrica hereditaria, OMIM:127400; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.262 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Early onset or syndromic epilepsy v2.601 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Inherited white matter disorders v1.163 ADAR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from both mono- and biallelic to biallelic only. Monoallelic variants have been linked to brain calcification in AD disease (MIM# 127400) with neurological symptoms, however, white matter abnormalities were not reported.
Inherited white matter disorders v1.163 ADAR Arina Puzriakova Mode of inheritance for gene: ADAR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.162 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Aicardi-Goutieres syndrome 6, OMIM:615010; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Intracerebral calcification disorders v1.35 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6; Aicardi-Goutieres syndrome; Aicardi-Goutières, isolated spasticity, bilateral striatal necrosis to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Adult onset leukodystrophy v1.48 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
White matter disorders and cerebral calcification - narrow panel v1.246 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres Syndrome; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Aicardi-Goutieres syndrome; Aicardi-Gouti res, isolated spasticity, bilateral striatal necrosis; Aicardi-Goutieres syndrome 6 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Retinal disorders v2.293 COQ5 Sarah Leigh Classified gene: COQ5 as Amber List (moderate evidence)
Retinal disorders v2.293 COQ5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated amber.
Retinal disorders v2.293 COQ5 Sarah Leigh Gene: coq5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.292 COQ5 Sarah Leigh gene: COQ5 was added
gene: COQ5 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: COQ5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ5 were set to 36266294
Phenotypes for gene: COQ5 were set to ?Coenzyme Q10 deficiency, primary, 9, OMIM:619028; coenzyme q10 deficiency, primary, 9, MONDO:0033615
Review for gene: COQ5 was set to AMBER
Added comment: Associated with Coenzyme Q10 deficiency, primary, 9, OMIM:619028 and as limited Gen2Phen gene for this condition. PMID: 36266294 reports three variants in two unrelated cases with retinitis pigmentosa.
Sources: Literature
Retinal disorders v2.291 COQ4 Sarah Leigh gene: COQ4 was added
gene: COQ4 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to 36266294
Phenotypes for gene: COQ4 were set to Coenzyme Q10 deficiency, primary, 7, OMIM:616276; neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome, MONDO:0014562
Review for gene: COQ4 was set to RED
Added comment: Associated with Coenzyme Q10 deficiency, primary, 7, OMIM:616276 and as strong Gen2Phen gene for this condition. PMID: 36266294 reports two variants in a case with retinitis pigmentosa.
Sources: Literature
Retinal disorders v2.290 COQ2 Sarah Leigh Classified gene: COQ2 as Amber List (moderate evidence)
Retinal disorders v2.290 COQ2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.290 COQ2 Sarah Leigh Gene: coq2 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.289 COQ2 Sarah Leigh gene: COQ2 was added
gene: COQ2 was added to Retinal disorders. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: COQ2.
Mode of inheritance for gene: COQ2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ2 were set to 36266294
Phenotypes for gene: COQ2 were set to Coenzyme Q10 deficiency, primary, 1, OMIM:607426; coenzyme Q10 deficiency, primary, 1, MONDO:0011829
Review for gene: COQ2 was set to GREEN
Added comment: Associated with Coenzyme Q10 deficiency, primary, 1, OMIM:607426 and as definitive Gen2Phen gene for this condition. PMID: 36266294 reports four variants in three unrelated cases with retinitis pigmentosa.
Sources: Literature
Structural basal ganglia disorders v1.33 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Likely inborn error of metabolism v2.324 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Fetal anomalies v1.981 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from DYSCHROMATOSIS SYMMETRICA HEREDITARIA 1; AICARDI-GOUTIERES SYNDROME ASSOCIATED WITH A TYPE I INTERFERON SIGNATURE to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Undiagnosed metabolic disorders v1.565 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6 615010; Dyschromatosis symmetrica hereditaria 127400 to Aicardi-Goutieres syndrome 6, OMIM:615010; Dyschromatosis symmetrica hereditaria, OMIM:127400
Adult onset neurodegenerative disorder v2.290 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010; dystonia to Aicardi-Goutieres syndrome 6, OMIM:615010
Adult onset hereditary spastic paraplegia v1.103 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 autosomal recessive; Dyschromatosis symmetrica hereditaria, autosomal dominant, 127400 to Aicardi-Goutieres syndrome 6, OMIM:615010
Childhood onset hereditary spastic paraplegia v2.150 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Hereditary spastic paraplegia v1.296 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Aicardi-Goutieres syndrome 6, 615010 to Aicardi-Goutieres syndrome 6, OMIM:615010
Primary immunodeficiency or monogenic inflammatory bowel disease v2.580 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; AGS6; Type 1 interferonopathies; Classical AGS, BSN, SP; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders
COVID-19 research v1.133 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders
Pigmentary skin disorders v1.53 ADAR Arina Puzriakova Phenotypes for gene: ADAR were changed from AGS6; DYSCHROMATOSIS SYMMETRICA HEREDITARIA; DSH, AICARDI-GOUTIERES SYNDROME 6; Dyschromatosis symmetrica hereditaria (AKA reticulate acropigmentation of Dohi) to Dyschromatosis symmetrica hereditaria, OMIM:127400; Aicardi-Goutieres syndrome 6, OMIM:615010
Pigmentary skin disorders v1.52 ADAR Arina Puzriakova Publications for gene: ADAR were set to 12916015; 23001123
Retinal disorders v2.288 PDSS1 Sarah Leigh Classified gene: PDSS1 as Amber List (moderate evidence)
Retinal disorders v2.288 PDSS1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Retinal disorders v2.288 PDSS1 Sarah Leigh Gene: pdss1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.287 PDSS1 Sarah Leigh gene: PDSS1 was added
gene: PDSS1 was added to Retinal disorders. Sources: Literature
Q4_22_MOI, Q4_22_promote_green tags were added to gene: PDSS1.
Mode of inheritance for gene: PDSS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDSS1 were set to 36266294
Phenotypes for gene: PDSS1 were set to Coenzyme Q10 deficiency, primary, 2, OMIM:614651; deafness-encephaloneuropathy-obesity-valvulopathy syndromeMONDO:0013837
Review for gene: PDSS1 was set to GREEN
Added comment: Associated with Coenzyme Q10 deficiency, primary, 2, OMIM:614651 and as strong Gen2Phen gene for this condition. PMID: 36266294 reports nine variants in six unrelated cases with retinitis pigmentosa.
Sources: Literature
Intellectual disability v3.1748 FBXW7 Julia Baptista reviewed gene: FBXW7: Rating: GREEN; Mode of pathogenicity: None; Publications: 35395208; Phenotypes: developmental delay, ID, language disorder, hypotonia, brain anomalies, gastrointestinal issues; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1748 ACOX1 Arina Puzriakova Added comment: Comment on mode of inheritance: Adding 'watchlist_moi' tag to monitor for evidence supporting association of monoallelic variants in this gene with ID. To date, three unrelated cases have been reported (PMID: 32169171) with dominant variants. Two patients had impaired cognition while one remained cognitively intact. These cases should be picked up via other routes (neuropathy, hearing loss) but monitoring evidence pertaining to monoallelic variants may be of value.
Intellectual disability v3.1748 ACOX1 Arina Puzriakova Mode of inheritance for gene: ACOX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1747 ACOX1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ACOX1.
Likely inborn error of metabolism v2.323 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Tag Q4_22_MOI was removed from gene: ACOX1.
Intellectual disability v3.1747 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, 264470; ADRENOLEUKODYSTROPHY PSEUDONEONATAL (PSEUDO-NALD) to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v2.600 ACOX1 Arina Puzriakova Publications for gene: ACOX1 were set to 18536048
Likely inborn error of metabolism v2.322 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Early onset or syndromic epilepsy v2.599 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960
Inherited white matter disorders v1.161 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960; General Leukodystrophy & Mitochondrial Leukoencephalopathy
White matter disorders and cerebral calcification - narrow panel v1.245 ACOX1 Arina Puzriakova Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470; Mitchell syndrome, OMIM:618960; General Leukodystrophy & Mitochondrial Leukoencephalopathy
Intellectual disability v3.1746 ADAR Tracy Lester reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1746 BAP1 Rachel Challis gene: BAP1 was added
gene: BAP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAP1 were set to 35051358
Phenotypes for gene: BAP1 were set to Intellectual disability; short stature; autism spectrum disorder
Review for gene: BAP1 was set to GREEN
gene: BAP1 was marked as current diagnostic
Added comment: 11 de novo BAP1 missense variants identified predominantly in UCH domain. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. Analysis of blood from affected patients demonstrated impaired H2A deubiquitination compared to controls.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.579 RANBP2 Dmitrijs Rots reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35748970, 25522933, 29687329, 30796099, 35381605; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1746 YARS Dmitrijs Rots changed review comment from: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.; to: 12 patients with homozygous p.(Arg367Trp) have distinct NDD reported in PMID: 34536092.
Intellectual disability v3.1746 YARS Dmitrijs Rots reviewed gene: YARS: Rating: ; Mode of pathogenicity: None; Publications: PMID: 34536092; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.51 NODAL Arina Puzriakova commented on gene: NODAL
Fetal anomalies v1.980 EDA Eleanor Williams Tag Q3_22_expert_review was removed from gene: EDA.
Neonatal cholestasis v1.26 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neonatal cholestasis v1.25 GNAS Sarah Leigh Deleted their comment
Neonatal cholestasis v1.25 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: this gene is imprinted, but maternal and paternal alleles are imprinted in different conditions
Neonatal cholestasis v1.25 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.222 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Skeletal dysplasia v2.222 GNAS Sarah Leigh edited their review of gene: GNAS: Added comment: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Skeletal dysplasia panel is representing various phenotypes, the MOI has been set to monoallelic, imprinted status unknown.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.222 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia 103580; Pseudopseudohypoparathyroidism 612463; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ib 603233; Pseudohypoparathyroidism Ic 612462; ACTH-independent macronodular adrenal hyperplasia 219080 IC; McCune-Albright syndrome, somatic, mosaic 174800 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Congenital hypothyroidism v2.13 GNAS Sarah Leigh changed review comment from: Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal allele. Therefore, the mode of inheritance for GNAS in this panel should be monoallelic maternally imprinted.; to: Pseudohypothyroidism Ia & Ic are caused by GNAS variants arising in the maternal alleles, therefore the paternal alleles are imprinted. In Pseudohypothyroidism Ib the imprinting of the maternal allele is disrupted by deletions in STX16. Therefore, the mode of inheritance for GNAS in this panel should be monoallelic, imprinted status unknown as either allele could be imprinted.
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: FASTKD2.
Fetal anomalies v1.980 EDA Eleanor Williams Tag Q3_22_expert_review tag was added to gene: EDA.
Congenital hypothyroidism v2.13 GNAS Sarah Leigh edited their review of gene: GNAS: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Classified gene: KIF24 as Amber List (moderate evidence)
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update, on the basis of three unrelated cases harbouring distinct biallelic variants in this gene, all presenting with variable skeletal manifestations.
Skeletal dysplasia v2.221 KIF24 Arina Puzriakova Gene: kif24 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.220 KIF24 Arina Puzriakova gene: KIF24 was added
gene: KIF24 was added to Skeletal dysplasia. Sources: Literature
Q4_22_promote_green tags were added to gene: KIF24.
Mode of inheritance for gene: KIF24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF24 were set to 35748595
Phenotypes for gene: KIF24 were set to Skeletal dysplasia
Review for gene: KIF24 was set to GREEN
Added comment: Reilly et al., 2022 (PMID: 35748595) identified six individuals from three unrelated families affected by a spectrum of skeletal abnormalities ranging from a lethal fetal skeletal ciliopathy to acromesomelic skeletal dysplasia and a less severe spondylometaphyseal dysplasia. All subjects harboured different biallelic missense variants in KIF24 which segregated with the phenotype. In vitro studies showed that ciliogenesis and cytokinesis were severely affected in amnioblasts of one affected fetus.
Sources: Literature
Severe early-onset obesity v2.52 GNAS Sarah Leigh reviewed gene: GNAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v2.52 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Congenital Obesity; Pseudohypoparathyroidism Ia, OMIM:103580; Pseudohypoparathyroidism Ib, OMIM:603233; Pseudohypoparathyroidism Ic, OMIM:612462 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Severe early-onset obesity v2.51 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Neurofibromatosis Type 1 v1.32 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168 to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Neurofibromatosis Type 1 v1.31 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome, 174800; Pseudohypoparathyroidism Ia to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Neurofibromatosis Type 1 v1.30 GNAS Sarah Leigh Publications for gene: GNAS were set to 1944469,1594625
Fetal anomalies v1.980 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; progressive osseous heteroplasia, MONDO:0008153; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Mosaic skin disorders - deep sequencing v1.24 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from McCune-Albright syndrome to McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168
Limb disorders v2.83 GNAS Sarah Leigh Tag mosaicism tag was added to gene: GNAS.
Tag Q4_22_MOI tag was added to gene: GNAS.
Limb disorders v2.83 GNAS Sarah Leigh edited their review of gene: GNAS: Added comment: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Limb disorders panel is encompassing various phenotypes, the MOI should been set to monoallelic, imprinted status unknown.; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.83 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from ACTH-independent macronodular adrenal hyperplasia 219080 IC; McCune-Albright syndrome, somatic, mosaic 174800; Osseous heteroplasia, progressive 166350; Pseudohypoparathyroidism Ia 103580; Pseudohypoparathyroidism Ib 603233; Pseudohypoparathyroidism Ic 612462; Pseudopseudohypoparathyroidism 612463 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Intellectual disability v3.1746 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580McCune-Albright syndrome, 174800Pseudohypoparathyroidism Ic, 612462Osseous heteroplasia, progressive, 166350Pseudohypoparathyroidism Ib, 603233Prolonged bleeding time, brachydactyly and mental retardationAcromegaly, 102200Pseudopseudohypoparathyroidism, 612463Prolonged bleeding time, brachydactyly, and mental retardationACTH-independent macronodular adrenal hyperplasia, 219080; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA (AIMAH) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Fetal anomalies v1.979 DMPK Eleanor Williams Tag Q3_21_expert_review tag was added to gene: DMPK.
Intellectual disability v3.1745 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 is associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in this condition should be monoallelic paternally imprinted. Because intellectual disability is seen in these phenotypes, the MOI has been set to monoallelic, imprinted status unknown.
Intellectual disability v3.1745 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.979 GNAS Sarah Leigh Added comment: Comment on mode of inheritance: Disease causing variants in the GNAS locus have differing expression panels. Pseudohypothyroidism Ia, Ib & Ic are all caused by GNAS variants arising in the maternal alleles, therefore, the mode of inheritance (MOI) for GNAS in these conditions should be monoallelic maternally imprinted. Pseudopseudohypoparathyroidism, OMIM:612463 and Osseous heteroplasia, progressive, OMIM:166350 are associated with variants in the paternal alleles therefore, the mode of inheritance for GNAS in these conditions should be monoallelic paternally imprinted. Because the Fetal anomalies panel is representing various phenotypes, the MOI has been set to monoallelic, imprinted status unknown.
Fetal anomalies v1.979 GNAS Sarah Leigh Mode of inheritance for gene: GNAS was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.978 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from GNAS HYPERFUNCTION; ALBRIGHT HEREDITARY OSTEODYSTROPHY; ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; PSEUDOHYPOPARATHYROIDISM TYPE 1B to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911; McCune-Albright syndrome, somatic, mosaic, OMIM:174800; panostotic fibrous dysplasia, MONDO:0043168; Osseous heteroplasia, progressive, OMIM:166350; ACTH-independent macronodular adrenal hyperplasia. OMIM:219080; ACTH-independent macronodular adrenal hyperplasia 1, MONDO:0020735; Pseudopseudohypoparathyroidism, OMIM:612463; pseudopseudohypoparathyroidism, MONDO:0012912
Congenital hypothyroidism v2.13 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:00 to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:0012911
Congenital hypothyroidism v2.12 GNAS Sarah Leigh Tag Q4_22_MOI tag was added to gene: GNAS.
Congenital hypothyroidism v2.12 GNAS Sarah Leigh reviewed gene: GNAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Tag Q4_22_MOI tag was added to gene: STX16.
Tag Q4_22_promote_green tag was added to gene: STX16.
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh edited their review of gene: STX16: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Classified gene: STX16 as Amber List (moderate evidence)
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Familial hypoparathyroidism v2.7 STX16 Sarah Leigh Gene: stx16 has been classified as Amber List (Moderate Evidence).
Familial hypoparathyroidism v2.6 STX16 Sarah Leigh Entity copied from Genomic imprinting v0.147
Familial hypoparathyroidism v2.6 STX16 Sarah Leigh gene: STX16 was added
gene: STX16 was added to Familial hypoparathyroidism. Sources: Literature
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STX16 were set to 14561710; 15579741; 15800843; 33320452; 32337648; 35119251
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB OMIM:603233; pseudohypoparathyroidism type 1B:MONDO:0011301
Proteinuric renal disease v2.77 EMP2 Eleanor Williams Tag Q2_22_expert_review tag was added to gene: EMP2.
Childhood onset dystonia, chorea or related movement disorder v1.261 AP1S2 Arina Puzriakova changed review comment from: 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.; to: 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 it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Intellectual disability v3.1744 AP1S2 Arina Puzriakova changed review comment from: 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.; to: 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 it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Hydrocephalus v2.132 AP1S2 Arina Puzriakova changed review comment from: 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.; to: 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 it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Fetal anomalies v1.977 AP1S2 Arina Puzriakova changed review comment from: 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.; to: 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 it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease).
Ichthyosis and erythrokeratoderma v1.73 TRPV3 Eleanor Williams commented on gene: TRPV3
Ichthyosis and erythrokeratoderma v1.73 TRPV3 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: TRPV3.
Adult onset neurodegenerative disorder v2.289 STUB1 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: STUB1.
Adult onset neurodegenerative disorder v2.289 STUB1 Eleanor Williams commented on gene: STUB1
Adult onset neurodegenerative disorder v2.289 STUB1 Eleanor Williams Mode of inheritance for gene: STUB1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.288 STUB1 Eleanor Williams Tag Q3_22_rating tag was added to gene: STUB1.
Tag Q3_22_MOI tag was added to gene: STUB1.
Adult onset neurodegenerative disorder v2.288 STUB1 Eleanor Williams Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.287 STUB1 Eleanor Williams Tag Q3_22_rating was removed from gene: STUB1.
Tag Q3_22_MOI was removed from gene: STUB1.
Adult onset neurodegenerative disorder v2.287 STUB1 Eleanor Williams Tag Q3_22_rating tag was added to gene: STUB1.
Intellectual disability v3.1744 ROR2 Arina Puzriakova Classified gene: ROR2 as Green List (high evidence)
Intellectual disability v3.1744 ROR2 Arina Puzriakova Added comment: Comment on list classification: Following a Red review by Tracy Lester (Genetics laboratory, Oxford UK) this gene was re-curated showing the neurocognitive function in patients with monoallelic and biallelic variants is typically normal. Cases are more likely to be picked up via skeletal abnormalities route. Therefore, ROR2 should be downgraded to Red on this panel at the next GMS panel update.
Intellectual disability v3.1744 ROR2 Arina Puzriakova Gene: ror2 has been classified as Green List (High Evidence).
Intellectual disability v3.1743 ROR2 Arina Puzriakova Tag Q4_22_demote_red tag was added to gene: ROR2.
Tag Q4_22_NHS_review tag was added to gene: ROR2.
DDG2P v2.83 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROBINOW SYNDROME, AUTOSOMAL DOMINANT 180700; BRACHYDACTYLY, TYPE B1 113000; ROR2-RELATED DISORDERS AR 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Fetal anomalies v1.977 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROR2-RELATED DISORDERS AR; BRACHYDACTYLY, TYPE B1; ROBINOW SYNDROME, AUTOSOMAL DOMINANT to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Skeletal dysplasia v2.219 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Brachydactyly, type B1 113000; Robinow syndrome, autosomal recessive 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Intellectual disability v3.1743 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from BRACHYDACTYLY, TYPE B1 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
Limb disorders v2.82 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Brachydactyly, type B1 113000; Robinow syndrome, autosomal recessive 268310 to Brachydactyly, type B1, OMIM:113000 (AD); Robinow syndrome, autosomal recessive, OMIM:268310 (AR)
IUGR and IGF abnormalities v1.54 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from Robinow to Robinow syndrome, autosomal recessive, OMIM:268310
Clefting v2.71 ROR2 Arina Puzriakova Phenotypes for gene: ROR2 were changed from ROBINOW SYNDROME, AUTOSOMAL RECESSIVE; RRS to Robinow syndrome, autosomal recessive, OMIM:268310
Fetal anomalies v1.976 COL1A2 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: COL1A2.
Congenital hypothyroidism v2.12 GNAS Sarah Leigh Phenotypes for gene: GNAS were changed from Pseudohypoparathyroidism Ia, 103580 (Hypothyroidism) to Pseudohypoparathyroidism Ia, OMIM:103580; pseudohypoparathyroidism type 1A, MONDO:0007078; Pseudohypoparathyroidism Ib, OMIM:603233; pseudohypoparathyroidism type 1B, MONDO:0011301; Pseudohypoparathyroidism Ic, OMIM:612462; pseudohypoparathyroidism type 1C, MONDO:00
Early onset or syndromic epilepsy v2.598 CLPB Eleanor Williams Tag Q3_21_MOI was removed from gene: CLPB.
Tag Q3_22_MOI tag was added to gene: CLPB.
Pigmentary skin disorders v1.51 GNAS Sarah Leigh Tag mosaicism tag was added to gene: GNAS.
Pigmentary skin disorders v1.51 GNAS Sarah Leigh Tag somatic tag was added to gene: GNAS.
Cerebral vascular malformations v2.63 SETD5 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: SETD5.
Cerebral vascular malformations v2.63 CNOT3 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: CNOT3.
Cerebral vascular malformations v2.63 CHD4 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: CHD4.
Rare anaemia v1.43 RHAG Arina Puzriakova Phenotypes for gene: RHAG were changed from Anemia, hemolytic, Rh-null, regulator type (BIALLELIC, autosomal or pseudoautosomal), 268150; 268150 Anemia, hemolytic, Rh-null, regulator type; Overhydrated hereditary stomatocytosis (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 185000; 185000 Overhydrated hereditary stomatocytosis; Stomatocytosis to Anemia, hemolytic, Rh-null, regulator type, OMIM:268150 (AR); Overhydrated hereditary stomatocytosis, OMIM:185000 (AD)
Cytopenias and congenital anaemias v1.107 RHAG Arina Puzriakova Phenotypes for gene: RHAG were changed from Stomatocytosis; Overhydrated hereditary stomatocytosis (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 185000; Anemia, hemolytic, Rh-null, regulator type (BIALLELIC, autosomal or pseudoautosomal), 268150 to Anemia, hemolytic, Rh-null, regulator type, OMIM:268150 (AR); Overhydrated hereditary stomatocytosis, OMIM:185000 (AD)
Intellectual disability v3.1742 PDZD8 Eleanor Williams commented on gene: PDZD8
Intellectual disability v3.1742 PDZD8 Eleanor Williams Tag Q3_22_MOI was removed from gene: PDZD8.
Intellectual disability v3.1742 NRCAM Eleanor Williams commented on gene: NRCAM
Intellectual disability v3.1742 NRCAM Eleanor Williams Tag Q3_22_MOI was removed from gene: NRCAM.
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh edited their review of gene: CNOT3: Changed rating: AMBER
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh changed review comment from: Green rating recommended based on four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) with CNOT3 variants reported in PMID: 31474762, all of these cases had features of moyamoya disease.; to: After consultation with Helen Brittain (Clinical Fellow, Genomics England), SETD5 has been given an amber rating as the evidence of association was from a single publication. PMID: 31474762 reported CNOT3 variants in four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672), all of these cases had features of moyamoya disease.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh changed review comment from: Comment on list classification: Moyamoya disease MONDO:0016820 is relevant to this panel - Cerebral vascular malformations.
PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).; to: Comment on list classification: After consultation with Helen Brittain (Clinical Fellow, Genomics England), CHD4 has been given an amber rating, as the clinical features of the cases reported may not be relevant to this panel. PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh edited their review of gene: CHD4: Changed rating: AMBER
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Deleted their comment
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh changed review comment from: Amber rating based on SETD5 variants reported in PMID: 24680889, 2302093, 25138099 & 31474762. There was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.; to: After consultation with Helen Brittain (Clinical Fellow, Genomics England), SETD5 has been given an amber rating. SETD5 variants were reported in PMID: 24680889, 2302093, 25138099 & 31474762, but there was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.
Intellectual disability v3.1742 DOCK8 Eleanor Williams Tag Q3_22_MOI tag was added to gene: DOCK8.
Intellectual disability v3.1742 DOCK8 Eleanor Williams Tag Q3_22_MOI was removed from gene: DOCK8.
Intellectual disability v3.1742 CHKA Eleanor Williams commented on gene: CHKA
Intellectual disability v3.1742 CHKA Eleanor Williams Tag Q3_22_MOI was removed from gene: CHKA.
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams changed review comment from: Removed the Q3_22_MOI tag as the MOI has been proposed to be Monoallelic by all.; to: Removed the Q3_22_MOI tag as the MOI has been proposed to be Monoallelic by all reviewers
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams commented on gene: ATP6V0A1
Intellectual disability v3.1742 ATP6V0A1 Eleanor Williams Tag Q3_22_MOI was removed from gene: ATP6V0A1.
Cerebral vascular malformations v2.63 CNOT3 Sarah Leigh edited their review of gene: CNOT3: Added comment: Green rating recommended based on four unrelated cases of Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) with CNOT3 variants reported in PMID: 31474762, all of these cases had features of moyamoya disease.; Changed rating: GREEN
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh edited their review of gene: CHD4: Added comment: Green recommendation based on seven unrelated cases of Sifrim-Hitz-Weiss syndrome (OMIM:617159) with CHD4 variants reported in PMID: 31474762, who all had ischemic stroke due to bilateral moyamoya angiopathy.; Changed rating: GREEN
Inherited bleeding disorders v1.174 SERPINC1 Arina Puzriakova Phenotypes for gene: SERPINC1 were changed from Antithrombin deficiency; Thrombophilia due to antithrombin III deficiency 613118; Antithrombin III Deficiency; Antithrombin-III Deficiency to Thrombophilia due to antithrombin III deficiency, OMIM:613118
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh edited their review of gene: SETD5: Changed rating: AMBER
Cerebral vascular malformations v2.63 SETD5 Sarah Leigh edited their review of gene: SETD5: Added comment: Amber rating based on SETD5 variants reported in PMID: 24680889, 2302093, 25138099 & 31474762. There was insufficient clinical data to classify the cases reported as having features of Moyamoya disease.; Changed rating: GREEN
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Classified gene: HK1 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Added comment: Comment on list classification: Recommended for GREEN rating following GMS review. Sufficient cases. The paper has not yet been published but has been accepted for publication. Note that the variants are in a non-coding region and therefore may not be prioritised by tiering in the current Genomics England pipeline.
Congenital hyperinsulinism v2.30 HK1 Eleanor Williams Gene: hk1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Classified gene: ZNF808 as Amber List (moderate evidence)
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for GREEN rating following GMs review. Paper not yet published but from GLH source.
Neonatal diabetes v2.60 ZNF808 Eleanor Williams Gene: znf808 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.63 SETD5 Eleanor Williams Tag Q3_22_expert_review was removed from gene: SETD5.
Cerebral vascular malformations v2.63 CNOT3 Eleanor Williams Tag Q3_22_expert_review was removed from gene: CNOT3.
Cerebral vascular malformations v2.63 CHD4 Eleanor Williams Tag Q3_22_expert_review was removed from gene: CHD4.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to CHD4 variants.
Cerebral vascular malformations v2.63 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946 to Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.62 CNOT3 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to CNOT3 variants.
Cerebral vascular malformations v2.62 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864 to Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Cerebral vascular malformations v2.61 SETD5 Sarah Leigh Added comment: Comment on phenotypes: Moyamoya disease MONDO:0016820 is not specific to SETD5 variants.
Cerebral vascular malformations v2.61 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336 to Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Primary immunodeficiency or monogenic inflammatory bowel disease v2.579 TCF3 Arina Puzriakova Phenotypes for gene: TCF3 were changed from Agammaglobulinemia; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency; Recurrent bacterial infections; Predominantly Antibody Deficiencies to Agammaglobulinemia 8A, autosomal dominant, OMIM:616941; Agammaglobulinemia 8B, autosomal recessive, OMIM:619824; Recurrent bacterial infections; Predominantly Antibody Deficiencies
COVID-19 research v1.132 TCF3 Arina Puzriakova Phenotypes for gene: TCF3 were changed from Agammaglobulinemia; Recurrent bacterial infections; Agammaglobulinemia 8, autosomal dominant, 616941; Primary immunodeficiency; Predominantly Antibody Deficiencies to Agammaglobulinemia 8A, autosomal dominant, OMIM:616941; Agammaglobulinemia 8B, autosomal recessive, OMIM:619824; Recurrent bacterial infections; Predominantly Antibody Deficiencies
Inherited bleeding disorders v1.173 TBXA2R Arina Puzriakova Phenotypes for gene: TBXA2R were changed from Thromboxane A2 receptor defect to {Bleeding disorder, platelet-type, 13, susceptibility to}, OMIM:614009
Bleeding and platelet disorders v1.45 TBXA2R Arina Puzriakova Phenotypes for gene: TBXA2R were changed from 614009.BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO; BDPLT13; 614009 BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO to {Bleeding disorder, platelet-type, 13, susceptibility to}, OMIM:614009
Monogenic hearing loss v2.248 FOXI1 Eleanor Williams Tag Q1_22_expert_review tag was added to gene: FOXI1.
Intellectual disability v3.1742 TGFB1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.; to: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. Cognition is typically normal in Camurati-Engelmann disease (caused by monoallelic TGFB1 variants).
Intellectual disability v3.1742 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease, 131300; {Cystic fibrosis lung; disease, modifier of}, 219700 to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
Intellectual disability v3.1741 TGFB1 Arina Puzriakova Publications for gene: TGFB1 were set to
Intellectual disability v3.1740 TGFB1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' to 'biallelic' inline with review by Zornitza Stark indicating two unrelated families with GDD/ID and biallelic variants in this gene. Added watchlist_moi tag to monitor for further cases. There was no evidence linking monoallelic variants to ID.
Intellectual disability v3.1740 TGFB1 Arina Puzriakova Mode of inheritance for gene: TGFB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1739 TGFB1 Arina Puzriakova Tag watchlist_moi tag was added to gene: TGFB1.
Osteopetrosis v1.28 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease OMIM:131300 to Camurati-Engelmann disease, OMIM:131300
DDG2P v2.82 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from CAMURATI-ENGELMANN DISEASE 131300 to Camurati-Engelmann disease, OMIM:131300
Fetal anomalies v1.976 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from CAMURATI-ENGELMANN DISEASE to Camurati-Engelmann disease, OMIM:131300
Skeletal dysplasia v2.218 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Camurati-Engelmann disease 131300; Camurati-Engelmann disease 131300 to Camurati-Engelmann disease, OMIM:131300
Primary immunodeficiency or monogenic inflammatory bowel disease v2.578 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; 618213; Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM; TGFB1 deficiency; Diseases of Immune Dysregulation; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
COVID-19 research v1.131 TGFB1 Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213
Structural eye disease v1.151 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from [Skin/hair/eye pigmentation 3, blue/green eyes]; Albinism, oculocutaneous, type IB, 606952; Eye Disorders; Waardenburg syndrome/albinism, digenic, 103470; [Skin/hair/eye pigmentation 3, light/dark/freckling skin], 601800; Albinism, oculocutaneous, type IA, 203100; {Melanoma, cutaneous malignant, susceptibility to, 8} to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Structural eye disease v1.150 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1739 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Albinism, oculocutaneous, type IA, 203100; Waardenburg; syndrome/albinism, digenic, 103470; Albinism, oculocutaneous, type IB, 606952; [Skin/hair/eye pigmentation 3, light/dark/freckling skin], 601800; {Melanoma, cutaneous malignant, susceptibility to, 8}, 601800; [Skin/hair/eye pigmentation 3, blue/green eyes], 601800 to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Pigmentary skin disorders v1.51 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from ALBINISM, OCULOCUTANEOUS, TYPE IA; Oculocutaneous albinism; OCA1B; OCA1A, ALBINISM, OCULOCUTANEOUS, TYPE IB to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Ocular and oculo-cutaneous albinism v1.23 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' only.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Ocular and oculo-cutaneous albinism v1.23 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Infantile nystagmus v1.6 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' only.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Infantile nystagmus v1.6 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.25 TYR Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update.

Biallelic variants are associated with oculocutaneous albinism. Many cases have been reported in literature (ClinGen Definitive gene-disease classification) and therefore this is appropriate for inclusion on this panel.

SNPs in TYR have been found to influence hair, eye and skin pigmentation and some studies have demonstrated an increased susceptibility to cutaneous melanoma due to certain sequence variants. There is some evidence suggesting ocular albinism may result from digenic inheritance of a TYR SNP (R402Q) alongside a heterozygous variant in the MITF gene. However, neither of these scenarios are within the remit of this panel and therefore should not be included.
Albinism or congenital nystagmus v1.25 TYR Arina Puzriakova Mode of inheritance for gene: TYR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Infantile nystagmus v1.5 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Oculocutaneous Albinism; Albinism, oculocutaneous, type IA; Albinism, oculocutaneous, type IB; Waardenburg syndrome/albinism, digenic to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Ocular and oculo-cutaneous albinism v1.22 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Oculocutaneous Albinism; Albinism, oculocutaneous, type IA; Albinism, oculocutaneous, type IB; Waardenburg syndrome/albinism, digenic to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Albinism or congenital nystagmus v1.24 TYR Arina Puzriakova Phenotypes for gene: TYR were changed from Albinism, oculocutaneous, type IA; Waardenburg syndrome/albinism, digenic; Albinism, oculocutaneous, type IB; Oculocutaneous Albinism to Albinism, oculocutaneous, type IA, OMIM:203100; Albinism, oculocutaneous, type IB, OMIM:606952; Waardenburg syndrome/albinism, digenic, OMIM:103470
Albinism or congenital nystagmus v1.23 TYR Arina Puzriakova Tag Q4_22_MOI tag was added to gene: TYR.
Intellectual disability v3.1738 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325{Schizophrenia, susceptibility to, 17}, 614332; AUTISM to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Early onset or syndromic epilepsy v2.598 NRXN1 Arina Puzriakova Phenotypes for gene: NRXN1 were changed from Pitt-Hopkins-like syndrome 2, 614325 to Pitt-Hopkins-like syndrome 2, OMIM:614325 (AR); Complex neurodevelopmental disorder (AD)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.47 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Gene has been re-curated and the MOI should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.

Association with monoallelic variants is well-established. There are now at least four families in literature with recessive variants and myopathy (PMIDs: 14659406; 25666907; 17372140; 31130376). Most commonly described is scapuloperoneal and proximal distribution of muscle weakness, which are within the scope of this panel.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.47 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.46 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Scapuloperoneal syndrome, myopathic type, OMIM:181430; MYH7-related late-onset scapuloperoneal muscular dystrophy, MONDO:0008409; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Hypertrophic cardiomyopathy 1, MONDO:0008647; Cardiomyopathy, dilated, 1S, OMIM:613426; Dilated cardiomyopathy 1S, MONDO:0013262; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal recessive, OMIM:255160; Scapuloperoneal syndrome, myopathic type, OMIM:181430
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.45 MYH7 Arina Puzriakova Publications for gene: MYH7 were set to 15322983
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 MYH7 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: MYH7.
Congenital myopathy v2.93 MYH7 Arina Puzriakova Phenotypes for gene: MYH7 were changed from Laing distal myopathy, OMIM:160500; Laing early-onset distal myopathy, MONDO:0008050; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal dominant, MONDO:0012018 to Laing distal myopathy, OMIM:160500; Myopathy, myosin storage, autosomal dominant, OMIM:608358; Myopathy, myosin storage, autosomal recessive, OMIM:255160
Congenital myopathy v2.92 MYH7 Arina Puzriakova Publications for gene: MYH7 were set to 15322983
Congenital myopathy v2.91 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: There are now at least four families in literature with recessive variants and myopathy (PMIDs: 14659406; 25666907; 17372140; 31130376). Congenital manifestation in some cases. Therefore, the MOI can now be updated from 'monoallelic' to 'both mono- and biallelic' at the next GMS panel update.
Congenital myopathy v2.91 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital myopathy v2.90 MYH7 Arina Puzriakova Tag Q4_22_MOI tag was added to gene: MYH7.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.; to: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to DCM.
Dilated and arrhythmogenic cardiomyopathy v1.34 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to DCM.
Dilated and arrhythmogenic cardiomyopathy v1.34 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated and arrhythmogenic cardiomyopathy v1.33 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.
Dilated Cardiomyopathy and conduction defects v1.81 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.80 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Hypertrophic cardiomyopathy v2.42 MYH7 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with monoallelic variants is well-established. To date, only four families have been reported with recessive variants (PMIDs: 14659406; 25666907; 17372140; 31130376). Of these, one family developed dilated cardiomyopathy and one had hypertrophic cardiomyopathy, while cardiac function was normal in the remaining two families. Therefore, maintaining MOI of monoallelic only at this time but with a watchlist_moi tag to monitor for evidence linking biallelic variants linked to HCM.
Hypertrophic cardiomyopathy v2.42 MYH7 Arina Puzriakova Mode of inheritance for gene: MYH7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy v2.41 MYH7 Arina Puzriakova Tag watchlist_moi tag was added to gene: MYH7.
Paediatric or syndromic cardiomyopathy v1.81 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Arrhythmogenic right ventricular dysplasia 12 to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Dilated and arrhythmogenic cardiomyopathy v1.33 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease (601214); Arrhythmogenic right ventricular dysplasia 12; Arrhythmogenic right ventricular dysplasia 12 (611528) to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Arrhythmogenic right ventricular cardiomyopathy v2.18 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12 , OMIM:611528 to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Dilated Cardiomyopathy and conduction defects v1.80 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12, OMIM:611528
Arrhythmogenic right ventricular cardiomyopathy v2.17 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Arrhythmogenic right ventricular dysplasia 12 ; Arrhythmogenic right ventricular dysplasia 12 (611528); Naxos disease (601214) to Naxos disease, OMIM:601214; Arrhythmogenic right ventricular dysplasia 12 , OMIM:611528
Palmoplantar keratodermas v1.21 JUP Arina Puzriakova Added comment: Comment on mode of inheritance: Pathogenic heterozygous germline variants in JUP are associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) without abnormalities of hair or skin. On the other hand, recessive variants are associated with Naxos disease which manifests a range of ectodermal features including palmoplantar keratoderma.

Therefore, the MOI should be changed from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update.
Palmoplantar keratodermas v1.21 JUP Arina Puzriakova Mode of inheritance for gene: JUP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.20 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease; Desmosomal disorders to Naxos disease, OMIM:601214; Palmoplantar keratoderma, keratoderma with woolly hair
Palmoplantar keratodermas v1.19 JUP Arina Puzriakova Tag Q4_22_MOI tag was added to gene: JUP.
Epidermolysis bullosa and congenital skin fragility v1.55 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Severe generalised Epidermolysis bullosa simplex to Naxos disease, OMIM:601214; Generalised skin fragility, epidermolysis bullosa
Epidermolysis bullosa v1.11 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, 601214; Severe generalised Epidermolysis bullosa simplex to Naxos disease, OMIM:601214; Generalised skin fragility, epidermolysis bullosa
Palmoplantar keratoderma and erythrokeratodermas v1.26 JUP Arina Puzriakova Phenotypes for gene: JUP were changed from Naxos disease, 601214; palmoplantar keratoderma (PPK), keratoderma with woolly hair; KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY; WOOLLY HAIR, PALMOPLANTAR KERATODERMA, AND CARDIAC ABNORMALITIES; PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR to Naxos disease, OMIM:601214; Palmoplantar keratoderma, keratoderma with woolly hair, generalised skin fragility, epidermolysis bullosa
Fetal anomalies v1.975 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Arrhythmogenic right ventricular dysplasia 8 607450; Keratosis palmoplantaris striata II, 612908; Cardiomyopathy, dilated, with woolly hair and keratoderma 605676; Skin fragility-woolly hair syndrome 607655; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 615821; Epidermolysis bullosa, lethal acantholytic 609638 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638 (AR); Skin fragility-woolly hair syndrome, OMIM:607655 (AR); Keratosis palmoplantaris striata II, OMIM:612908 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Dilated and arrhythmogenic cardiomyopathy v1.32 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic (609638); Skin fragility-woolly hair syndrome (607655); Arrhythmogenic right ventricular dysplasia 8; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (615821); Arrhythmogenic right ventricular dysplasia 8 (607450); Keratosis palmoplantaris striata II (612908); Cardiomyopathy, dilated, with woolly hair and keratoderma (605676) to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Dilated Cardiomyopathy and conduction defects v1.79 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Dilated cardiomyopathy with woolly hair and keratoderma to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD)
Paediatric or syndromic cardiomyopathy v1.80 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 to Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD)
Arrhythmogenic right ventricular cardiomyopathy v2.16 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Keratosis palmoplantaris striata II (612908); Skin fragility-woolly hair syndrome (607655); Arrhythmogenic right ventricular dysplasia 8 (607450); Epidermolysis bullosa, lethal acantholytic (609638); Arrhythmogenic right ventricular dysplasia 8 ; Cardiomyopathy, dilated, with woolly hair and keratoderma (605676); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (615821) to Arrhythmogenic right ventricular dysplasia 8, OMIM:607450 (AD); Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD)
Palmoplantar keratodermas v1.19 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Desmosomal disorders to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Keratosis palmoplantaris striata II, OMIM:612908 (AD)
Epidermolysis bullosa and congenital skin fragility v1.54 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic, OMIM:609638 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638; Skin fragility-woolly hair syndrome, OMIM:607655
Epidermolysis bullosa v1.10 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Epidermolysis bullosa, lethal acantholytic, 609638; Severe generalised Epidermolysis bullosa simplex; Lethal acantholytic epidermolysis bullosa; Skin fragility-woolly hair syndrome,607655 to Epidermolysis bullosa, lethal acantholytic, OMIM:609638; Skin fragility-woolly hair syndrome, OMIM:607655
Palmoplantar keratoderma and erythrokeratodermas v1.25 DSP Arina Puzriakova Phenotypes for gene: DSP were changed from Striate keratoderma with woolly hair and cardiomyopathy; Keratosis palmoplantaris striata II, 612908; CARVAJAL SYNDROME; Dilated cardiomyopathy with woolly hair and keratoderma, 605676; Arrhythmogenic right ventricular dysplasia 8, 607450; Skin fragility-woolly hair syndrome, 607655; Epidermolysis bullosa, lethal acantholytic; Keratosis palmoplantaris striata II; Skin fragility-woolly hair syndrome; striate keratoderma; diffuse keratoderma; lethal acantholytic epidermolysis bullosa, 609638; alopecia, follicular hyperkeratoses and keratoderma; oligodontia or hypodontia to Cardiomyopathy, dilated, with woolly hair and keratoderma, OMIM:605676 (AR); Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis, OMIM:615821 (AD); Keratosis palmoplantaris striata II, OMIM:612908 (AD)
Structural eye disease v1.149 ARR3 Dmitrijs Rots gene: ARR3 was added
gene: ARR3 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: ARR3 was set to Other
Publications for gene: ARR3 were set to 35001458
Penetrance for gene: ARR3 were set to unknown
Review for gene: ARR3 was set to AMBER
Added comment: 3 multigenerational families with X-linked dominant, female limited high myopia reported in 35001458. Each family has different trucating variant in ARR3
Sources: Literature
Intellectual disability v3.1737 PRRT2 Dmitrijs Rots reviewed gene: PRRT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36180924; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.597 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 31997314, 31997314; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1737 OTUD7A Dmitrijs Rots reviewed gene: OTUD7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 36180924, 33381903; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.90 CCDC78 Tracy Lester reviewed gene: CCDC78: Rating: RED; Mode of pathogenicity: None; Publications: 25635128; Phenotypes: congenital myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1737 MTSS1L Eleanor Williams Tag Q4_22_rating was removed from gene: MTSS1L.
Tag Q4_22_promote_green tag was added to gene: MTSS1L.
Intellectual disability v3.1737 DPH5 Eleanor Williams Tag Q4_22_rating was removed from gene: DPH5.
Tag Q4_22_promote_green tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Eleanor Williams Tag Q4_22_rating was removed from gene: DPH5.
Tag Q4_22_promote_green tag was added to gene: DPH5.
Intellectual disability v3.1737 DOHH Eleanor Williams Tag Q4_22_rating was removed from gene: DOHH.
Tag Q4_22_promote_green tag was added to gene: DOHH.
Severe microcephaly v2.319 DOHH Eleanor Williams Tag Q4_22_rating was removed from gene: DOHH.
Tag Q4_22_promote_green tag was added to gene: DOHH.
Congenital hyperinsulinism v2.29 AKT2 Eleanor Williams Tag Q4_22_rating was removed from gene: AKT2.
Tag Q4_21_rating tag was added to gene: AKT2.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams commented on gene: SLC12A6: Removed the for-review tag as this is a 100,000 genomes project panel that does not need GMS approval for changes.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams Added comment: Comment on mode of inheritance: Changing the mode of inheritance as this is a 100K only panel.
Hereditary neuropathy v1.455 SLC12A6 Eleanor Williams Mode of inheritance for gene: SLC12A6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.454 SLC12A6 Eleanor Williams Tag for-review was removed from gene: SLC12A6.
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Classified gene: CAPN15 as Green List (high evidence)
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Added comment: Comment on list classification: Removed for-review tag and promoting this gene to green as this is a 100K only panel.
Anophthalmia or microphthalmia v1.51 CAPN15 Eleanor Williams Gene: capn15 has been classified as Green List (High Evidence).
Anophthalmia or microphthalmia v1.50 CAPN15 Eleanor Williams Tag for-review was removed from gene: CAPN15.
Endocrine neoplasia v1.25 PTEN Eleanor Williams Tag Q2_21_expert_review tag was added to gene: PTEN.
Endocrine neoplasia v1.25 PMS2 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: PMS2.
Endocrine neoplasia v1.25 MSH6 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MSH6.
Endocrine neoplasia v1.25 MSH2 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MSH2.
Endocrine neoplasia v1.25 MLH1 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: MLH1.
Possible mitochondrial disorder - nuclear genes v1.160 PDK3 Eleanor Williams Tag Q1_22_expert_review tag was added to gene: PDK3.
Childhood onset dystonia, chorea or related movement disorder v1.261 AFG3L2 Eleanor Williams commented on gene: AFG3L2
Childhood onset dystonia, chorea or related movement disorder v1.261 AFG3L2 Eleanor Williams Tag Q2_21_rating tag was added to gene: AFG3L2.
Skeletal muscle channelopathy v1.39 SLC2A1 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC2A1.
Tag Q2_21_expert_review tag was added to gene: SLC2A1.
Skeletal muscle channelopathy v1.39 SLC1A3 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC1A3.
Tag Q2_21_expert_review tag was added to gene: SLC1A3.
Skeletal muscle channelopathy v1.39 PYGM Eleanor Williams Tag Q2_21_rating tag was added to gene: PYGM.
Tag Q2_21_expert_review tag was added to gene: PYGM.
Skeletal muscle channelopathy v1.39 CACNA1A Eleanor Williams Tag Q2_21_rating tag was added to gene: CACNA1A.
Tag Q2_21_expert_review tag was added to gene: CACNA1A.
Skeletal muscle channelopathy v1.39 ATP1A2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ATP1A2.
Tag Q2_21_expert_review tag was added to gene: ATP1A2.
Fetal anomalies v1.974 FOXP4 Eleanor Williams Tag Q2_21_rating tag was added to gene: FOXP4.
Tag Q2_21_expert_review tag was added to gene: FOXP4.
Congenital myopathy v2.90 MYH8 Eleanor Williams Tag Q2_21_rating tag was added to gene: MYH8.
Tag Q2_21_expert_review tag was added to gene: MYH8.
Monogenic hearing loss v2.248 COL9A3 Eleanor Williams Tag Q2_21_rating tag was added to gene: COL9A3.
Tag Q2_21_expert_review tag was added to gene: COL9A3.
Mitochondrial disorders v2.177 XPNPEP3 Eleanor Williams Tag Q1_22_rating was removed from gene: XPNPEP3.
Tag Q2_21_rating tag was added to gene: XPNPEP3.
Structural eye disease v1.149 TSC2 Eleanor Williams commented on gene: TSC2
Structural eye disease v1.149 TSC2 Eleanor Williams Tag Q1_22_NHS_review was removed from gene: TSC2.
Pancreatitis v2.16 TRPV6 Eleanor Williams commented on gene: TRPV6
Pancreatitis v2.16 TRPV6 Eleanor Williams Tag Q1_22_NHS_review was removed from gene: TRPV6.
Intellectual disability v3.1737 FBXW7 Eleanor Williams commented on gene: FBXW7
Intellectual disability v3.1737 FBXW7 Eleanor Williams Tag Q3_22_phenotype was removed from gene: FBXW7.
Pituitary hormone deficiency v2.102 ROBO1 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: ROBO1.
Tag Q3_22_NHS_review tag was added to gene: ROBO1.
Intellectual disability v3.1737 ANK3 Eleanor Williams commented on gene: ANK3
Intellectual disability v3.1737 ANK3 Eleanor Williams Tag Q2_22_MOI was removed from gene: ANK3.
Tag Q3_22_MOI tag was added to gene: ANK3.
Bleeding and platelet disorders v1.44 F12 Eleanor Williams commented on gene: F12
Bleeding and platelet disorders v1.44 F12 Eleanor Williams Tag Q2_22_rating tag was added to gene: F12.
Congenital muscular dystrophy v2.31 MYMK Eleanor Williams commented on gene: MYMK
Congenital muscular dystrophy v2.31 MYMK Eleanor Williams Tag Q3_21_rating tag was added to gene: MYMK.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 DCLRE1B Eleanor Williams commented on gene: DCLRE1B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 DCLRE1B Eleanor Williams Tag Q3_21_rating tag was added to gene: DCLRE1B.
Severe microcephaly v2.319 DPP6 Eleanor Williams commented on gene: DPP6
Severe microcephaly v2.319 DPP6 Eleanor Williams Tag Q4_21_rating tag was added to gene: DPP6.
Adult onset leukodystrophy v1.47 RNASET2 Eleanor Williams commented on gene: RNASET2
Adult onset leukodystrophy v1.47 RNASET2 Eleanor Williams Tag Q4_21_rating tag was added to gene: RNASET2.
Adult onset leukodystrophy v1.47 POLR1C Eleanor Williams commented on gene: POLR1C
Adult onset leukodystrophy v1.47 POLR1C Eleanor Williams Tag Q4_21_rating tag was added to gene: POLR1C.
Hydrocephalus v2.132 HYLS1 Eleanor Williams commented on gene: HYLS1
Hydrocephalus v2.132 HYLS1 Eleanor Williams Tag Q4_21_rating tag was added to gene: HYLS1.
Adult onset leukodystrophy v1.47 COL4A2 Eleanor Williams commented on gene: COL4A2
Adult onset leukodystrophy v1.47 COL4A2 Eleanor Williams Tag Q4_21_rating tag was added to gene: COL4A2.
Hydrocephalus v2.132 MYMK Eleanor Williams commented on gene: MYMK
Hydrocephalus v2.132 MYMK Eleanor Williams Tag Q4_21_rating tag was added to gene: MYMK.
Congenital hyperinsulinism v2.29 GPC3 Eleanor Williams Tag Q4_21_rating tag was added to gene: GPC3.
Congenital hyperinsulinism v2.29 AKT2 Eleanor Williams Tag Q4_22_rating tag was added to gene: AKT2.
Adult onset leukodystrophy v1.47 AARS Eleanor Williams commented on gene: AARS
Adult onset leukodystrophy v1.47 AARS Eleanor Williams Tag Q4_21_rating tag was added to gene: AARS.
Adult onset dystonia, chorea or related movement disorder v1.174 GBA Eleanor Williams commented on gene: GBA
Adult onset dystonia, chorea or related movement disorder v1.174 GBA Eleanor Williams Tag Q4_21_rating tag was added to gene: GBA.
Adult onset leukodystrophy v1.47 MARS Eleanor Williams commented on gene: MARS
Adult onset leukodystrophy v1.47 MARS Eleanor Williams Tag Q4_21_rating tag was added to gene: MARS.
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Deleted their comment
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams commented on gene: SNIP1
Early onset or syndromic epilepsy v2.597 SNIP1 Eleanor Williams Tag Q4_21_expert_review was removed from gene: SNIP1.
Tag Q3_22_rating tag was added to gene: SNIP1.
Tag Q3_22_expert_review tag was added to gene: SNIP1.
Holoprosencephaly v2.30 DISP1 Eleanor Williams commented on gene: DISP1
Holoprosencephaly v2.30 DISP1 Eleanor Williams Tag Q2_21_rating tag was added to gene: DISP1.
Hydrocephalus v2.132 ERF Eleanor Williams commented on gene: ERF
Hydrocephalus v2.132 ERF Eleanor Williams Tag Q2_21_rating tag was added to gene: ERF.
Cerebral vascular malformations v2.60 SETD5 Eleanor Williams commented on gene: SETD5
Cerebral vascular malformations v2.60 SETD5 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SETD5.
Tag Q3_22_rating tag was added to gene: SETD5.
Tag Q3_22_expert_review tag was added to gene: SETD5.
Cerebral vascular malformations v2.60 CHD4 Eleanor Williams commented on gene: CHD4
Cerebral vascular malformations v2.60 CHD4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CHD4.
Tag Q3_22_rating tag was added to gene: CHD4.
Tag Q3_22_expert_review tag was added to gene: CHD4.
Hypogonadotropic hypogonadism (GMS) v1.54 FGF17 Eleanor Williams commented on gene: FGF17
Hypogonadotropic hypogonadism (GMS) v1.54 FGF17 Eleanor Williams Tag Q2_21_expert_review was removed from gene: FGF17.
Tag Q3_22_rating tag was added to gene: FGF17.
Tag Q3_22_expert_review tag was added to gene: FGF17.
Hypogonadotropic hypogonadism (GMS) v1.54 DUSP6 Eleanor Williams commented on gene: DUSP6
Hypogonadotropic hypogonadism (GMS) v1.54 DUSP6 Eleanor Williams Tag Q2_21_expert_review was removed from gene: DUSP6.
Tag Q3_22_rating tag was added to gene: DUSP6.
Tag Q3_22_expert_review tag was added to gene: DUSP6.
Hypogonadotropic hypogonadism (GMS) v1.54 CCDC141 Eleanor Williams commented on gene: CCDC141
Hypogonadotropic hypogonadism (GMS) v1.54 CCDC141 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CCDC141.
Laterality disorders and isomerism v1.51 NODAL Eleanor Williams commented on gene: NODAL
Laterality disorders and isomerism v1.51 NODAL Eleanor Williams Tag Q2_21_expert_review was removed from gene: NODAL.
Tag Q3_22_rating tag was added to gene: NODAL.
Tag Q3_22_expert_review tag was added to gene: NODAL.
Lysosomal storage disorder v1.78 VPS33A Eleanor Williams commented on gene: VPS33A
Lysosomal storage disorder v1.78 VPS33A Eleanor Williams Tag Q2_21_expert_review was removed from gene: VPS33A.
Tag Q3_22_rating tag was added to gene: VPS33A.
Tag Q3_22_expert_review tag was added to gene: VPS33A.
Rare anaemia v1.42 RPL27 Eleanor Williams commented on gene: RPL27
Rare anaemia v1.42 RPL27 Eleanor Williams Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Haematological malignancies cancer susceptibility v2.36 RPL27 Eleanor Williams Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Haematological malignancies cancer susceptibility v2.36 RPL27 Eleanor Williams commented on gene: RPL27
Cytopenia - NOT Fanconi anaemia v1.72 RPL27 Eleanor Williams commented on gene: RPL27
Cytopenia - NOT Fanconi anaemia v1.72 RPL27 Eleanor Williams Tag Q2_21_expert_review was removed from gene: RPL27.
Tag Q3_22_rating tag was added to gene: RPL27.
Tag Q3_22_expert_review tag was added to gene: RPL27.
Ataxia and cerebellar anomalies - narrow panel v2.306 SPG7 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SPG7.
Tag Q3_22_rating tag was added to gene: SPG7.
Tag Q3_22_expert_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v2.306 SPG7 Eleanor Williams commented on gene: SPG7
Ataxia and cerebellar anomalies - narrow panel v2.306 CYP2U1 Eleanor Williams commented on gene: CYP2U1
Ataxia and cerebellar anomalies - narrow panel v2.306 CYP2U1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CYP2U1.
Tag Q3_22_rating tag was added to gene: CYP2U1.
Tag Q3_22_expert_review tag was added to gene: CYP2U1.
White matter disorders and cerebral calcification - narrow panel v1.244 CYP7B1 Eleanor Williams commented on gene: CYP7B1
White matter disorders and cerebral calcification - narrow panel v1.244 CYP7B1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CYP7B1.
Tag Q3_22_rating tag was added to gene: CYP7B1.
Tag Q3_22_expert_review tag was added to gene: CYP7B1.
Childhood solid tumours v2.35 MAX Eleanor Williams commented on gene: MAX
Childhood solid tumours v2.35 MAX Eleanor Williams Tag Q2_21_expert_review was removed from gene: MAX.
Tag Q3_22_rating tag was added to gene: MAX.
Tag Q3_22_expert_review tag was added to gene: MAX.
Cerebral vascular malformations v2.60 CNOT3 Eleanor Williams commented on gene: CNOT3
Cerebral vascular malformations v2.60 CNOT3 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CNOT3.
Tag Q3_22_rating tag was added to gene: CNOT3.
Tag Q3_22_expert_review tag was added to gene: CNOT3.
Segmental overgrowth disorders - Deep sequencing v2.16 NLRP2 Eleanor Williams commented on gene: NLRP2
Segmental overgrowth disorders - Deep sequencing v2.16 NLRP2 Eleanor Williams Tag Q2_21_expert_review was removed from gene: NLRP2.
Tag Q3_22_rating tag was added to gene: NLRP2.
Tag Q3_22_expert_review tag was added to gene: NLRP2.
Hypertrophic cardiomyopathy v2.41 JPH2 Eleanor Williams commented on gene: JPH2
Hypertrophic cardiomyopathy v2.41 JPH2 Eleanor Williams Tag Q2_21_expert_review was removed from gene: JPH2.
Tag Q3_22_rating tag was added to gene: JPH2.
Tag Q3_22_expert_review tag was added to gene: JPH2.
Differences in sex development v2.66 FGFR2 Eleanor Williams commented on gene: FGFR2
Hypogonadotropic hypogonadism (GMS) v1.54 SPRY4 Eleanor Williams commented on gene: SPRY4
Hypogonadotropic hypogonadism (GMS) v1.54 SPRY4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SPRY4.
Tag Q3_22_rating tag was added to gene: SPRY4.
Tag Q3_22_expert_review tag was added to gene: SPRY4.
Cardiac arrhythmias - additional genes v1.15 ANK2 Eleanor Williams Tag Q3_21_expert_review was removed from gene: ANK2.
Tag Q3_22_rating tag was added to gene: ANK2.
Tag Q3_22_expert_review tag was added to gene: ANK2.
Cutaneous photosensitivity with a likely genetic cause v1.10 HMBS Eleanor Williams commented on gene: HMBS
Cutaneous photosensitivity with a likely genetic cause v1.10 HMBS Eleanor Williams Tag Q3_21_expert_review was removed from gene: HMBS.
Tag Q3_22_rating tag was added to gene: HMBS.
Tag Q3_22_expert_review tag was added to gene: HMBS.
Rare anaemia v1.42 RPS27 Eleanor Williams commented on gene: RPS27
Rare anaemia v1.42 RPS27 Eleanor Williams Tag Q3_21_expert_review was removed from gene: RPS27.
Tag Q3_22_rating tag was added to gene: RPS27.
Tag Q3_22_expert_review tag was added to gene: RPS27.
Retinal disorders v2.286 PRPF6 Eleanor Williams commented on gene: PRPF6
Retinal disorders v2.286 PRPF6 Eleanor Williams Tag Q3_21_expert_review was removed from gene: PRPF6.
Tag Q3_22_rating tag was added to gene: PRPF6.
Tag Q3_22_expert_review tag was added to gene: PRPF6.
Osteogenesis imperfecta v2.48 DSPP Eleanor Williams commented on gene: DSPP: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Osteogenesis imperfecta v2.48 DSPP Eleanor Williams Tag Q3_21_expert_review was removed from gene: DSPP.
Tag Q3_22_rating tag was added to gene: DSPP.
Tag Q3_22_expert_review tag was added to gene: DSPP.
Sarcoma susceptibility v1.72 FANCC Eleanor Williams commented on gene: FANCC
Fetal anomalies v1.974 SCUBE3 Eleanor Williams commented on gene: SCUBE3: Updating tags to be Q3_22_expert_review and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)
Fetal anomalies v1.974 SCUBE3 Eleanor Williams Tag Q4_21_expert_review was removed from gene: SCUBE3.
Tag Q3_22_rating tag was added to gene: SCUBE3.
Tag Q3_22_expert_review tag was added to gene: SCUBE3.
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams commented on gene: CLPB
Early onset or syndromic epilepsy v2.597 CLPB Eleanor Williams Tag Q4_21_expert_review was removed from gene: CLPB.
Tag Q3_21_MOI tag was added to gene: CLPB.
Tag Q3_22_rating tag was added to gene: CLPB.
Tag Q3_22_expert_review tag was added to gene: CLPB.
Malformations of cortical development v2.149 DAG1 Eleanor Williams commented on gene: DAG1
Malformations of cortical development v2.149 DAG1 Eleanor Williams Tag Q4_21_expert_review was removed from gene: DAG1.
Tag Q3_22_rating tag was added to gene: DAG1.
Tag Q3_22_expert_review tag was added to gene: DAG1.
Rhabdomyolysis and metabolic muscle disorders v1.78 FKTN Eleanor Williams commented on gene: FKTN
Rhabdomyolysis and metabolic muscle disorders v1.78 FKTN Eleanor Williams Tag Q4_21_expert_review was removed from gene: FKTN.
Tag Q3_22_rating tag was added to gene: FKTN.
Tag Q3_22_expert_review tag was added to gene: FKTN.
Sarcoma susceptibility v1.72 FANCC Eleanor Williams Tag Q3_22_rating tag was added to gene: FANCC.
Epidermolysis bullosa and congenital skin fragility v1.53 SPINK5 Eleanor Williams Tag Q3_22_rating tag was added to gene: SPINK5.
Haematological malignancies cancer susceptibility v2.36 MBD4 Eleanor Williams Tag Q3_22_rating tag was added to gene: MBD4.
Renal ciliopathies v1.64 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Renal ciliopathies v1.64 ZNF423 Eleanor Williams commented on gene: ZNF423
Neurological ciliopathies v1.32 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Neurological ciliopathies v1.32 ZNF423 Eleanor Williams commented on gene: ZNF423
Cystic kidney disease v2.53 ZNF423 Eleanor Williams commented on gene: ZNF423
Cystic kidney disease v2.53 ZNF423 Eleanor Williams Tag Q1_22_expert_review was removed from gene: ZNF423.
Tag Q3_22_rating tag was added to gene: ZNF423.
Tag Q3_22_expert_review tag was added to gene: ZNF423.
Intellectual disability v3.1737 DPH5 Sarah Leigh Tag Q4_22_rating tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Tag Q4_22_rating tag was added to gene: DPH5.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Classified gene: DPH5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.597 DPH5 Sarah Leigh Gene: dph5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1737 DPH5 Sarah Leigh Classified gene: DPH5 as Amber List (moderate evidence)
Intellectual disability v3.1737 DPH5 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 v3.1737 DPH5 Sarah Leigh Gene: dph5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1736 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh edited their review of gene: DPH5: Added comment: Not associated with a phenotype in OMIM, but as moderate Gen2Phen gene for DPH5-related neurodevelopmental disorder. PMID: 35482014 reports four DPH5 variants in fives cases from three unrelated families. Biallelic NM_001077394.2:c.521dup (p.Asn174LysfsTer10) was identified in a consanguinous family (PMID: 35482014, family 3), the index case, an affected sibling and cousin all died in infancy. Affected members families 1 & 2 (PMID: 35482014) were seen in childhood, all had profound intellectual disability and seizures were seen in both families. A supportive mouse model was described, as were in vitro functonal studies (PMID: 35482014).; Changed rating: GREEN
Intellectual disability v3.1736 DPH5 Sarah Leigh Added comment: Comment on phenotypes: As described by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4902).
Intellectual disability v3.1736 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Added comment: Comment on phenotypes: As described by Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4902)
Early onset or syndromic epilepsy v2.596 DPH5 Sarah Leigh Phenotypes for gene: DPH5 were changed from Abnormality of prenatal development or birth; Neonatal hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the cardiovascular system; Abnormality of the globe; Feeding difficulties; Short stature; Abnormality of head or neck to DPH5-related neurodevelopmental disorder
Intellectual disability v3.1735 ROR2 Tracy Lester reviewed gene: ROR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1735 PRDM13 Sarah Leigh Publications for gene: PRDM13 were set to 34730112
Clefting v2.70 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Only two cases with clefting have been reported to date. Following consultation with Clinical team, decided to maintain Green rating as CNVs with variable penetrance are reported in clinical practice and can be relevant diagnostically; however, adding watchlist tag to monitor for clear evidence of particularly reduced penetrance at which stage the rating may be reviewed.; Changed phenotypes to: 26097203
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova edited their review of Region: ISCA-37423-Gain: Added comment: Only two cases with epilepsy have been reported to date. Following consultation with Clinical team, decided to maintain Green rating as CNVs with variable penetrance are reported in clinical practice and can be relevant diagnostically; however, adding watchlist tag to monitor for clear evidence of particularly reduced penetrance at which stage the rating may be reviewed.; Changed publications to: 26097203
Early onset or syndromic epilepsy v2.595 ISCA-37423-Gain Arina Puzriakova Tag watchlist tag was added to Region: ISCA-37423-Gain.
Clefting v2.70 ISCA-37423-Gain Arina Puzriakova Tag watchlist tag was added to Region: ISCA-37423-Gain.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 LYN Boaz Palterer gene: LYN was added
gene: LYN was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LYN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LYN were set to 36122175
Phenotypes for gene: LYN were set to Autoinflammatory; Neutrophilic vasculitis; Liver fibrosis; Chronic urticaria; Atopic dermatitis; Fever
Penetrance for gene: LYN were set to unknown
Review for gene: LYN was set to GREEN
Added comment: Louvrier et al. described 1 patient ( PMID 36122175 ) and De Jesus et al ( https://www.medrxiv.org/content/10.1101/2022.09.27.22280319v1.full.pdf ) 3 additional patients, for a total of 4 kindreds with de novo LYN mutations.
Strong functional evidence: p.Tyr508His, p.Tyr508Phe and p.Tyr508* cause inhibition loss, leading to Tyr397 autophosphorylation and functional GOF.
Sources: Literature
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Classified gene: MTSS1L as Amber List (moderate evidence)
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases with shared phenotype and supported by functional studies to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1734 MTSS1L Arina Puzriakova Gene: mtss1l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1733 MTSS1L Arina Puzriakova gene: MTSS1L was added
gene: MTSS1L was added to Intellectual disability. Sources: Literature
new-gene-name, Q4_22_rating tags were added to gene: MTSS1L.
Mode of inheritance for gene: MTSS1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MTSS1L were set to 36067766
Phenotypes for gene: MTSS1L were set to Global developmental delay; Intellectual disability; Ophthalmological anomalies; Microcephaly; Mild facial dysmorphisms
Review for gene: MTSS1L was set to GREEN
Added comment: Huang et al. 2022 (PMID: 36067766) reported five unrelated individuals with the same heterozygous de novo variant (c.2011C>T; p.Arg671Trp) in MTSS2 (formally known as MTSS1L). Linkage analysis was not performed but given the variants arose de novo and the mixed ethnicity of the affected individuals (4 European, 1 Chinese) a founder effect can be ruled out.

Subjects displayed a shared phenotype of GDD and/or ID, ophthalmological anomalies (most commonly nystagmus), microcephaly (primary in 2, relative in 3) and shared mild facial dysmorphisms. The single adult patient also presented with seizures and optic atrophy.

Functional studies showed the variant leads to a decrease in mRNA level but does not impact protein levels of MTSS2. However, a Drosophila model demonstrated that loss of the fly ortholog results in defects in locomotor and visual functions which were rescued by human MTSS2 and only partially rescued by the MTSS2 c.2011C>T variant. Overexpression of the c.2011C>T variant caused similar phenotypes as the LoF mutant indicating a possible dominant-negative effect.
Sources: Literature
Skeletal muscle channelopathy v1.39 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG: Added the tag of Q4_21_rating as this STR only had an expert review tag and would not be picked up for a GMS report with just that.
Skeletal muscle channelopathy v1.39 CNBP_CCTG Eleanor Williams Tag Q4_21_rating tag was added to STR: CNBP_CCTG.
Possible mitochondrial disorder - nuclear genes v1.160 PDK3 Eleanor Williams Tag Q1_22_rating tag was added to gene: PDK3.
Intellectual disability v3.1732 RELN Dmitrijs Rots changed review comment from: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense.; to: Multiple individuals with monoallelic and biallelic variants with different phenotypes are reported: 35769015. Monoallelic variants are mainly missense. The inheritance should be changed to both.
Intellectual disability v3.1732 RELN Dmitrijs Rots reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lisencephaly, seizures, autism; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Adult onset leukodystrophy v1.47 TPP2 Eleanor Williams Phenotypes for gene: TPP2 were changed from White matter abnormalities; autoimmunity; immunodefficiency; developmental delay to White matter abnormalities; Immunodeficiency 78 with autoimmunity and developmental delay, OMIM:619220
Adult onset leukodystrophy v1.46 TPP2 Eleanor Williams changed review comment from: Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.

2 cases reported of homozygous missense variants in TPP2 and a MS-type phenotype. However, 1 of the variants is also found in some MS patients in the heterozygous state.

PMID: 33586135 - Atallah et al 2021- (not PMID: 25414442) summarises 14 patients with TPP2 pathogenic variants reported in their study and other publications. They report that 'the adult form, described in four patients, manifests as a chronic non-infectious brain inflammation with demyelinating brain disease and calcifications somewhat similar to multiple sclerosis.'. These 4 patients are reported in PMID: 30533531 (Reinthaler et al 2018) who describe a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. A Jordian patient with MS was also identified to have a homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2. This variant also occurs in heterozygous form in other MS cases and in 6 ExAC control individuals so the authors acknowledge that it may not be pathogenic.; to: Associated with Immunodeficiency 78 with autoimmunity and developmental delay, #619220 in OMIM.

2 cases reported of homozygous missense variants in TPP2 and a MS-type phenotype. However, 1 of the variants is also found in some MS patients in the heterozygous state.

PMID: 33586135 - Atallah et al 2021- (not PMID: 25414442) summarises 14 patients with TPP2 pathogenic variants reported in their study and other publications. They report that 'the adult form, described in four patients, manifests as a chronic non-infectious brain inflammation with demyelinating brain disease and calcifications somewhat similar to multiple sclerosis.'. These 4 patients are reported in PMID: 30533531 (Reinthaler et al 2018) who describe a Syrian family with milder symptoms of sterile brain inflammation mimicking MS and no developmental delay. A missense variant, c.82T>G, p.Cys28Gly, in TPP2 was identified in all 3 affected siblings of the family. A Jordian patient with MS was also identified to have a homozygous missense variant (c.2027C>T, p.Thr676Ile) in TPP2. This variant also occurs in heterozygous form in other MS cases and in 6 ExAC control individuals so the authors acknowledge that it may not be pathogenic. Age of diagnosis for these patients was 35 year plus.

Other cases with variants in this gene are reported in PMIDS: 25414442; 25525876; 30533531, however these present in childhood with a recurrent respiratory infections, autoimmune cytopenias, developmental delay and progressive combined immunodeficiency.
Adult onset leukodystrophy v1.46 TPP2 Eleanor Williams Publications for gene: TPP2 were set to 33586135
Adult onset leukodystrophy v1.45 TPP2 Eleanor Williams Publications for gene: TPP2 were set to PMID:25414442
Adult onset leukodystrophy v1.44 TPP2 Eleanor Williams Classified gene: TPP2 as Amber List (moderate evidence)
Adult onset leukodystrophy v1.44 TPP2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases (4 individuals) with homozygous variants in this gene reported with an MS-like phenotype, but some doubt over the pathogenicity of the variant in 1 case.
Adult onset leukodystrophy v1.44 TPP2 Eleanor Williams Gene: tpp2 has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v1.43 TPP2 Eleanor Williams reviewed gene: TPP2: Rating: ; Mode of pathogenicity: None; Publications: 33586135, 25414442, 25525876, 30533531; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1732 DOHH Sarah Leigh Classified gene: DOHH as Amber List (moderate evidence)
Intellectual disability v3.1732 DOHH 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 v3.1732 DOHH Sarah Leigh Gene: dohh has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.319 DOHH Sarah Leigh Classified gene: DOHH as Amber List (moderate evidence)
Severe microcephaly v2.319 DOHH Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.319 DOHH Sarah Leigh Gene: dohh has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.318 DOHH Sarah Leigh Entity copied from Intellectual disability v3.1731
Severe microcephaly v2.318 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Severe microcephaly. Sources: Literature
Q4_22_rating, Q4_22_MOI tags were added to gene: DOHH.
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Intellectual disability v3.1731 DOHH Sarah Leigh Tag Q4_22_rating tag was added to gene: DOHH.
Tag Q4_22_MOI tag was added to gene: DOHH.
Intellectual disability v3.1731 DOHH Sarah Leigh gene: DOHH was added
gene: DOHH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to 35858628
Phenotypes for gene: DOHH were set to DOHH associated neurodevelopmental disorder
Review for gene: DOHH was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35858628 reports six DOHH variants in three unrelated cases of a neurodevelopmental disorder. All of these cases had intellectual disability, microcephaly and hypotonia.
Sources: Literature
Intellectual disability v3.1730 TPP2 Arina Puzriakova Tag Q3_22_MOI was removed from gene: TPP2.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.44 SYNE2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: SYNE2.
Tag Q3_22_NHS_review tag was added to gene: SYNE2.
Early onset dystonia v1.128 XK Sarah Leigh Classified gene: XK as Red List (low evidence)
Early onset dystonia v1.128 XK Sarah Leigh Gene: xk has been classified as Red List (Low Evidence).
Early onset dystonia v1.127 XK Sarah Leigh edited their review of gene: XK: Changed rating: RED
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Ataxia and cerebellar anomalies - narrow panel v2.306 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Ataxia and cerebellar anomalies - narrow panel v2.305 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Ataxia and cerebellar anomalies - narrow panel v2.305 CACNA1A Sarah Leigh reviewed gene: CACNA1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amyotrophic lateral sclerosis/motor neuron disease v1.62 KIF5A Sarah Leigh Phenotypes for gene: KIF5A were changed from Amyotrophic lateral sclerosis to {Amyotrophic lateral sclerosis, susceptibility to, 25}, OMIM:617921; amyotrophic lateral sclerosis, susceptibility to, 25, MONDO:0060670
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh reviewed gene: KIF5A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh Classified gene: KIF5A as Green List (high evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.61 KIF5A Sarah Leigh Gene: kif5a has been classified as Green List (High Evidence).
Familial cerebral small vessel disease v1.14 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance has been changed to Both mono and biallelic
Familial cerebral small vessel disease v1.14 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral vascular malformations v2.60 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Cerebral vascular malformations v2.60 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v2.59 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Tag Q3_22_expert_review tag was added to gene: COL3A1.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Pneumothorax - familial v2.38 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v1.44 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be considered for changing to Both mono and biallelic following GMS review.
Bleeding and platelet disorders v1.44 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v1.43 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Tag Q3_22_expert_review tag was added to gene: COL3A1.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams changed review comment from: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changes to Both mono and biallelic following GMS review.; to: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changed to Both mono and biallelic following GMS review.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic variants are associated with Polymicrogyria with or without vascular-type EDS OMIM:618343, therefore the mode of inheritance should be changes to Both mono and biallelic following GMS review.
Ehlers Danlos syndrome with a likely monogenic cause v2.66 COL3A1 Eleanor Williams Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndrome with a likely monogenic cause v2.65 COL3A1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL3A1.
Thoracic aortic aneurysm or dissection (GMS) v1.27 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: As this is a red gene the mode of inheritance has been left as it is, Both mono and biallelic. However, if promoted to green the evidence for biallelic cases should be reviewed.
Thoracic aortic aneurysm or dissection (GMS) v1.27 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.974 COL1A2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as both mono and biallelic for now, but only Ehlers-Danlos syndrome, cardiac valvular type is associated with biallelic variants and this does not seem relevant to the fetal panel. Recommendation to change to Monoallelic only, if the GMS groups agree.
Fetal anomalies v1.974 COL1A2 Eleanor Williams Mode of inheritance for gene: COL1A2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.973 COL1A2 Eleanor Williams Tag Q3_22_MOI tag was added to gene: COL1A2.
Rare multisystem ciliopathy disorders v1.164 TTC21B Eleanor Williams commented on gene: TTC21B
Rare multisystem ciliopathy disorders v1.164 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Renal ciliopathies v1.64 TTC21B Eleanor Williams commented on gene: TTC21B
Renal ciliopathies v1.64 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Unexplained kidney failure in young people v1.116 TTC21B Eleanor Williams commented on gene: TTC21B
Unexplained kidney failure in young people v1.116 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Cystic kidney disease v2.53 TTC21B Eleanor Williams commented on gene: TTC21B
Cystic kidney disease v2.53 TTC21B Eleanor Williams Tag watchlist_moi tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.22 TTC21B Eleanor Williams Tag Q2_22_expert_review tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.22 TTC21B Eleanor Williams Publications for gene: TTC21B were set to
Tubulointerstitial kidney disease v1.21 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now. It does appear that monoallelic variants are potential genetic modifiers and are found in combination with variants in other renal disease associated genes (see PMID: 26940125, PMID: 21258341) so seeking GMS review as to the best mode of inheritance.
Tubulointerstitial kidney disease v1.21 TTC21B Eleanor Williams Mode of inheritance for gene: TTC21B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Tag Q3_22_expert_review tag was added to gene: TTC21B.
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now. It does appear that monoallelic variants are potential genetic modifiers and are found in combination with variants in other renal disease associated genes (see PMID: 26940125, PMID: 21258341) so seeking GMS review as to the best mode of inheritance.
Unexplained young onset end-stage renal disease v1.41 TTC21B Eleanor Williams Mode of inheritance for gene: TTC21B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v1.40 TTC21B Eleanor Williams Tag Q3_22_MOI tag was added to gene: TTC21B.
Intellectual disability v3.1730 TPP2 Eleanor Williams Classified gene: TPP2 as Amber List (moderate evidence)
Intellectual disability v3.1730 TPP2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber with a recommendation for GREEN rating following GMS review. Clinical advice was to be inclusive since the intellectual disability phenotype is relatively consistent.
Intellectual disability v3.1730 TPP2 Eleanor Williams Gene: tpp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1729 TPP2 Eleanor Williams Tag Q3_22_rating tag was added to gene: TPP2.
Tag Q3_22_MOI tag was added to gene: TPP2.
Nephrocalcinosis or nephrolithiasis v2.40 RRAGD Eleanor Williams Mode of inheritance for gene: RRAGD was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Classified gene: RRAGD as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation of green rating following GMS review.
Nephrocalcinosis or nephrolithiasis v2.39 RRAGD Eleanor Williams Gene: rragd has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v2.38 RRAGD Eleanor Williams Tag Q3_22_rating tag was added to gene: RRAGD.
Tag Q3_22_MOI tag was added to gene: RRAGD.
Tag Q3_22_NHS_review tag was added to gene: RRAGD.
Nephrocalcinosis or nephrolithiasis v2.38 RRAGD Eleanor Williams Phenotypes for gene: RRAGD were changed from hypomagnesaemia, nephrocalcinosis, salt wasting, cardiomyopathy to hypomagnesaemia; nephrocalcinosis; salt wasting; cardiomyopathy; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130
Nephrocalcinosis or nephrolithiasis v2.37 RRAGD Eleanor Williams Mode of inheritance for gene: RRAGD was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nephrocalcinosis or nephrolithiasis v2.36 RRAGD Eleanor Williams commented on gene: RRAGD
Retinal disorders v2.286 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Retinitis pigmentosa 79, OMIM:617460, MONDO:0044320 to Retinitis pigmentosa 79, OMIM:617460; retinitis pigmentosa 79,MONDO:0044320
Intellectual disability v3.1729 HK1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: HK1.
Tag Q3_22_NHS_review tag was added to gene: HK1.
Intellectual disability v3.1729 HK1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as biallelic for now but with the recommendation of changing to monallelic following GMS review.
Intellectual disability v3.1729 HK1 Eleanor Williams Mode of inheritance for gene: HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1728 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807
Intellectual disability v3.1727 HK1 Eleanor Williams commented on gene: HK1: As noted by Tracy Lester, the cases reported by Okur et al. 2019 - PMID: 30778173 are have heterozygous de novo variants in HK1 and a phenotype of developmental delay, intellectual disability, structural brain abnormality, and visual impairments, therefore the mode of inheritance should be changed from biallelic to monoallelic.
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH Eleanor Williams Classified gene: ASPH as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH 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. There are sufficient cases with a cardiac phenotype relevant to this panel.
Thoracic aortic aneurysm or dissection (GMS) v1.26 ASPH Eleanor Williams Gene: asph has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.25 ASPH Eleanor Williams Tag Q3_22_rating tag was added to gene: ASPH.
Tag Q3_22_MOI tag was added to gene: ASPH.
Tag Q3_22_NHS_review tag was added to gene: ASPH.
Thoracic aortic aneurysm or dissection (GMS) v1.25 ASPH Eleanor Williams Phenotypes for gene: ASPH were changed from ocular features; anterior segment abnormalities; distinctive facial appearance; aortic root dilatation to Traboulsi syndrome, OMIM:601552; facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, MONDO:0011106
Thoracic aortic aneurysm or dissection (GMS) v1.24 ASPH Eleanor Williams Publications for gene: ASPH were set to PMID: 35918038
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Eleanor Williams commented on gene: ASPH
Neonatal diabetes v2.59 ZNF808 Eleanor Williams Phenotypes for gene: ZNF808 were changed from to neonatal diabetes mellitus, MONDO:0016391; pancreatic agenesis, MONDO:0009832
Neonatal diabetes v2.58 ZNF808 Eleanor Williams Mode of inheritance for gene: ZNF808 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.57 ZNF808 Eleanor Williams Tag Q3_22_rating tag was added to gene: ZNF808.
Tag Q3_22_NHS_review tag was added to gene: ZNF808.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams changed review comment from: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; to: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without an identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams changed review comment from: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) there are 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; to: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.
Neonatal diabetes v2.57 ZNF808 Eleanor Williams edited their review of gene: ZNF808: Added comment: The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) there are 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without and identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.; Changed phenotypes to: neonatal diabetes mellitus, MONDO:0016391, pancreatic agenesis, MONDO:0009832
Neonatal diabetes v2.57 FICD Eleanor Williams changed review comment from: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.; to: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). Age of diabetes onset was a mean of 29 weeks (range 12-43). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.
Neonatal diabetes v2.57 EIF2B1 Eleanor Williams changed review comment from: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.; to: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). Onset of diabetes was at 21 weeks or less in 4 patients, and at 56 weeks in the 5th. The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: ONECUT1.
Tag Q3_21_expert_review was removed from gene: ONECUT1.
Tag Q3_22_NHS_review tag was added to gene: ONECUT1.
Tag Q3_22_expert_review tag was added to gene: ONECUT1.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: ONECUT1.
Tag Q3_21_expert_review tag was added to gene: ONECUT1.
Tag Q3_22_rating tag was added to gene: ONECUT1.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Classified gene: ONECUT1 as Amber List (moderate evidence)
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, but with a recommendation for green rating following GMS expert review as to whether the age of onset of the cases indicates this gene-disease association is suitable for this panel. In 1 case the age of onset was 1 day old, in the other 14 months. The age of onset in the 3rd case is not known.
Neonatal diabetes v2.57 ONECUT1 Eleanor Williams Gene: onecut1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.56 ONECUT1 Eleanor Williams Phenotypes for gene: ONECUT1 were changed from to ONECUT1-associated neonatal diabetes; neonatal diabetes mellitus, MONDO:0016391
Neonatal diabetes v2.55 ONECUT1 Eleanor Williams Publications for gene: ONECUT1 were set to
Neonatal diabetes v2.54 ONECUT1 Eleanor Williams Mode of inheritance for gene: ONECUT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.53 ONECUT1 Eleanor Williams commented on gene: ONECUT1: Not associated with a phenotype in OMIM but is associated with ONECUT1-associated neonatal diabetes (strong) in Gene2Phenotype.

As reported by the reviewer Philippi et al 2021 report two unrelated (French and Turkish) patients from consanguineous families with homozgyous variants in OMECUT1 (1 nonsense, 1 missense) and a phenotype characterised by characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia. Diabetes onset was at 1 day and 14 months in the two children respectively. Studies of the heterozygous carriers suggests that they are part of a distinctive subgroup of diabetic patients with early-onset, non-autoimmune diabetes, who respond well to diabetes treatment.

Note the eligibility criteria for this panel indicates that patients should be diagnosed with diabetes at less than 9 months of age.
Intellectual disability v3.1727 FICD Eleanor Williams Entity copied from Diabetes - neonatal onset v2.53
Intellectual disability v3.1727 FICD Eleanor Williams gene: FICD was added
gene: FICD was added to Intellectual disability. Sources: Expert review,Expert Review Amber
watchlist tags were added to gene: FICD.
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FICD were set to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities.
Neonatal diabetes v2.53 FICD Eleanor Williams Tag watchlist tag was added to gene: FICD.
Neonatal diabetes v2.53 FICD Eleanor Williams Classified gene: FICD as Amber List (moderate evidence)
Neonatal diabetes v2.53 FICD Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with a watchlist tag added.
3 cases reported but all with the same variant and 2 families share a common haplotype. Some functional data. In addition the paper is still at the pre-print stage and so has not yet been peer reviewed.
Neonatal diabetes v2.53 FICD Eleanor Williams Gene: ficd has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.52 FICD Eleanor Williams Phenotypes for gene: FICD were changed from to Neonatal diabetes; Neonatal insulin-dependent diabetes mellitus, HP:0000857; severe neurodevelopmental delay, HP:0012758; skeletal abnormalities.
Neonatal diabetes v2.51 FICD Eleanor Williams Mode of inheritance for gene: FICD was changed from to BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.50 FICD Eleanor Williams commented on gene: FICD: Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.
Neonatal diabetes v2.50 CNOT1 Eleanor Williams Tag Q3_22_NHS_review tag was added to gene: CNOT1.
Pituitary hormone deficiency v2.102 MAGEL2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: MAGEL2.
Congenital hyperinsulinism v2.29 MAGEL2 Sarah Leigh Added comment: Comment on phenotypes: Congenital hyperinsulinism with hypoglycaemia
Congenital hyperinsulinism v2.29 MAGEL2 Sarah Leigh Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, OMIM:615547; Schaaf-Yang syndrome, MONDO:0014243
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Classified gene: MAGEL2 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.28 MAGEL2 Sarah Leigh Gene: magel2 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.27 MAGEL2 Sarah Leigh Tag Q3_22_rating tag was added to gene: MAGEL2.
Tag Q3_22_MOI tag was added to gene: MAGEL2.
Tag Q3_22_NHS_review tag was added to gene: MAGEL2.
Congenital hyperinsulinism v2.27 NSD1 Sarah Leigh Tag Q3_22_NHS_review tag was added to gene: NSD1.
Congenital hyperinsulinism v2.27 NSD1 Sarah Leigh Phenotypes for gene: NSD1 were changed from Sotos syndrome (OMIM#117550) to Sotos syndrome, OMIM:117550; Sotos syndrome 1, MONDO:0007299
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh changed review comment from: Comment on publications: this article is a preprint, the PMID will be added when avaiable; to: Comment on publications: this article is a preprint, the PMID will be added when available
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Tag non-coding-known-pathogenic tag was added to gene: HK1.
Tag Q3_22_rating tag was added to gene: HK1.
Tag Q3_22_MOI tag was added to gene: HK1.
Tag Q3_22_NHS_review tag was added to gene: HK1.
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh edited their review of gene: HK1: Changed rating: GREEN
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh changed review comment from: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism in the preprint https://doi.org/10.1101/2021.12.03.21267240; to: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism (Wakeling et al Nature Genetics 2022 (accepted for publication) medRxiv preprint doi: https://doi.org/10.1101/2021.12.03.21267240).
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh edited their review of gene: HK1: Added comment: Fourteen non-coding de novo mutations affecting a 42bp conserved region, encompassed by a regulatory element in intron 2 of HK1 have been associated with congenital hyperinsulinism in the preprint https://doi.org/10.1101/2021.12.03.21267240; Changed rating: AMBER
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Classified gene: HK1 as Amber List (moderate evidence)
Congenital hyperinsulinism v2.26 HK1 Sarah Leigh Gene: hk1 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.25 HK1 Sarah Leigh Phenotypes for gene: HK1 were changed from to Congenital hyperinsulinism
Congenital hyperinsulinism v2.24 HK1 Sarah Leigh Added comment: Comment on publications: this article is a preprint, the PMID will be added when avaiable
Congenital hyperinsulinism v2.24 HK1 Sarah Leigh Publications for gene: HK1 were set to
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Tag Q3_22_rating tag was added to gene: EIF2B1.
Tag Q3_22_NHS_review tag was added to gene: EIF2B1.
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Classified gene: EIF2B1 as Amber List (moderate evidence)
Neonatal diabetes v2.50 EIF2B1 Eleanor Williams Gene: eif2b1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Classified gene: EIF2B1 as Red List (low evidence)
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, but with a recommendation for green status.
Neonatal diabetes v2.49 EIF2B1 Eleanor Williams Gene: eif2b1 has been classified as Red List (Low Evidence).
Neonatal diabetes v2.48 EIF2B1 Eleanor Williams Phenotypes for gene: EIF2B1 were changed from to Permanent neonatal/early onset diabetes and transient liver dysfunction
Neonatal diabetes v2.47 EIF2B1 Eleanor Williams Publications for gene: EIF2B1 were set to
Neonatal diabetes v2.46 EIF2B1 Eleanor Williams Mode of inheritance for gene: EIF2B1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.45 EIF2B1 Eleanor Williams commented on gene: EIF2B1: Associated with Leukoencephalopathy with vanishing white matter, #603896 (AR) in OMIM.

As expert reviewer reports De Franco et al 2020 (PMID:31882561) screened patients with Permanent neonatal diabetes (PNDM) and early onset diabetes using a targeted next generation sequencing assay, including the known monogenic diabetes genes and additional candidate genes, such as EIF2B1. 5 de novo EIF2B1 variants were identified, p.(Gly44Asp), p.(Gly44Val), p.(Ser77Asn), p.(Leu34Trp), p.(*306Thrext*12). The patients do not exhibit severe neurological features seen in cases with homozygous variants in EIF2B1 but two reported cases displayed mild learning disability or attention deficit disorder.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Tag Q3_22_rating tag was added to gene: CACNA1D.
Tag Q3_22_NHS_review tag was added to gene: CACNA1D.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh edited their review of gene: CACNA1D: Added comment: Associated with phenotype in OMIM and as strong Gen2Phen gene for Primary aldosteronism, seizures, and neurologic abnormalities (OMIM:615474). Two variants have been reported in two unrelated cases of congenital hyperinsulinaemic hypoglycaemia; PMID: 28318089 reports: c.1319G>A (p.G403D) in a case who also has heart defects and severe hypotonia and PMID: 32336187 reports: c.812T>A (p.L271H) in a case who also has primary hyperaldosteronism and hypotonia. A third de novo case has been reported in the review provided by Eleanor Williams on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH.; Changed rating: GREEN
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Classified gene: CACNA1D as Amber List (moderate evidence)
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.23 CACNA1D Sarah Leigh Gene: cacna1d has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.45 CNOT1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review.; to: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review, however the pancreatic agenesis is associated with one missense variant only.
Holoprosencephaly v2.30 CNOT1 Eleanor Williams Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis, 618500; pancreatic agenesis and holoprosencephaly syndrome to Holoprosencephaly 12, with or without pancreatic agenesis, OMIM:618500; holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Classified gene: CNOT1 as Amber List (moderate evidence)
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Amber for now, however an additional case with the same variant as other cases and a holoprosencephaly phenotype has been reported, and so the rating should reviewed by the GMS.
Holoprosencephaly v2.29 CNOT1 Eleanor Williams Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.22 CACNA1D Sarah Leigh Publications for gene: CACNA1D were set to 28318089
Holoprosencephaly v2.28 CNOT1 Eleanor Williams Tag Q3_22_rating tag was added to gene: CNOT1.
Tag Q3_22_expert_review tag was added to gene: CNOT1.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Tag Q3_22_rating tag was added to gene: CNOT1.
Tag Q3_22_expert_review tag was added to gene: CNOT1.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Classified gene: CNOT1 as Amber List (moderate evidence)
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review.
Neonatal diabetes v2.45 CNOT1 Eleanor Williams Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Neonatal diabetes v2.44 CNOT1 Eleanor Williams Phenotypes for gene: CNOT1 were changed from to Holoprosencephaly 12, with or without pancreatic agenesis, OMIM:618500; holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787
Neonatal diabetes v2.43 CNOT1 Eleanor Williams Publications for gene: CNOT1 were set to
Neonatal diabetes v2.42 CNOT1 Eleanor Williams Added comment: Comment on mode of pathogenicity: Only one missense variant reported in all cases. All de novo.
Neonatal diabetes v2.42 CNOT1 Eleanor Williams Mode of pathogenicity for gene: CNOT1 was changed from to Other
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1C.
Neonatal diabetes v2.41 CNOT1 Eleanor Williams Mode of inheritance for gene: CNOT1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Holoprosencephaly v2.28 CNOT1 Eleanor Williams Publications for gene: CNOT1 were set to 31006513; 31006510
Holoprosencephaly v2.27 CNOT1 Eleanor Williams commented on gene: CNOT1
Neonatal diabetes v2.40 CNOT1 Eleanor Williams commented on gene: CNOT1: Associated with Holoprosencephaly 12, with or without pancreatic agenesis, 618500 (AD) in OMIM and HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS (strong) in Gene2Phenotype.

3 publications reporting 6 unrelated probands with the same de novo missense variant in CNOT and a holoprosencephaly phenotype. 5/6 also had pancreatic agenesis.

PMID:35481434 - Cospain et al 2022 - report a foetus with semi-lobar HPE diagnosed at ultrasound and total pancreas agenesis identified at general autopsy. WES found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo.

PMID:31006513 - de Franco et al 2019 - looked at an international cohort of 107 individuals diagnosed with pancreatic agenesis and identified 3 unrelated individuals with CNOT1 variant c.1603C>T [p.Arg535Cys]. In 2 patients it was confirmed as de novo (maternal DNA not available for the 3rd). 2 of the patients had definite holoprosencephaly and one had possible holoprosencephaly. They report that the DDD study5 has identified other de novo CNOT1 variants in three individuals with developmental delay (2 missense and 1 nonsense) but none of them had holoprosencephaly or diabetes. Mice heterozygous for p.Arg535Cys variant showed no phenotype, but homozygotes (embryonically lethal) were found to have significant reduction in the size of the pancreas and neurological abnormalities.

PMID:31006510 - Kruszka et al 2019 - 2 unrelated individuals with semilobar holoprosencephaly with de novo variants in CNOT1 (c.1603C>T [p.Arg535Cys]) identified by WES. Both probands also presented with hearing loss and global developmental delay. Proband 1 also had diabetes insipidus, neonatal diabetes mellitus requiring insulin, pancreatic exocrine insufficiency requiring enzyme therapy.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Tag Q3_22_rating tag was added to gene: CACNA1C.
Tag Q3_22_NHS_review tag was added to gene: CACNA1C.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Classified gene: CACNA1C as Amber List (moderate evidence)
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Congenital hyperinsulinism v2.21 CACNA1C Sarah Leigh Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Congenital hyperinsulinism v2.20 CACNA1C Sarah Leigh edited their review of gene: CACNA1C: Added comment: Associated with in OMIM and as definitive Gen2Phen gene for Timothy syndrome (OMIM:601005). At least two CACNA1C variants have been reported in numerous cases of Timothy syndrome.
PMID: 35897673 reports novel heterozygous CACNA1C variant in a patient with congenital hyperinsulinism (CHI), which appears to have gain-of-function and loss-of-function effects at the electrophysiological level, explaining the hyperinsulinism and resulting hypoglycemia in the patient reported. It appeared that c.1679T>C, p.L566P (NM_000719.6) reported in this patient has a minor effects on the cardiac action potential in an in silico model, in contrast to c.1216G>T, p.G406R (NM_000719.6) which is associated with the Long QT in Timothy syndrome (OMIM:601005). Therefore the authors conclude that this represents a novel congeital non-syndromic hyperinsulinism.
Hypoglycemia is also seen in Timothy syndrome patients with c.1216G>T, p.G406R (Table S3, PMID: 35897673), it would therefore be appropriate to screen other patients with hyperinsulinism / hypoglycemia for CACNA1C variants.; Changed rating: GREEN
Congenital hyperinsulinism v2.20 CACNA1C Sarah Leigh Phenotypes for gene: CACNA1C were changed from non-syndromic congeital hyperinsulinism to non-syndromic congeital hyperinsulinism; Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979
Congenital hyperinsulinism v2.19 CACNA1C Sarah Leigh Added comment: Comment on mode of pathogenicity: In vitro studies show that c.1679T>C, p.Leu566Pro (NM_000719.6) appears to have loss-of-function effects by altering current amplitudes in mutant channels and a gain-of-function effect by slowing the voltage-dependent inactivation (PMID: 35897673).
Congenital hyperinsulinism v2.19 CACNA1C Sarah Leigh Mode of pathogenicity for gene: CACNA1C was changed from to Other
Congenital hyperinsulinism v2.18 CACNA1C Sarah Leigh Phenotypes for gene: CACNA1C were changed from to non-syndromic congeital hyperinsulinism
Nephrocalcinosis or nephrolithiasis v2.36 RRAGD Detlef Bockenhauer gene: RRAGD was added
gene: RRAGD was added to Nephrocalcinosis or nephrolithiasis. Sources: Other
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to hypomagnesaemia, nephrocalcinosis, salt wasting, cardiomyopathy
Penetrance for gene: RRAGD were set to Complete
Mode of pathogenicity for gene: RRAGD 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: RRAGD was set to GREEN
Added comment: so far only a single paper, but with 9 patients/families
Sources: Other
Congenital hyperinsulinism v2.17 MAGEL2 Sarah Leigh Mode of inheritance for gene: MAGEL2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Congenital hyperinsulinism v2.16 MAGEL2 Sarah Leigh Publications for gene: MAGEL2 were set to
Congenital hyperinsulinism v2.15 HK1 Sarah Leigh Mode of inheritance for gene: HK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.14 CACNA1C Sarah Leigh Publications for gene: CACNA1C were set to
Congenital hyperinsulinism v2.13 CACNA1C Sarah Leigh Mode of inheritance for gene: CACNA1C was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Tag Q3_22_rating tag was added to gene: TBC1D32.
Tag Q3_22_NHS_review tag was added to gene: TBC1D32.
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Classified gene: TBC1D32 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.102 TBC1D32 Sarah Leigh Gene: tbc1d32 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v1.18 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Neurological ciliopathies v1.32 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Ophthalmological ciliopathies v1.31 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556
Rare multisystem ciliopathy disorders v1.164 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Structural eye disease v1.149 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 24285566
Fetal anomalies v1.973 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556
Malformations of cortical development v2.149 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Hydrocephalus v2.132 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32573025; 31130284; 32060556; 24285566
Pituitary hormone deficiency v2.101 TBC1D32 Sarah Leigh reviewed gene: TBC1D32: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.101 TBC1D32 Sarah Leigh Phenotypes for gene: TBC1D32 were changed from to Syndromic Hypopituitarism; orofaciodigital syndrome
Pituitary hormone deficiency v2.100 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to 32060556; 35875813
Pituitary hormone deficiency v2.99 TBC1D32 Sarah Leigh Mode of inheritance for gene: TBC1D32 was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.98 TBC1D32 Sarah Leigh Publications for gene: TBC1D32 were set to
Pituitary hormone deficiency v2.97 SOX2 Sarah Leigh Phenotypes for gene: SOX2 were changed from Microphthalmia, syndromic 3 (206900) to Microphthalmia, syndromic 3, OMIM:206900; anophthalmia/microphthalmia-esophageal atresia syndrome, MONDO:0008799
Intellectual disability v3.1726 SCAMP5 Sarah Leigh Tag watchlist was removed from gene: SCAMP5.
Tag Q3_22_rating tag was added to gene: SCAMP5.
Intellectual disability v3.1726 SCAMP5 Sarah Leigh edited their review of gene: SCAMP5: Added comment: PMIDs: 31439720; 33390987 report a total of six indiviuals with de novo heterozygous SCAMP5, p.Gly180Trp variants. All cases had neurodevelopmental disorders including intellectual disability and seizures.; Changed rating: GREEN
Intellectual disability v3.1726 SCAMP5 Sarah Leigh changed review comment from: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.; to: Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.
Intellectual disability v3.1726 SCAMP5 Sarah Leigh Classified gene: SCAMP5 as Amber List (moderate evidence)
Intellectual disability v3.1726 SCAMP5 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 v3.1726 SCAMP5 Sarah Leigh Gene: scamp5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1725 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363; 33390987
Intellectual disability v3.1724 SCAMP5 Sarah Leigh Publications for gene: SCAMP5 were set to 31439720; 20071347; 32020363
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Classified gene: SIX3 as Red List (low evidence)
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.96 SIX3 Sarah Leigh Gene: six3 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.95 SIX3 Sarah Leigh reviewed gene: SIX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.95 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 35951005; 34974160; 32796691
Pituitary hormone deficiency v2.94 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from Holoprosencephaly 2,OMIMM157170 to Holoprosencephaly 2, OMIM:157170; alobar holoprosencephaly, MONDO:0019757
Pituitary hormone deficiency v2.93 SIX3 Sarah Leigh Phenotypes for gene: SIX3 were changed from Holoprosencephaly 2 (157170) to Holoprosencephaly 2,OMIMM157170
Pituitary hormone deficiency v2.92 SIX3 Sarah Leigh Publications for gene: SIX3 were set to 35951005
Pituitary hormone deficiency v2.91 SIX3 Sarah Leigh Publications for gene: SIX3 were set to
Intellectual disability v3.1723 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Structural eye disease v1.148 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Anophthalmia/Microphthalmia to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Intellectual disability v3.1723 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, 611038 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.50 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Fetal anomalies v1.972 RAX Sarah Leigh Phenotypes for gene: RAX were changed from MICROPHTHALMIA ISOLATED TYPE 3 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.49 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604 to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Anophthalmia or microphthalmia v1.48 RAX Sarah Leigh Phenotypes for gene: RAX were changed from Anophthalmia/Microphthalmia to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Structural eye disease v1.147 RAX Sarah Leigh Publications for gene: RAX were set to 24033328; 14662654; 18783408
Intellectual disability v3.1722 RAX Sarah Leigh Publications for gene: RAX were set to 18039390; 24033328; 30811539; 18783408; 14662654
Intellectual disability v3.1721 RAX Sarah Leigh Publications for gene: RAX were set to 18039390; 24033328
Anophthalmia or microphthalmia v1.47 RAX Sarah Leigh Publications for gene: RAX were set to 30811539; 18783408; 14662654
Fetal anomalies v1.971 RAX Sarah Leigh Publications for gene: RAX were set to
Anophthalmia or microphthalmia v1.46 RAX Sarah Leigh Publications for gene: RAX were set to
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Tag watchlist tag was added to gene: RAX.
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Classified gene: RAX as Amber List (moderate evidence)
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on this panel at the moment..
Pituitary hormone deficiency v2.90 RAX Sarah Leigh Gene: rax has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.89 RAX Sarah Leigh reviewed gene: RAX: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.89 RAX Sarah Leigh Classified gene: RAX as Amber List (moderate evidence)
Pituitary hormone deficiency v2.89 RAX Sarah Leigh Gene: rax has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.88 RAX Sarah Leigh Publications for gene: RAX were set to 30811539
Pituitary hormone deficiency v2.87 RAX Sarah Leigh Phenotypes for gene: RAX were changed from to Microphthalmia, isolated 3, OMIM:611038; isolated microphthalmia 3, MONDO:0012604
Pituitary hormone deficiency v2.86 RAX Sarah Leigh Publications for gene: RAX were set to
Pituitary hormone deficiency v2.85 RAX Sarah Leigh Mode of inheritance for gene: RAX was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Tag Q3_22_rating tag was added to gene: PCSK1.
Tag Q3_22_NHS_review tag was added to gene: PCSK1.
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Classified gene: PCSK1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.84 PCSK1 Sarah Leigh Gene: pcsk1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.83 PCSK1 Sarah Leigh reviewed gene: PCSK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intestinal failure or congenital diarrhoea v1.50 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from Obesity with impaired prohormone processing, OMIM:600955 to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Severe early-onset obesity v2.51 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from {Obesity, susceptibility to, BMIQ12}, OMIM:612362; Obesity with impaired prohormone processing, 600955; {Obesity, susceptibility to, BMIQ12}, OMIM:612362 to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Pituitary hormone deficiency v2.83 PCSK1 Sarah Leigh Phenotypes for gene: PCSK1 were changed from to Obesity with impaired prohormone processing, OMIM:600955; obesity due to prohormone convertase I deficiency, MONDO:0010961; {Obesity, susceptibility to, BMIQ12},OMIM:612362
Intestinal failure or congenital diarrhoea v1.49 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Severe early-onset obesity v2.50 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Pituitary hormone deficiency v2.82 PCSK1 Sarah Leigh Publications for gene: PCSK1 were set to
Pituitary hormone deficiency v2.81 PCSK1 Sarah Leigh Mode of inheritance for gene: PCSK1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 ALPK1 Dmitrijs Rots gene: ALPK1 was added
gene: ALPK1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ALPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALPK1 were set to 35868845
Phenotypes for gene: ALPK1 were set to ROSAH syndrome
Penetrance for gene: ALPK1 were set to unknown
Mode of pathogenicity for gene: ALPK1 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: ALPK1 was set to GREEN
Added comment: GoF missense variants in ALPK1 cause autoinflammatory condition ROSAH, with most individuals having inflammation, immune therapy available.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 UBA1 Dmitrijs Rots commented on gene: UBA1: NRAS and KRAS SOMATIC variants are included as Amber in this panel
Intellectual disability v3.1720 HK1 Tracy Lester reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Simon Thomas changed review comment from: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature; to: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature
Thoracic aortic aneurysm or dissection (GMS) v1.23 ASPH Simon Thomas gene: ASPH was added
gene: ASPH was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPH were set to PMID: 35918038
Phenotypes for gene: ASPH were set to ocular features; anterior segment abnormalities; distinctive facial appearance; aortic root dilatation
Penetrance for gene: ASPH were set to unknown
Added comment: Biallelic variants in ASPH are associated with Traboulsi syndrome Jones et al (PMID: 35918038) report seven further individuals from six apparently unrelated families identified through genetics clinics with confirmed molecular diagnoses and features consistent with Traboulsi syndrome. These patients exhibited additional cardiac, musculoskeletal and haematological features thus expanding the phenotypic spectrum of Traboulsi syndrome and demonstrating considerable overlap with Marfan syndrome. Specifically, five individuals had aortic root dilatation, with childhood onset in some, and one undergoing aortic root repair aged 47 years for severe aortic regurgitation and aortic root dilatation. Therefore ASPH should be considered for inclusion in the R125 TAAD/Marfan panel.
Sources: Literature
Early onset or syndromic epilepsy v2.595 CAPRIN1 Konstantinos Varvagiannis edited their review of gene: CAPRIN1: Changed rating: GREEN
Pituitary hormone deficiency v2.80 TCF7L1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TCF7L1.
Tag Q3_22_NHS_review tag was added to gene: TCF7L1.
Pituitary hormone deficiency v2.80 TCF7L1 Sarah Leigh reviewed gene: TCF7L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TGIF1.
Tag Q3_22_NHS_review tag was added to gene: TGIF1.
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh edited their review of gene: TGIF1: Changed rating: GREEN
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh changed review comment from: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).; to: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Classified gene: TGIF1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review as there are three variants in three unrelated cases with pituitary involvement.
Pituitary hormone deficiency v2.80 TGIF1 Sarah Leigh Gene: tgif1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Deleted their comment
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh edited their review of gene: TGIF1: Added comment: Associated with Holoprosencephaly 4 (OMIM:142946) and as definitive Gen2Phen gene for Holoprosencephaly. An association between TGIF1 and pituitary hormone deficiency has only been made with three variants in three unrelated cases (PMIDs: 23476075;34440302).; Changed rating: AMBER
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Classified gene: TGIF1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN on the Pituitary hormone deficiency at the next major review.
Pituitary hormone deficiency v2.79 TGIF1 Sarah Leigh Gene: tgif1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.78 TGIF1 Sarah Leigh Publications for gene: TGIF1 were set to 23476075
Pituitary hormone deficiency v2.77 TGIF1 Sarah Leigh Phenotypes for gene: TGIF1 were changed from Holoprosencephaly 4 (142946) to Holoprosencephaly 4,OMIM:142946; holoprosencephaly 4, MONDO:0007734
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Classified gene: RNPC3 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.76 RNPC3 Sarah Leigh Gene: rnpc3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.75 RNPC3 Sarah Leigh reviewed gene: RNPC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.75 RNPC3 Sarah Leigh Phenotypes for gene: RNPC3 were changed from Pituitary hormone deficiency, combined or isolated, 7, OMIM:618160 to Pituitary hormone deficiency, combined or isolated 7, OMIM:618160; isolated growth hormone deficiency, type 5, MONDO:0032569
Pituitary hormone deficiency v2.74 RNPC3 Sarah Leigh Tag watchlist was removed from gene: RNPC3.
Tag Q3_22_rating tag was added to gene: RNPC3.
Tag Q3_22_NHS_review tag was added to gene: RNPC3.
Pituitary hormone deficiency v2.74 RNPC3 Sarah Leigh Publications for gene: RNPC3 were set to 24480542; 29866761; 32462814; 33650182
Pituitary hormone deficiency v2.73 WDR11 Sarah Leigh Publications for gene: WDR11 were set to 28453858
Pituitary hormone deficiency v2.72 WDR11 Sarah Leigh reviewed gene: WDR11: Rating: RED; Mode of pathogenicity: None; Publications: 20887964, 34413497, 28453858; Phenotypes: ; Mode of inheritance: None
Pituitary hormone deficiency v2.72 WDR11 Sarah Leigh Publications for gene: WDR11 were set to
Pituitary hormone deficiency v2.71 WDR11 Sarah Leigh Phenotypes for gene: WDR11 were changed from Hypogonadotropic hypogonadism 14 with or without anosmia (614858) to Hypogonadotropic hypogonadism 14 with or without anosmia, OMIM:614858; hypogonadotropic hypogonadism 14 with or without anosmia, MONDO:0013926
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Tag Q3_21_NHS_review tag was added to gene: ROBO1.
Tag Q3_22_rating tag was added to gene: ROBO1.
Tag Q3_22_MOI tag was added to gene: ROBO1.
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh edited their review of gene: ROBO1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 28402530 reports three ROBO1 variants in three unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). Segregation is reported for two of these variants: c.2928_2929delG, p.Ala977Glnfs*40 is found in affected dizygotic twins and c.719G>C, p.Cys240Ser is found an affected child and her affected paternal aunt.; Changed rating: GREEN
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Added comment: Comment on phenotypes: In the context of the Pituitary hormone deficiency panel, the Mondo term: pituitary stalk interruption syndrome (MONDO:0019828) could be applied, however, this Mondo term is a general description and is not specific to a conidition associated with ROBO1 variants.
Pituitary hormone deficiency v2.70 ROBO1 Sarah Leigh Phenotypes for gene: ROBO1 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.69 ROBO1 Sarah Leigh Publications for gene: ROBO1 were set to
Pituitary hormone deficiency v2.68 ROBO1 Sarah Leigh Mode of inheritance for gene: ROBO1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Classified gene: ROBO1 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Pituitary hormone deficiency v2.67 ROBO1 Sarah Leigh Gene: robo1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Tag watchlist tag was added to gene: FAT2.
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Classified gene: FAT2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the moment, however, if additional FAT2 variants are reported to be associated with pituitary stalk interruption syndrome, this rating may change.
Pituitary hormone deficiency v2.66 FAT2 Sarah Leigh Gene: fat2 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.65 FAT2 Sarah Leigh edited their review of gene: FAT2: Added comment: Not associated with a pituitary phenotype in OMIM, Gen2Phen or MONDO. PMID: 33108146 reports four FAT2 variants in four unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). However, one of these variants (rs1024234841) is synonymous and in silico tools do not predict an effect on splicing and another variant (rs377026428) is digenic with a DCHS2 variant and so its contribution to disease causation is uncertain.; Changed rating: AMBER
Pituitary hormone deficiency v2.65 FAT2 Sarah Leigh Mode of inheritance for gene: FAT2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.64 FAT2 Sarah Leigh Added comment: Comment on phenotypes: In the context of the Pituitary hormone deficiency panel, the Mondo term: pituitary stalk interruption syndrome (MONDO:0019828) could be applied, however, this Mondo term is a general description and is not specific to a conidition associated with FAT2 variants.
Pituitary hormone deficiency v2.64 FAT2 Sarah Leigh Phenotypes for gene: FAT2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to Spinocerebellar ataxia 45, OMIM:617769; spinocerebellar ataxia 45, MONDO:0033480
Pituitary hormone deficiency v2.63 FAT2 Sarah Leigh Publications for gene: FAT2 were set to 33108146
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Classified gene: PAX6 as Red List (low evidence)
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Added comment: Comment on list classification: Leaving rating as red, only 1 patient is reported with a variant in PAX and a pituitary hormone deficiency. Another patient is reported with deletion of the enhancer region of PAX6, but the PAX6 coding region was unaffected. Awaiting further cases before considering promoting to amber or green.
Pituitary hormone deficiency v2.62 PAX6 Eleanor Williams Gene: pax6 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.61 PAX6 Eleanor Williams commented on gene: PAX6: PMID: 25342853 - Takagi et al 2015 - studied 88 (syndromic: 30; non-syndromic: 58) Japanese congenital hypopituitarism patients and performed aCGH on the syndromic patients, and analysed PAX6 in all 88 patients. They found 1 heterozygous 310-kb deletion of the PAX6 enhancer region, and 1 non-syndromic patient with a p.N116S variant. Both showed isolated GH deficiency.
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Classified gene: NKX2-1 as Red List (low evidence)
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Added comment: Comment on list classification: There is only 1 reported case to date of a patient with haploinsufficiency in NKX2-1 and pituitary hormone deficiency, so rating this gene as red for now.
Pituitary hormone deficiency v2.61 NKX2-1 Eleanor Williams Gene: nkx2-1 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.60 NKX2-1 Eleanor Williams Phenotypes for gene: NKX2-1 were changed from to Choreoathetosis, hypothyroidism, and neonatal respiratory distress, OMIM:610978; brain-lung-thyroid syndrome, MONDO:0012593
Pituitary hormone deficiency v2.59 NKX2-1 Eleanor Williams Publications for gene: NKX2-1 were set to
Pituitary hormone deficiency v2.58 NKX2-1 Eleanor Williams Mode of inheritance for gene: NKX2-1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.57 NKX2-1 Eleanor Williams commented on gene: NKX2-1: Associated with Choreoathetosis, hypothyroidism, and neonatal respiratory distress #610978 (AD) in OMIM.

Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome, Prasad et al 2019 (PMID:31707387) report a case of a patient with profound hypopituitarism in the early neonatal period in addition to undetectable tissue on thyroid ultrasonography, who was subsequently diagnosed with brain-lung-thyroid syndrome. She was found by CGH microarray to have 2 de novo deletions, a 4.9-Mb deletion in 14q13.2-q21.1 and a 404-kb deletion in 3 p12.3-p13. The 14q deletion contains 21 genes including NKX2-1. The deletion of this gene was thought to explain the phenotype.
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Classified gene: MAGEL2 as Red List (low evidence)
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber but with a recommendation for green rating following GMS review. More than 3 patients reported with plausible disease causing variants in MAGEL2 and a pituitary hormone deficiency
Pituitary hormone deficiency v2.57 MAGEL2 Eleanor Williams Gene: magel2 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.56 MAGEL2 Eleanor Williams Phenotypes for gene: MAGEL2 were changed from to Schaaf-Yang syndrome, OMIM:615547; Schaaf-Yang syndrome, MONDO:0014243
Pituitary hormone deficiency v2.55 MAGEL2 Eleanor Williams Publications for gene: MAGEL2 were set to
Pituitary hormone deficiency v2.54 MAGEL2 Eleanor Williams Mode of inheritance for gene: MAGEL2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: MAGEL2.
Tag Q3_22_NHS_review tag was added to gene: MAGEL2.
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: MAGEL2.
Tag Q3_22_rating tag was added to gene: MAGEL2.
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams changed review comment from: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency; to: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency
Pituitary hormone deficiency v2.53 MAGEL2 Eleanor Williams edited their review of gene: MAGEL2: Added comment: Associated with Schaaf-Yang syndrome #615547 (AD) in OMIM.

PMID: 31504653 - Gregory et al 2019 - report 4 patients from 3 unrelated families (2 White European, 1 White Chilean) with the same c.1996dup, p.Q666Pfs*47. variant in MAGEL2, who all presented with variable congenital hypopituitarism (CH) and arthrogryposis. In 2 cases it was found to be a de novo variant. In the other two it would found not to be maternally inherited but paternal DNA was not available.

PMID: 29359444 - Enya et al 2018 - report 3 patients from 2 Japanese families with Schaaf-Yang syndrome with arthrogryposis and endocrinological abnormalities. In both families variants in MAGEL2 were identified (c.1912C>T, p.Gln638*, inherited from the heterozygous father, and the de novo variant c.3131C>A, p.Ser1044*). The patient with the p.Ser1044* was was diagnosed with panhypopituitarism.

PMID: 30323850 - Hidalgo-Santos et al 2018 - report a patient with Schaaf-Yang syndrome and a de novo variant in MAGEL2 (c.3019 C > T, p.Gln1007*). The patient presented with distal contractures, hypotonia, autism spectrum disorder, digestive abnormalities, partial hypopituitarism with central hypothyroidism and growth hormone (GH) deficiency; Changed publications to: 31504653, 29359444, 30323850; Changed phenotypes to: Schaaf-Yang syndrome, OMIM:615547
Pituitary hormone deficiency v2.53 L1CAM Eleanor Williams changed review comment from: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.; to: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier and so there is insufficient evidence to say whether biallelic variants are required for a clinical phenotype in females. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.
Pituitary hormone deficiency v2.53 L1CAM Eleanor Williams Phenotypes for gene: L1CAM were changed from to CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350
Pituitary hormone deficiency v2.52 L1CAM Eleanor Williams Publications for gene: L1CAM were set to
Pituitary hormone deficiency v2.51 L1CAM Eleanor Williams Added comment: Comment on mode of inheritance: Using the default X linked mode of inheritance as only 1 case reported to date in a male, whose mother was a heterozygous carrier. For L1 syndrome female carriers have been noted to show minor features, such as adducted thumbs or mild intellectual deficits.
Pituitary hormone deficiency v2.51 L1CAM Eleanor Williams Mode of inheritance for gene: L1CAM was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.50 L1CAM Eleanor Williams commented on gene: L1CAM: PMID: 31504653 - Gregory et al 2019 - investigated 5 patients from 4 unrelated families who presented with variable congenital hypopituitarism (CH) and arthrogryposis. 1 Afro-Caribbean male patient was found by WES to have a hemizygous L1CAM c.1354G>A, p.G452R variant. This patient also had hydrocephalus and other features consistent with L1 syndrome.
Pituitary hormone deficiency v2.50 KCNQ1 Eleanor Williams commented on gene: KCNQ1: No new evidence reported since the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group at that point agreed that there is insufficient evidence to rate this gene as green. Therefore leaving this gene amber for now.
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: IGSF1.
Tag Q3_22_NHS_review tag was added to gene: IGSF1.
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Added comment: Comment on mode of inheritance: Heterozygous female carriers may show a phenotype related to the pituitary gland. In PMID: 24108313 (Joustra et al 2013) they report 6 females were biochemically hypothyroid, and 2 were prolactin deficient. (hypothyroid is linked to decreased function of the pituitary gland and prolactin is produced in the pituitary gland). PMID: 30086211 (Roche et al 2018) also report a heterozygous female with central hypothyroidism.

Therefore it is proposed to change the mode of inheritance to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease
Pituitary hormone deficiency v2.50 IGSF1 Eleanor Williams Mode of inheritance for gene: IGSF1 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams edited their review of gene: IGSF1: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams edited their review of gene: IGSF1: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.49 IGSF1 Eleanor Williams Phenotypes for gene: IGSF1 were changed from Hypothyroidism, central, and testicular enlargement (300888) to Hypothyroidism, central, and testicular enlargement, OMIM:300888
Pituitary hormone deficiency v2.48 IFT172 Eleanor Williams Phenotypes for gene: IFT172 were changed from to retinopathy, metaphyseal dysplasia
Pituitary hormone deficiency v2.47 IFT172 Eleanor Williams Publications for gene: IFT172 were set to
Pituitary hormone deficiency v2.46 IFT172 Eleanor Williams Mode of inheritance for gene: IFT172 was changed from to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.45 IFT172 Eleanor Williams commented on gene: IFT172: PMID: 25664603 - Lucas-Herald et al 2015 - first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood. He responded well to recombinant human growth hormone. He was found by WES to have compound heterozygous variants; a missense mutation, c.5179T>C (p.Cys1727Arg), and a novel splice site mutation in intron 4, c.337–2A>C. The parents were heterozygotes.

A PubMed search did not find any other cases were growth hormone deficiency is reported along with IFT172 variants.
Pituitary hormone deficiency v2.45 GPR161 Eleanor Williams Phenotypes for gene: GPR161 were changed from No OMIM number; pituitary stalk interruption syndrome to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.44 GPR161 Eleanor Williams Mode of inheritance for gene: GPR161 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.43 GPR161 Eleanor Williams commented on gene: GPR161: No phenotype association in OMIM.
As stated previously Karaca et al. (2015) (PMID:25322266) report that a homozygous missense variant IN GPR161 was found in 2 members of a family by WES. Both affected individuals had a clinical diagnosis of Pituitary stalk interruption syndrome (PSIS).
A search of PubMed did not find any further reported cases therefore this gene should remain red at this time.
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams changed review comment from: Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S,Dattani MT, Pitteloud N.J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.; to: Review on behalf of Professor Mehul Dattani, UCL GOS Institute of Child Health/Great Ormond Street Hospital for Children. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S,Dattani MT, Pitteloud N.J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.PMID: 22319038
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams commented on gene: FGFR1: Review from Professor Dattani confirms that this gene should be green.
Pituitary hormone deficiency v2.43 FGFR1 Eleanor Williams Phenotypes for gene: FGFR1 were changed from Hypogonadotropic hypogonadism 2 with or without anosmia (147950); Hartsfield syndrome (615465); Pfeiffer syndrome (101600); Jackson-Weiss syndrome (123150) to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Jackson-Weiss syndrome, OMIM:123150
Intellectual disability v3.1720 PTPA Konstantinos Varvagiannis gene: PTPA was added
gene: PTPA was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTPA were set to Complete
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysNDD.

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

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

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

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

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

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

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Pituitary hormone deficiency v2.42 EIF2S3 Eleanor Williams Phenotypes for gene: EIF2S3 were changed from hypopituitarism; glucose intolerance; MEHMO syndrome, OMIM:300148 to hypopituitarism, MONDO:0005152; glucose intolerance, MONDO:0001076; MEHMO syndrome, OMIM:300148; MEHMO syndrome, MONDO:0010258
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Tag watchlist tag was added to gene: EIF2S3.
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Classified gene: EIF2S3 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Added comment: Comment on list classification: Promoting to Amber. 2 cases reported with hypopituitarism. In another case growth hormone deficiency is noted so adding the watchlist tag.
Pituitary hormone deficiency v2.41 EIF2S3 Eleanor Williams Gene: eif2s3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.40 EIF2S3 Eleanor Williams Phenotypes for gene: EIF2S3 were changed from to hypopituitarism; glucose intolerance; MEHMO syndrome, OMIM:300148
Pituitary hormone deficiency v2.39 EIF2S3 Eleanor Williams Publications for gene: EIF2S3 were set to 30878599; 23063529; 27333055,; 28055140
Pituitary hormone deficiency v2.38 EIF2S3 Eleanor Williams Publications for gene: EIF2S3 were set to
Pituitary hormone deficiency v2.37 EIF2S3 Eleanor Williams Added comment: Comment on mode of inheritance: No female cases reported to date.
Pituitary hormone deficiency v2.37 EIF2S3 Eleanor Williams Mode of inheritance for gene: EIF2S3 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.36 EIF2S3 Eleanor Williams Mode of inheritance for gene: EIF2S3 was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.35 EIF2S3 Eleanor Williams edited their review of gene: EIF2S3: Added comment: Associated with MEHMO syndrome in OMIM #300148 (XLR)

PMID: 30878599 - Gregory et al 2019 - X-chromosome exome sequencing identified a missense variant in EIF2S3 (p.Pro432Ser) in 3 related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. The authors state this is the first time this combination of phenotypes has been reported in the literature.

Several other studies (PMID: 23063529,PMID: 27333055, PMID: 28055140) report the more severe MEHMO syndrome phenotype with severe learning difficulties, all in males. Heterozygous females are unaffected.
In PMID: 27333055 (Moortgat et al 2016) the growth hormone deficiency is noted in 2 related males, but for 1 it is reported that the pituitary gland and stalk were normal (not mentioned for the other). In PMID: 28055140 (Skopkova et al 2017) panhypopituitarism and partial hypopituitarism are noted as a clinical feature in two unrelated Slovakian patients (both with the same p.Ile465Serfs*4 variant).; Changed phenotypes to: HYPOPITUITARISM, GLUCOSE INTOLERANCE, FEATURES OF MEHMO SYNDROME, MEHMO syndrome, OMIM:300148; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Classified gene: BMP4 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 3 cases reported, but in one another gene was also deleted, and in the other only 3 genes were sequenced.
Pituitary hormone deficiency v2.35 BMP4 Eleanor Williams Gene: bmp4 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.34 BMP4 Eleanor Williams Phenotypes for gene: BMP4 were changed from Microphthalmia, syndromic 6 (607932) to Microphthalmia, syndromic 6, OMIM:607932
Pituitary hormone deficiency v2.33 BMP4 Eleanor Williams Publications for gene: BMP4 were set to 24289245
Pituitary hormone deficiency v2.32 BMP4 Eleanor Williams commented on gene: BMP4: PMID: 31120642 - Rodríguez-Contreras et al 2019 - report a 6 yo patient with combined pituitary hormone deficiency (CPHD ) who was found to have a de novo pathogenic loss-of-function variant (NM_001202.5:c.794G > A, p.(Trp265*)) in BMP4 following NGS using a custom 310 gene panel. His clinical phenotype included macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism.

PMID: 24289245 - Breitfeld et al 2014 - sequenced BMP2, 4 and 7 in 19 subjects with combined pituitary hormone deficiency (CPHD). 1 proband was found to have a p.Arg300Pro variant in BMP4 that is predicted to have functional consequences.

PMID: 18252212 - Bakrania et al 2008 - screened 215 individuals with ocular malformation defects for variants in BMP4 and gene deletions by MLPA. They report 1 case with pituitary abormalities along with bilateral anophthalmia, microcephaly, sensorineural deafness, cryptorchidism, partial callosal agenesis, cerebellar abnormalities, and developmental delay . The proband had a deletion of del(14)(q22.2q23.1) which encompasses BMP4 and OTX2. Using in situ hybridization in human embryos, they showed expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits.

Also:
PMID: 35633847 - Calcaterra et al 2022 - report a child with a novel variant p.Glu93* in exon 3 of BMP4. She was found to have an ectopic posterior pituitary but normal hormonal assessment, associated to craniocervical junction dysmorphism and limb anomaly.
Pituitary hormone deficiency v2.32 BRAF Eleanor Williams Classified gene: BRAF as Amber List (moderate evidence)
Pituitary hormone deficiency v2.32 BRAF Eleanor Williams Gene: braf has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Tag Q3_21_NHS_review was removed from gene: BRAF.
Tag Q3_22_NHS_review tag was added to gene: BRAF.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Tag Q3_21_NHS_review tag was added to gene: BRAF.
Tag Q3_22_rating tag was added to gene: BRAF.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Classified gene: BRAF as Red List (low evidence)
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, but with a green recommendation following GMS review. 5 cases reported with functional data implicating pituitary hormone deficiencies.
Pituitary hormone deficiency v2.31 BRAF Eleanor Williams Gene: braf has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.30 BRAF Eleanor Williams Phenotypes for gene: BRAF were changed from to Cardiofaciocutaneous syndrome, OMIM:115150; cardiofaciocutaneous syndrome, MONDO:0015280
Pituitary hormone deficiency v2.29 BRAF Eleanor Williams Publications for gene: BRAF were set to
Pituitary hormone deficiency v2.28 BRAF Eleanor Williams Added comment: Comment on mode of pathogenicity: All missense, activating variants
Pituitary hormone deficiency v2.28 BRAF Eleanor Williams Mode of pathogenicity for gene: BRAF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Pituitary hormone deficiency v2.27 BRAF Eleanor Williams Mode of inheritance for gene: BRAF was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.26 BRAF Eleanor Williams edited their review of gene: BRAF: Added comment: PMID: 33795686 - Gualtieri et al 2021 - report 5 unrelated patients with 4 different missense variants in BRAF. WES did not find any other likely causative variants. They all had Cardio-Facio-Cutaneous (CFC) syndrome and were identified to have features of Septo-Optic Dysplasia (SOD). Functional studies using HEK293T cells showed that the BRAF genetic variants are pathogenic and result in activation of the ERK/MAPK pathway. Mice expressing one of the variants found BRAF p.Q257R showed abnormalities in terminal differentiation of hormone-producing cells.; Changed publications to: 33795686; Changed phenotypes to: Cardiofaciocutaneous syndrome, OMIM:115150, cardiofaciocutaneous syndrome, MONDO:0015280
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Classified gene: ARNT2 as Red List (low evidence)
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Red. Still only 1 family with variants in this gene and pituitary hormone deficiency reported.
Pituitary hormone deficiency v2.26 ARNT2 Eleanor Williams Gene: arnt2 has been classified as Red List (Low Evidence).
Pituitary hormone deficiency v2.25 ARNT2 Eleanor Williams Phenotypes for gene: ARNT2 were changed from ?Webb-Dattani syndrome (615926) to ?Webb-Dattani syndrome, OMIM:615926
Pituitary hormone deficiency v2.24 ARNT2 Eleanor Williams commented on gene: ARNT2: Provisionally associated with Webb-Dattani syndrome in OMIM (#615926, AR)

As reviewers note PMID: 24022475 - Webb et al 2013 reports a novel homozygous frameshift variant in ARNT2 in a consanguineous family with six affected children. Phenotypic features include microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract.

A search of PubMed did not find any other reported cases.
Skeletal dysplasia v2.217 MYH3 Eleanor Williams Phenotypes for gene: MYH3 were changed from Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469 to Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469; contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, MONDO:0008338
Skeletal dysplasia v2.216 MYH3 Eleanor Williams Phenotypes for gene: MYH3 were changed from to Contractures, pterygia, and spondylocarpostarsal fusion syndrome 1A, OMIM:178110; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B, OMIM:618469
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Classified gene: MYH3 as Amber List (moderate evidence)
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a green recommendation following GMS review.
Skeletal dysplasia v2.215 MYH3 Eleanor Williams Gene: myh3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.214 MYH3 Eleanor Williams Tag Q3_22_rating tag was added to gene: MYH3.
Skeletal dysplasia v2.214 MYH3 Eleanor Williams Publications for gene: MYH3 were set to 35169139
Skeletal dysplasia v2.213 MYH3 Eleanor Williams reviewed gene: MYH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25957469, 27381093, 28205584, 29314551, 29805041, 35169139; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Tag watchlist tag was added to gene: DCHS2.
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Classified gene: DCHS2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be rated GREEN at the next major review. However, this may change if further DCHS2 variants are found in cases of pituitary stalk interruption syndrome.
Pituitary hormone deficiency v2.24 DCHS2 Sarah Leigh Gene: dchs2 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh edited their review of gene: DCHS2: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 33108146 reports three DCHS2 variants in three unrelated cases with pituitary stalk interruption syndrome (MONDO:0019828, which is a non-gene specific phenotype). However, one of these variants is digenic with a FAT2 variant and so its contribution to disease causation is uncertain. A Dchs2–/– mouse model has been examined and has defects in hypothalamic-pituitary development, but the phenotype is not consistent with the human condition.; Changed rating: AMBER
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh Classified gene: DCHS2 as Amber List (moderate evidence)
Pituitary hormone deficiency v2.23 DCHS2 Sarah Leigh Gene: dchs2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1720 DCHS2 Sarah Leigh Mode of inheritance for gene: DCHS2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.22 DCHS2 Sarah Leigh Mode of inheritance for gene: DCHS2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.21 FAT2 Sarah Leigh Phenotypes for gene: FAT2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.20 FAT2 Sarah Leigh Publications for gene: FAT2 were set to
Pituitary hormone deficiency v2.19 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to 29165578; 33108146
Intellectual disability v3.1719 DCHS2 Sarah Leigh Added comment: Comment on phenotypes: This Mondo term is a general description and not specific to a conidition associated with DCHS2 variants.
Intellectual disability v3.1719 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.18 DCHS2 Sarah Leigh Added comment: Comment on phenotypes: This Mondo term is a general description and not specific to a conidition associated with DCHS2 variants.
Pituitary hormone deficiency v2.18 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1718 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Pituitary hormone deficiency v2.17 DCHS2 Sarah Leigh Phenotypes for gene: DCHS2 were changed from to pituitary stalk interruption syndrome, MONDO:0019828
Intellectual disability v3.1717 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to 22005931; 26126179; 26876984; 26350204
Pituitary hormone deficiency v2.16 DCHS2 Sarah Leigh Publications for gene: DCHS2 were set to
Intellectual disability v3.1716 CDK9 Sarah Leigh Tag Q3_22_rating was removed from gene: CDK9.
Tag Q3_22_MOI was removed from gene: CDK9.
Tag watchlist tag was added to gene: CDK9.
Intellectual disability v3.1716 CDK9 Sarah Leigh Deleted their comment
Bilateral congenital or childhood onset cataracts v2.111 CDK9 Sarah Leigh Entity copied from Intellectual disability v3.1716
Bilateral congenital or childhood onset cataracts v2.111 CDK9 Sarah Leigh gene: CDK9 was added
gene: CDK9 was added to Cataracts. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: CDK9.
Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901
Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures
Penetrance for gene: CDK9 were set to Complete
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Tag watchlist tag was added to gene: NRCAM.
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh Tag watchlist tag was added to gene: NRCAM.
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh Tag Q3_22_rating was removed from gene: NRCAM.
Tag Q3_22_MOI was removed from gene: NRCAM.
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh Deleted their comment
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Deleted their comment
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Tag Q3_22_rating was removed from gene: NRCAM.
Tag Q3_22_MOI was removed from gene: NRCAM.
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh Entity copied from Intellectual disability v3.1716
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh gene: NRCAM was added
gene: NRCAM was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM.
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Penetrance for gene: NRCAM were set to Complete
Skeletal dysplasia v2.213 NRCAM Sarah Leigh Entity copied from Intellectual disability v3.1716
Skeletal dysplasia v2.213 NRCAM Sarah Leigh gene: NRCAM was added
gene: NRCAM was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM.
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Penetrance for gene: NRCAM were set to Complete
Intellectual disability v3.1716 ANK3 Sarah Leigh Tag Q2_22_MOI tag was added to gene: ANK3.
Tag Q3_22_rating tag was added to gene: ANK3.
Tag Q3_22_NHS_review tag was added to gene: ANK3.
Intellectual disability v3.1716 ANK3 Sarah Leigh Added comment: Comment on mode of inheritance: Due to the reports of heterozygous variants in PMIDs: 23390136; 28687526; 34218362, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1716 ANK3 Sarah Leigh Mode of inheritance for gene: ANK3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1715 ANK3 Sarah Leigh Classified gene: ANK3 as Amber List (moderate evidence)
Intellectual disability v3.1715 ANK3 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 v3.1715 ANK3 Sarah Leigh Gene: ank3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1714 ANK3 Sarah Leigh edited their review of gene: ANK3: Added comment: Associated with Intellectual developmental disorder, autosomal recessive 37 (OMIM:615493) in OMIM, but not associated with a phenotype in Gen2Phen. At least six ANK3 variants have now been associated with an autosomal dominant neurodevelopmental condition (PMIDs: 23390136; 28687526; 34218362). These terminating variants affect the transcripts for all of the ANK3 isoforms and are de novo (where trio evidence is available).; Changed rating: GREEN; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1714 ANK3 Sarah Leigh Publications for gene: ANK3 were set to 23390136; 34218362
Intellectual disability v3.1713 ANK3 Sarah Leigh Phenotypes for gene: ANK3 were changed from ?Mental retardation, autosomal recessive, 37 615493 to Intellectual developmental disorder, autosomal recessive 37, OMIM:615493; intellectual disability-hypotonia-spasticity-sleep disorder syndrome, MONDO:0014210
Intellectual disability v3.1712 ANK3 Sarah Leigh Publications for gene: ANK3 were set to 23390136
Pituitary hormone deficiency v2.15 DCHS2 Eleanor Williams reviewed gene: DCHS2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: PSIS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 ROBO1 Eleanor Williams reviewed gene: ROBO1: Rating: ; Mode of pathogenicity: ; Publications: 28402530; Phenotypes: PSIS, VARIABLE EYE ABNORMALITIES; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 WDR11 Eleanor Williams reviewed gene: WDR11: Rating: ; Mode of pathogenicity: ; Publications: 28453858; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TGIF1 Eleanor Williams reviewed gene: TGIF1: Rating: ; Mode of pathogenicity: ; Publications: 34440302; Phenotypes: HYPOPITUITARISM, HOLOPROSENCEPHALY; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TCF7L1 Eleanor Williams reviewed gene: TCF7L1: Rating: ; Mode of pathogenicity: ; Publications: 26764381; Phenotypes: SEPTO-OPTIC DYSPLASIA; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 TBC1D32 Eleanor Williams reviewed gene: TBC1D32: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: HYPOPITUITARISM, OROFACIODIGITAL SYNDROME FEATURES, POLYDACTYLY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 SOX2 Eleanor Williams reviewed gene: SOX2: Rating: ; Mode of pathogenicity: ; Publications: 16932809; Phenotypes: SEVERE EYE DEFECTS, DIPLEGIA, HYPOGONADOTROPHIC HYPOGONADISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 SIX3 Eleanor Williams reviewed gene: SIX3: Rating: ; Mode of pathogenicity: ; Publications: 35951005; Phenotypes: HYPOPITUITARISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 RNPC3 Eleanor Williams reviewed gene: RNPC3: Rating: ; Mode of pathogenicity: ; Publications: 34906446; Phenotypes: GHT, TSH AND PROLACTIN DEFICIENCY, PRIMARY OVARIAN FAILURE, NEUROPATHY, INTELLECTUAL DISABILITY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 RAX Eleanor Williams reviewed gene: RAX: Rating: ; Mode of pathogenicity: ; Publications: 30811539; Phenotypes: ANOPHTHALMIA, CLAEFT PALATE, DIABETES INSIPIDUS, HYPOPITUITARISM; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 PCSK1 Eleanor Williams reviewed gene: PCSK1: Rating: ; Mode of pathogenicity: ; Publications: 30383237; Phenotypes: CONGENITAL DIARRHOEA, HYPOPITUITARISM, OBESITY; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 PAX6 Eleanor Williams reviewed gene: PAX6: Rating: ; Mode of pathogenicity: ; Publications: 25342853; Phenotypes: EYE ABNORMALITIES, GH DEFICIENCY; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 NKX2-1 Eleanor Williams reviewed gene: NKX2-1: Rating: ; Mode of pathogenicity: ; Publications: 31707387; Phenotypes: BRAIN-THYROID-LUNG SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 MAGEL2 Eleanor Williams reviewed gene: MAGEL2: Rating: ; Mode of pathogenicity: ; Publications: 31504653; Phenotypes: SCHAAF-YANG SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Pituitary hormone deficiency v2.15 L1CAM Eleanor Williams reviewed gene: L1CAM: Rating: ; Mode of pathogenicity: ; Publications: 31504653; Phenotypes: HYDROCEPHALUS, ARTHROGRYPOSIS; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 KCNQ1 Eleanor Williams reviewed gene: KCNQ1: Rating: ; Mode of pathogenicity: ; Publications: 29097701; Phenotypes: Maternally inherited gingival fibromatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 IGSF1 Eleanor Williams reviewed gene: IGSF1: Rating: ; Mode of pathogenicity: ; Publications: 23143598; Phenotypes: MACRO-ORCHIDISM, TSH, GH AND PROLACTIN DEFICIENCIES,; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 IFT172 Eleanor Williams reviewed gene: IFT172: Rating: ; Mode of pathogenicity: ; Publications: 25664603; Phenotypes: RETINOPATHY, METAPHYSEAL DYSPLASIA; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 GPR161 Eleanor Williams reviewed gene: GPR161: Rating: ; Mode of pathogenicity: ; Publications: 25322266; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.15 FGFR1 Eleanor Williams reviewed gene: FGFR1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: CLEFT LIP/PALATE, OPTIC NERVE HYPOPLASIA; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 FAT2 Eleanor Williams reviewed gene: FAT2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: PITUITARY STALK INTERRUPTION SYNDROME; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 EIF2S3 Eleanor Williams reviewed gene: EIF2S3: Rating: ; Mode of pathogenicity: ; Publications: 30878599; Phenotypes: HYPOPITUITARISM, GLUCOSE INTOLERANCE, FEATURES OF MEHMO SYNDROME; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Pituitary hormone deficiency v2.15 BMP4 Eleanor Williams reviewed gene: BMP4: Rating: ; Mode of pathogenicity: ; Publications: 31120642; Phenotypes: LEARNING DIFFICULTIES; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 BRAF Eleanor Williams reviewed gene: BRAF: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: CARDIOFACIOCUTANEOUS SYNDROME + HYPOPITUITARISM; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Pituitary hormone deficiency v2.15 ARNT2 Eleanor Williams reviewed gene: ARNT2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: HYPOPITUITARISM, LEARNING DIFFICULTIES, MICROCEPHALY, DIABETES INSIPIDUS; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v2.14 DCHS2 Eleanor Williams gene: DCHS2 was added
gene: DCHS2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: DCHS2 was set to
Pituitary hormone deficiency v2.14 ROBO1 Eleanor Williams gene: ROBO1 was added
gene: ROBO1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: ROBO1 was set to
Pituitary hormone deficiency v2.14 TBC1D32 Eleanor Williams gene: TBC1D32 was added
gene: TBC1D32 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: TBC1D32 was set to
Pituitary hormone deficiency v2.14 RAX Eleanor Williams gene: RAX was added
gene: RAX was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: RAX was set to
Pituitary hormone deficiency v2.14 PCSK1 Eleanor Williams gene: PCSK1 was added
gene: PCSK1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: PCSK1 was set to
Pituitary hormone deficiency v2.14 NKX2-1 Eleanor Williams gene: NKX2-1 was added
gene: NKX2-1 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: NKX2-1 was set to
Pituitary hormone deficiency v2.14 MAGEL2 Eleanor Williams gene: MAGEL2 was added
gene: MAGEL2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: MAGEL2 was set to
Pituitary hormone deficiency v2.14 L1CAM Eleanor Williams gene: L1CAM was added
gene: L1CAM was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: L1CAM was set to
Pituitary hormone deficiency v2.14 IFT172 Eleanor Williams gene: IFT172 was added
gene: IFT172 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: IFT172 was set to
Pituitary hormone deficiency v2.14 FAT2 Eleanor Williams gene: FAT2 was added
gene: FAT2 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: FAT2 was set to
Pituitary hormone deficiency v2.14 EIF2S3 Eleanor Williams gene: EIF2S3 was added
gene: EIF2S3 was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: EIF2S3 was set to
Pituitary hormone deficiency v2.14 BRAF Eleanor Williams gene: BRAF was added
gene: BRAF was added to Pituitary hormone deficiency. Sources: Expert review
Mode of inheritance for gene: BRAF was set to
Neonatal diabetes v2.40 ZNF808 Eleanor Williams reviewed gene: ZNF808: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Neonatal diabetes, pancreatic agenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 ONECUT1 Eleanor Williams reviewed gene: ONECUT1: Rating: ; Mode of pathogenicity: ; Publications: 34663987; Phenotypes: Neonatal diabetes, pancreatic agenesis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 FICD Eleanor Williams reviewed gene: FICD: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Neonatal diabetes, severe neurodevelopmental delay and skeletal abnormalities.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neonatal diabetes v2.40 EIF2B1 Eleanor Williams reviewed gene: EIF2B1: Rating: ; Mode of pathogenicity: ; Publications: 31882561; Phenotypes: Permanent neonatal/early onset diabetes and transient liver dysfunction.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.40 CNOT1 Eleanor Williams reviewed gene: CNOT1: Rating: ; Mode of pathogenicity: ; Publications: 31006513, 35481434, 31006510; Phenotypes: Neonatal diabetes, pancreatic agenesis and holoprosencephaly.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neonatal diabetes v2.39 ZNF808 Eleanor Williams gene: ZNF808 was added
gene: ZNF808 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: ZNF808 was set to
Neonatal diabetes v2.39 ONECUT1 Eleanor Williams gene: ONECUT1 was added
gene: ONECUT1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: ONECUT1 was set to
Neonatal diabetes v2.39 FICD Eleanor Williams gene: FICD was added
gene: FICD was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: FICD was set to
Neonatal diabetes v2.39 EIF2B1 Eleanor Williams gene: EIF2B1 was added
gene: EIF2B1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: EIF2B1 was set to
Neonatal diabetes v2.39 CNOT1 Eleanor Williams gene: CNOT1 was added
gene: CNOT1 was added to Diabetes - neonatal onset. Sources: Expert review
Mode of inheritance for gene: CNOT1 was set to
Congenital hyperinsulinism v2.12 NSD1 Eleanor Williams reviewed gene: NSD1: Rating: ; Mode of pathogenicity: ; Publications: :30719864; Phenotypes: Hyperinsulinaemic hypoglycaemia, distinctive facial features, overgrowth in childhood and developmental delay.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 MAGEL2 Eleanor Williams reviewed gene: MAGEL2: Rating: ; Mode of pathogenicity: ; Publications: 25473036, 29599419, 31397880; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Congenital hyperinsulinism v2.12 HK1 Eleanor Williams reviewed gene: HK1: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 CACNA1D Eleanor Williams reviewed gene: CACNA1D: Rating: ; Mode of pathogenicity: ; Publications: 28318089, 32336187; Phenotypes: congenital hyperinsulinism, hypotonia and heart defects; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.12 CACNA1C Eleanor Williams reviewed gene: CACNA1C: Rating: ; Mode of pathogenicity: ; Publications: 35897673; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital hyperinsulinism v2.11 MAGEL2 Eleanor Williams gene: MAGEL2 was added
gene: MAGEL2 was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: MAGEL2 was set to
Congenital hyperinsulinism v2.11 HK1 Eleanor Williams gene: HK1 was added
gene: HK1 was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: HK1 was set to
Congenital hyperinsulinism v2.11 CACNA1C Eleanor Williams gene: CACNA1C was added
gene: CACNA1C was added to Congenital hyperinsulinism. Sources: Expert review
Mode of inheritance for gene: CACNA1C was set to
Intellectual disability v3.1711 DOCK8 Sarah Leigh Tag Q3_22_rating tag was added to gene: DOCK8.
Tag Q3_22_MOI tag was added to gene: DOCK8.
Tag Q3_22_NHS_review tag was added to gene: DOCK8.
Tag Q3_22_expert_review tag was added to gene: DOCK8.
Intellectual disability v3.1711 DOCK8 Sarah Leigh Added comment: Comment on phenotypes: Biallelic DOCK8 variants are associated with Hyper-IgE recurrent infection syndrome, autosomal recessive, OMIM:243700;combined immunodeficiency due to DOCK8 deficiency, MONDO:0009478
Intellectual disability v3.1711 DOCK8 Sarah Leigh Phenotypes for gene: DOCK8 were changed from Mental retardation, autosomal dominant 2, 614113Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; HYPERIMMUNOGLOBULIN E RECURRENT INFECTION SYNDROME AUTOSOMAL RECESSIVE (AR-HIES) to Intellectual developmental disorder, autosomal dominant 2, OMIM:614113
Intellectual disability v3.1710 DOCK8 Sarah Leigh reviewed gene: DOCK8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 2, OMIM:614113; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1710 DOCK8 Sarah Leigh Publications for gene: DOCK8 were set to
Early onset or syndromic epilepsy v2.595 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Intellectual disability v3.1709 CACNA1A Sarah Leigh Phenotypes for gene: CACNA1A were changed from Developemental and epileptic encephalopathy 42, OMIM:617106 to Developemental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917
Intellectual disability v3.1708 CACNA1A Sarah Leigh Publications for gene: CACNA1A were set to 24896178; 27476654
Intellectual disability v3.1707 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Tag Q3_22_MOI tag was added to gene: CACNA1A.
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1707 CACNA1A Sarah Leigh edited their review of gene: CACNA1A: Added comment: PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 36063114, 34267336, 33445191, 27250579; Changed phenotypes to: Developmental and epileptic encephalopathy 42, OMIM:617106; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.594 CACNA1A Sarah Leigh Publications for gene: CACNA1A were set to 29056246; 27476654; 11564488; 20071244; 15452324; 8898206
Adult onset neurodegenerative disorder v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Adult onset neurodegenerative disorder v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI was removed from gene: STUB1.
Intellectual disability v3.1707 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Intellectual disability v3.1707 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.261 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Childhood onset dystonia, chorea or related movement disorder v1.261 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.287 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Cerebellar hypoplasia v1.67 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Cerebellar hypoplasia v1.67 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.308 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Hereditary ataxia v1.308 STUB1 Sarah Leigh Mode of inheritance for gene: STUB1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.305 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Ataxia and cerebellar anomalies - narrow panel v2.305 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.287 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.162 STUB1 Sarah Leigh Tag Q3_22_MOI tag was added to gene: STUB1.
Hereditary ataxia with onset in adulthood v2.162 STUB1 Sarah Leigh reviewed gene: STUB1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.307 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Ataxia and cerebellar anomalies - narrow panel v2.305 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Brain channelopathy v1.80 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.80 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to
Parkinson Disease and Complex Parkinsonism v1.110 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Parkinson Disease and Complex Parkinsonism v1.109 TBP Sarah Leigh Publications for gene: TBP were set to
Adult onset neurodegenerative disorder v2.287 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Hereditary ataxia with onset in adulthood v2.162 TBP_CAG Sarah Leigh Publications for STR: TBP_CAG were set to 20301611
Ataxia and cerebellar anomalies - narrow panel v2.304 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16; Spinocerebellar ataxia, autosomal recessive 16 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Intellectual disability v3.1706 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16, 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Hereditary ataxia v1.306 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Cerebellar hypoplasia v1.66 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Childhood onset dystonia, chorea or related movement disorder v1.260 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16, 615768 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Adult onset neurodegenerative disorder v2.286 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Hereditary ataxia with onset in adulthood v2.161 STUB1 Sarah Leigh Phenotypes for gene: STUB1 were changed from Autosomal recessive spinocerebellar ataxia type 16, 615768; Spinocerebellar ataxia, autosomal recessive 16 to Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768; autosomal recessive spinocerebellar ataxia 16, MONDO:0014339; Spinocerebellar ataxia 48, OMIM:618093; spinocerebellar ataxia 48, MONDO:0032526
Intellectual disability v3.1705 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Childhood onset dystonia, chorea or related movement disorder v1.259 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Cerebellar hypoplasia v1.65 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Hereditary ataxia v1.305 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Ataxia and cerebellar anomalies - narrow panel v2.303 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 24312598
Hereditary ataxia with onset in adulthood v2.160 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 32713943; 33564152; 35493319; 34906452
Adult onset neurodegenerative disorder v2.285 STUB1 Sarah Leigh Publications for gene: STUB1 were set to 25592071; 30381368
Hereditary ataxia with onset in adulthood v2.159 STUB1 Sarah Leigh Publications for gene: STUB1 were set to
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots changed review comment from: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 cases had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 cases had seizures reported.; to: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had movement disorder and homozygous variant (nonsense, splice, frameshift and missense) and 3/6 studies had seizures reported.
Childhood onset dystonia, chorea or related movement disorder v1.258 DNAJC6 Dmitrijs Rots gene: DNAJC6 was added
gene: DNAJC6 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: DNAJC6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC6 were set to 34175496
Review for gene: DNAJC6 was set to AMBER
Added comment: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had childhood-onset movement disorder (mostly parkinsonism) and homozygous variant (nonsense, splice, frameshift and missense).
Sources: Literature
Early onset or syndromic epilepsy v2.593 DNAJC6 Dmitrijs Rots reviewed gene: DNAJC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 34175496; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.212 MYH3 Dmitrijs Rots gene: MYH3 was added
gene: MYH3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MYH3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYH3 were set to 35169139
Review for gene: MYH3 was set to GREEN
Added comment: 17 individuals with variable vertebral and spine anomalies, as well as short stature reported in 35169139. Pathogenic variants in MYH3 cause not only Arthrogryposis.
Sources: Literature
Structural eye disease v1.146 NR2F1 Eleanor Williams Classified gene: NR2F1 as Red List (low evidence)
Structural eye disease v1.146 NR2F1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as 1 case reported.
Structural eye disease v1.146 NR2F1 Eleanor Williams Gene: nr2f1 has been classified as Red List (Low Evidence).
Structural eye disease v1.145 NR2F1 Eleanor Williams Mode of pathogenicity for gene: NR2F1 was changed from Other to None
Structural eye disease v1.144 NR2F1 Eleanor Williams changed review comment from: As Samantha Malka reports PMID:34787370 (Gazdagh et al 2022) report a severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in a patient with a de novo missense variant in the start codon of the NR2F1 gene. The patient showed a typical BBSOAS phenotype with developmental delay, seizures, optic atrophy however this patient also had colobomas and septo-optic dysplasia.; to: As Samantha Malka comments PMID:34787370 (Gazdagh et al 2022) report a severe case of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in a patient with a de novo missense variant in the start codon of the NR2F1 gene. The patient showed a typical BBSOAS phenotype with developmental delay, seizures, optic atrophy however this patient also had colobomas and septo-optic dysplasia.
Structural eye disease v1.144 NR2F1 Eleanor Williams commented on gene: NR2F1
Structural eye disease v1.144 NR2F1 Eleanor Williams Publications for gene: NR2F1 were set to PMID: 34787370
Structural eye disease v1.143 NR2F1 Eleanor Williams Phenotypes for gene: NR2F1 were changed from Bosch-Boonstra-Schaaf optic atrophy syndrome to Bosch-Boonstra-Schaaf optic atrophy syndrome, OMIM:615722; Bosch-Boonstra-Schaaf optic atrophy syndrome, MONDO:0014320
Structural eye disease v1.142 KIF7 Eleanor Williams Classified gene: KIF7 as Red List (low evidence)
Structural eye disease v1.142 KIF7 Eleanor Williams Added comment: Comment on list classification: Leaving rating as red. Although a second case with a variant in KIF7 is reported in Niceta et al (2020) the patient also has a homozygous variant in KIAA0556.
Structural eye disease v1.142 KIF7 Eleanor Williams Gene: kif7 has been classified as Red List (Low Evidence).
Structural eye disease v1.141 KIF7 Eleanor Williams Publications for gene: KIF7 were set to 21633164
Structural eye disease v1.140 KIAA0556 Eleanor Williams Classified gene: KIAA0556 as Red List (low evidence)
Structural eye disease v1.140 KIAA0556 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as one case reported with structural eye phenotype but the individual also had a biallelic variant in KIF7.
Structural eye disease v1.140 KIAA0556 Eleanor Williams Gene: kiaa0556 has been classified as Red List (Low Evidence).
Structural eye disease v1.139 KIAA0556 Eleanor Williams Phenotypes for gene: KIAA0556 were changed from Joubert syndrome 26 to Joubert syndrome 26, OMIM:616784; Joubert syndrome 26, MONDO:0014771
Structural eye disease v1.138 KIAA0556 Eleanor Williams Publications for gene: KIAA0556 were set to PMID: 32164589
Structural eye disease v1.137 EP300 Eleanor Williams Classified gene: EP300 as Red List (low evidence)
Structural eye disease v1.137 EP300 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red as 1 case with a structural eye phenotype reported
Structural eye disease v1.137 EP300 Eleanor Williams Gene: ep300 has been classified as Red List (Low Evidence).
Structural eye disease v1.136 EP300 Eleanor Williams Mode of inheritance for gene: EP300 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Structural eye disease v1.135 EP300 Eleanor Williams Phenotypes for gene: EP300 were changed from Rubinstein-Taybi syndrome 2 to Rubinstein-Taybi syndrome 2, OMIM:613684; Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, MONDO:0013364
Structural eye disease v1.134 EP300 Eleanor Williams Publications for gene: EP300 were set to PMID: 26279656
Structural eye disease v1.133 EP300 Eleanor Williams Mode of pathogenicity for gene: EP300 was changed from Other to None
Structural eye disease v1.132 EP300 Eleanor Williams commented on gene: EP300
Stickler syndrome v2.35 BMP4 Eleanor Williams changed review comment from: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert.; to: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert. Therefore it is recommended for a green rating following GMS review.
Stickler syndrome v2.35 BMP4 Eleanor Williams Classified gene: BMP4 as Amber List (moderate evidence)
Stickler syndrome v2.35 BMP4 Eleanor Williams Added comment: Comment on list classification: Although there is not 3 cases reported of patients with Stickler syndrome and variants in this gene, there is evidence of association with an eye phenotype. This gene has been reviewed as green by an Stickler syndrome expert.
Stickler syndrome v2.35 BMP4 Eleanor Williams Gene: bmp4 has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.34 BMP4 Eleanor Williams Publications for gene: BMP4 were set to 30568244
Stickler syndrome v2.33 BMP4 Eleanor Williams Mode of inheritance for gene: BMP4 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Stickler syndrome v2.32 BMP4 Eleanor Williams Tag Q3_22_rating tag was added to gene: BMP4.
Tag Q3_22_NHS_review tag was added to gene: BMP4.
Stickler syndrome v2.32 BMP4 Eleanor Williams commented on gene: BMP4
Stickler syndrome v2.32 VCAN Eleanor Williams Mode of inheritance for gene: VCAN was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Stickler syndrome v2.31 VCAN Eleanor Williams Classified gene: VCAN as Amber List (moderate evidence)
Stickler syndrome v2.31 VCAN Eleanor Williams Added comment: Comment on list classification: Promoted from grey to amber, with a recommendation for green rating following GMS expert review to decide whether this gene is appropriate for the panel.
Stickler syndrome v2.31 VCAN Eleanor Williams Gene: vcan has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.30 VCAN Eleanor Williams Tag Q3_22_rating tag was added to gene: VCAN.
Tag Q3_22_NHS_review tag was added to gene: VCAN.
Tag Q3_22_expert_review tag was added to gene: VCAN.
Stickler syndrome v2.30 VCAN Eleanor Williams Phenotypes for gene: VCAN were changed from Ocular-only Stickler syndrome; Wagner syndrome to Ocular-only Stickler syndrome; Wagner syndrome 1, OMIM:143200
Stickler syndrome v2.29 VCAN Eleanor Williams Publications for gene: VCAN were set to Snead M, Richards A. A frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration. Am J Ophthalmol. 2002 Sep; 134(3):473; author reply 473-4. doi: 10.1016/s0002-9394(02)01635-5. PMID: 12208278.
Stickler syndrome v2.28 VCAN Eleanor Williams Added comment: Comment on mode of pathogenicity: Disease associated variants all affect splicing.
Stickler syndrome v2.28 VCAN Eleanor Williams Mode of pathogenicity for gene: VCAN was changed from None to Other
Stickler syndrome v2.27 VCAN Eleanor Williams commented on gene: VCAN
Early onset or syndromic epilepsy v2.593 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 23252400; 31584066
Congenital disorders of glycosylation v2.94 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 23252400
Likely inborn error of metabolism v2.321 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Undiagnosed metabolic disorders v1.564 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
DDG2P v2.81 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to 21907012; 17120046
Fetal anomalies v1.970 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Intellectual disability v3.1704 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Congenital disorders of glycosylation v2.93 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Epileptic encephalopathy, early infantile, 15 615006; ST3GAL3-CDG (Disorders of protein N-glycosylation) to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Likely inborn error of metabolism v2.320 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Intellectual disability; Epileptic encephalopathy, early infantile, 15 615006; ST3GAL3-CDG (Disorders of protein N-glycosylation) to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Undiagnosed metabolic disorders v1.563 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from ST3GAL3-CDG (Disorders of protein N-glycosylation); Intellectual disability to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Fetal anomalies v1.969 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
DDG2P v2.80 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 611090 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Intellectual disability v3.1703 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Mental retardation, autosomal recessive 12, 611090Epileptic encephalopathy, early infantile, 15, 615006; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 12 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Early onset or syndromic epilepsy v2.592 ST3GAL3 Sarah Leigh Phenotypes for gene: ST3GAL3 were changed from Epileptic encephalopathy, early infantile, 15 to Developmental and epileptic encephalopathy 15, OMIM:615006; developmental and epileptic encephalopathy, 15, MONDO:0014003; Intellectual developmental disorder, autosomal recessive 12, OMIM:611090; intellectual disability, autosomal recessive 12, MONDO:0012612
Early onset or syndromic epilepsy v2.591 ST3GAL3 Sarah Leigh Publications for gene: ST3GAL3 were set to
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Tag watchlist tag was added to gene: HEATR3.
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh edited their review of gene: HEATR3: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), is was concluded that there is not enough evidence for skeletal dysplasia in the cases reported in PMID: 35213692 for HEATR3 to be rated green on this panel, as the height of the affected individuals ranged from <–4 SD to normal.; Changed rating: AMBER
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Tag Q3_22_rating was removed from gene: HEATR3.
Tag Q3_22_MOI was removed from gene: HEATR3.
Limb disorders v2.81 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. HEATR3 has been rated as Green as the affected members of 3/4 families identified had brachydactyly and other features of hands and/or feet.
Limb disorders v2.81 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Limb disorders v2.81 HEATR3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb disorders v2.81 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.80 HEATR3 Sarah Leigh Entity copied from Rare anaemia v1.42
Limb disorders v2.80 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Limb disorders. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: HEATR3.
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh Entity copied from Rare anaemia v1.42
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: HEATR3.
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
White matter disorders and cerebral calcification - narrow panel v1.244 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Fetal hydrops v1.55 PEX6 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for PEX6 has been set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.; to: Comment on mode of inheritance: The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal, in order to detect the dominant Peroxisome biogenesis disorder 4B (OMIM:614863). Incomplete penetrance has been noted for this gene, in order to highlight that unaffected parents may also carry rs61753230.
Intellectual disability v3.1702 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Intellectual disability v3.1702 HEATR3 Sarah Leigh Added comment: Comment on list classification: The amber rating reflects that mild ID has been associated with HEATR3 variants.
Intellectual disability v3.1702 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1701 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Early onset or syndromic epilepsy v2.590 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Severe microcephaly v2.317 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
The rating of this gene could be changed to green, if further disease associated variants are identified or supportive functional studies are reported.
Childhood onset dystonia, chorea or related movement disorder v1.258 XK Sarah Leigh Classified gene: XK as Red List (low evidence)
Childhood onset dystonia, chorea or related movement disorder v1.258 XK Sarah Leigh Added comment: Comment on list classification: Not appropriate for this panel, as older onset.
Childhood onset dystonia, chorea or related movement disorder v1.258 XK Sarah Leigh Gene: xk has been classified as Red List (Low Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh Tag Q3_22_rating was removed from gene: XK.
Tag Q3_22_MOI was removed from gene: XK.
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh edited their review of gene: XK: Changed rating: RED
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK could be predictive of possible future conditions.
Early onset dystonia v1.127 XK Sarah Leigh reviewed gene: XK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh Deleted their comment
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh Deleted their comment
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh Added comment: Comment on publications: 11761473;8004674;11032622;11261514;33652783;30128557;8619554
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh Publications for gene: XK were set to 11761473; 30128557; 8004674; 8619554
Early onset dystonia v1.127 XK Sarah Leigh Publications for gene: XK were set to 11761473; 8004674; 11032622; 11261514
Early onset dystonia v1.126 XK Sarah Leigh Publications for gene: XK were set to 11761473; 11761473
Fetal anomalies v1.968 SETD2 Arina Puzriakova Classified gene: SETD2 as Amber List (moderate evidence)
Fetal anomalies v1.968 SETD2 Arina Puzriakova Added comment: Comment on list classification: Following clinical review, it was agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.968 SETD2 Arina Puzriakova Gene: setd2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.967 SETD2 Arina Puzriakova Mode of pathogenicity for gene: SETD2 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
Fetal anomalies v1.966 SETD2 Arina Puzriakova Phenotypes for gene: SETD2 were changed from SETD2-associated Overgrowth Syndrome to microcephaly; profound intellectual disability; congenital anomalies; dysmorphic facial features
Fetal anomalies v1.965 SETD2 Arina Puzriakova Publications for gene: SETD2 were set to
Fetal anomalies v1.964 SETD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SETD2.
Tag Q3_22_NHS_review tag was added to gene: SETD2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Classified gene: IFNAR2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.577 IFNAR2 Arina Puzriakova Gene: ifnar2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.576 IFNAR2 Arina Puzriakova Publications for gene: IFNAR2 were set to 32048120; 26424569; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: IFNAR2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova reviewed gene: IFNAR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26424569, 33193576, 33544838, 35442417, 35944424; Phenotypes: Immunodeficiency 45, OMIM:616669; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.590 XK Sarah Leigh edited their review of gene: XK: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), the recommendation for XK has been changed to Amber. This is because there appear to be adult onset of neurological symptoms, including seizures. The scope of the Genetic epilepsy syndromes panel is targeting early onset severe or syndromic epilepsy.; Changed rating: AMBER
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Classified gene: ADAMTS15 as Amber List (moderate evidence)
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Arthrogryposis v3.163 ADAMTS15 Sarah Leigh Gene: adamts15 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.162 ADAMTS15 Sarah Leigh gene: ADAMTS15 was added
gene: ADAMTS15 was added to Arthrogryposis. Sources: Literature
Q3_22_rating, Q3_22_MOI tags were added to gene: ADAMTS15.
Mode of inheritance for gene: ADAMTS15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS15 were set to 35962790
Phenotypes for gene: ADAMTS15 were set to distal arthrogryposis
Review for gene: ADAMTS15 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported by PMID: 35962790 in four independent consanguineous families, the unaffected parents were heterozgous for the causative variants in each of the families.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.575 IFNAR2 Arina Puzriakova Phenotypes for gene: IFNAR2 were changed from Defects in Intrinsic and Innate Immunity; Severe viral infections (disseminated vaccine-strain measles, HHV6); ?Immunodeficiency 45, 616669 to Immunodeficiency 45, OMIM:616669
Early onset dystonia v1.125 HPRT1 Sarah Leigh Phenotypes for gene: HPRT1 were changed from Lesch-Nyhan syndrome, OMIM:300322; Dystonia to Lesch-Nyhan syndrome, OMIM:300322
Early onset or syndromic epilepsy v2.590 CACNA1A Hannah Robinson reviewed gene: CACNA1A: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36063114, PMID: 34267336, PMID: 33445191, PMID: 27250579; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset dystonia v1.124 HPRT1 Sarah Leigh Classified gene: HPRT1 as Green List (high evidence)
Early onset dystonia v1.124 HPRT1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numous variants have been reported in Lesch-Nyhan syndrome (OMIM:300322) cases.
Early onset dystonia v1.124 HPRT1 Sarah Leigh Gene: hprt1 has been classified as Green List (High Evidence).
Early onset dystonia v1.123 HPRT1 Sarah Leigh Publications for gene: HPRT1 were set to
Intellectual disability v3.1701 ERMARD Dmitrijs Rots reviewed gene: ERMARD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1701 SMAD3 Dmitrijs Rots reviewed gene: SMAD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.590 CAPRIN1 Konstantinos Varvagiannis gene: CAPRIN1 was added
gene: CAPRIN1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CAPRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAPRIN1 were set to 35979925; 35977029; 28135719; 31398340; https://doi.org/10.1101/2021.12.20.21267194
Phenotypes for gene: CAPRIN1 were set to Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures
Penetrance for gene: CAPRIN1 were set to Incomplete
Review for gene: CAPRIN1 was set to AMBER
Added comment: A cohort of 12 individuals harboring pathogenic CAPRIN1 variants is described in a recent report by Pavinato et al (2022 - PMID: 35979925).

DD, impaired speech/language development (100%), ID (83%), ASD (67%) and seizures (33%) are part of the phenotype (details below).

Enrichment for de novo LGD but also missense variants has also been demonstrated upon meta-analysis of different cohorts of 40,853 individuals with ID (N=31,625) or ASD (N=9,228) as discussed by Jia et al (2022 - PMID: 35977029).

Role of the gene:
Evidence supports among others, a role for CAPRIN1 in formation RNA-protein (stress) granules through interaction with other relevant proteins (e.g. G3BP1/2, FMRP) and regulation of gene expression (Pavinato et al - PMID: 35979925, Jia et al - PMID: 35977029).
Jia et al further demonstrated significant reduction of stress granule formation in CAPRIN1 KO HeLa lines.
Following generation of CAPRIN1+/- hiPSC line using CRISPR/Cas9 and differentiation into cortical neurons, Pavinato et al noted, altered neuronal structure, abnormal firing properties as well as increased neuronal degeneration possibly linked to presence of increased Ca+2 signals and increase in reactive oxygen species (ROS). Global de novo protein synthesis in neurons appeared to be impaired.

Variant type and inheritance :
All individuals reported by Paviato et al harbored pLoF (nonsense, frameshift, splicing and a synonymous variant resulting in abnormal splicing) variants. In most cases variants occurred de novo with the exception of 2 subjects having inherited pLoF variants from their affected/unaffected parent. Expressive variability, reduced penetrance and possibility of - a yet to be proven - sex bias are discussed (9M/3F).
Missense variants and enrichment for dn missense SNVs have also been shown in large cohorts. The impact of p.I373K has been studied.

Variant effect:
pLoF : Pavinato et al demonstrated reduced mRNA and protein levels for the truncating variants, and out-of frame exon skipping for a variant affecting splice donor site and a further SNV affecting the last nucleotide of ex8.
Missense SNVs : p.I373K abolished interaction with G3BP1/2 and disrupted stress granule formation in the study by Jia et al demonstrating a role of stress granules in pathogenesis of neurodevelopmental disorders.

Animal model:
As discussed by Pavinato et al abnormal neuronal structure and firing properties are observed in htz mouse models. Htz mice display features of ASD, difficulties in reversal learning (for ID), sporadic occurrence of seizures. Hearing impairment (as in 2-3 individuals described) due to reduced protection from noise exposure was reported in an ear-conditional ko model.

The report by Pavinato et al is summarized below.

For the study by Jia et al a summary can by found under the review of UBAP2L.

Reports of individuals in the context of larger cohorts were not here reviewed (eg. DDD study 2017, PMID: 28135719 || Ruzzo et al 2019, PMID: 31398340 || Fu et al 2021, https://doi.org/10.1101/2021.12.20.21267194).

----

Pavinato et al (2022 - PMID: 35979925) describe the phenotype associated with heterozygous CAPRIN1 pathogenic variants.

Overlapping features incl. impaired speech/language development (100%), ID (83%), ASD (67%), ADHD (82%), seizures (33% or 4/12 : absence seizures in 2, infantile spasms with absence epilepsy, secondary generalized epileptic seizures during sleep). Respiratory problems (50%), limb/skeletal anomalies (50%), feeding difficulties (33%), mild hearing hearing impairment (in 2 or 3). There was no evident dysmorphism, despite few recurrent features.

CAPRIN1 encodes cell cycle-associated protein 1. As the authors discuss, the gene is ubiquitously expressed with high expression in brain. The protein is known to interact with other RNA-binding proteins (eg. FMRP, G3BP1) for the formation of ribonucleoparticles / RNA granules. The gene localizes in neuronal RNA granules in dendrites. Previous studies have demonstrated a role in regulation of mRNA translation (acting as translational inhibitor with its overexpression leading to reduced protein synthesis). CAPRIN1 interacts with FMRP and CYFIP1, both also involved in regulation of mRNA translation.

One individual with microdeletion (~1.4 Mb spanning 8 genes with CAPRIN1 the only predicted to be haploinsufficient) as well as 11 additional subjects with nonsense/splicing variants were identified, following CMA, ES or GS. [The gene has a pHaplo of 0.98 and pLI of 0.97 (LOEUF 0.31)].

Variants were mostly de novo, although one individual had inherited a nonsense variant from his affected father while one further from her unaffected mother.

qRT-PCR showed reduced mRNA levels in patient fibroblasts and PBMCs while cycloheximide treatment in fibroblasts resulted in partial rescue in expression of mutant allele. Western blot in fibroblasts confirmed reduced protein levels.

cDNA analysis revealed that c.279+1G>T variant resulted in out-of-frame skipping of ex3, while c.879G>A (last base of ex8) resulted in out-of-frame skipping of ex8 and degradation by NMD, with cycloheximide restoring expression of mutant allele. [ NM_005898.5 ]

The authors generated a CAPRIN1+/- hiPSC line using CRISPR/Cas9 and hiPSCs were differentiated into cortical neurons. Htz immature neurons displayed altered neuronal structure, accompanied by reduced neurite length similar to previous observations in mice.

Increased neuronal degeneration was observed. Ca+2 signals (described in literature to trigger or contribute to neuronal death) were increased compared to controls. Increase in reactive oxygen species (ROS) following Ca+2 overload was also demonstrated, likely contributing to neuronal death.

Given the gene's role in regulation of mRNA translation, the authors assessed global de novo protein synthesis in neurons based on pyromicin incorporation (SUnSET assay) with findings supporting the impact of CAPRIN1 haploinsufficiency.

Heterozygous neurons were shown to display abnormal firing properties similar to a previously reported mouse model.

Mouse model : apart from the findings discussed above (abnormal neuronal structure and firing properties), heterozygous mice displayed similar features to the cohort described eg. reduced sociability and weaker preference for social novelty (as in ASD), difficulties in reversal learning (for ID), sporadic occurrence of seizures upon Morris water maze/contextual fearing tests and epileptic-like fEPSP after LTP. Breathing problems were noted in Carpin1-/- mice. Ear conditional ko was associated with early-onset progressive hearing loss and reduced protection from noise exposure which might be in line with few individuals with hearing impairment.
Sources: Literature
Intellectual disability v3.1701 CAPRIN1 Konstantinos Varvagiannis reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979925, 35977029, 28135719, 31398340, https://doi.org/10.1101/2021.12.20.21267194; Phenotypes: Global developmental delay, Delayed speech and language development, Intellectual disability, Autistic behavior, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.590 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to AMBER
Added comment: Seizures have been reported in several individuals although a formal diagnosis of epilepsy was retained in ~30% in a small cohort discussed below. Consider inclusion with amber rating.

-----

Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Intellectual disability v3.1701 UBAP2L Konstantinos Varvagiannis gene: UBAP2L was added
gene: UBAP2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP2L were set to 35977029
Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system
Penetrance for gene: UBAP2L were set to unknown
Review for gene: UBAP2L was set to GREEN
Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1).

Details provided below.

Not associated with any phenotype in OMIM, G2P or SysNDD.

--------

Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L.

Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each).

Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression.

Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants.

Variant effect/studies (NM_014847.4 / NP_055662.3) :
- Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping.
- In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels.
- 8 of the 9 nonsense/frameshift variants were predicted to result to NMD.
- 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream).
- Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions.
- The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization.

Mouse model :
- The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment.
- Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation.
- Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer.

Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs:
- Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly).
- Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M].
- Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C].
- Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules.
- Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT.
- Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation.
Sources: Literature
Fetal anomalies v1.964 SETD2 Rhiannon Mellis reviewed gene: SETD2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 32710489, 33255631; Phenotypes: microcephaly, profound intellectual disability, congenital anomalies, dysmorphic facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v1.132 KIAA0556 Samantha Malka gene: KIAA0556 was added
gene: KIAA0556 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: KIAA0556 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0556 were set to PMID: 32164589
Phenotypes for gene: KIAA0556 were set to Joubert syndrome 26
Penetrance for gene: KIAA0556 were set to Complete
Mode of pathogenicity for gene: KIAA0556 was set to Other
Review for gene: KIAA0556 was set to RED
Added comment: Niceta et al (2020) - published a case including coloboma with a patient with biallelic KIAA0556 mutations (patient also had biallelic mutations in KIF7)
Sources: Literature
Structural eye disease v1.132 KIF7 Samantha Malka Deleted their comment
Structural eye disease v1.132 KIF7 Samantha Malka commented on gene: KIF7: Niceta et al (2020) - published a case including coloboma with a patient with biallelic KIF7 mutations (patient also had biallelic mutations in KIAA0556)
Structural eye disease v1.132 KIF7 Samantha Malka reviewed gene: KIF7: Rating: RED; Mode of pathogenicity: Other; Publications: PMID: 32164589; Phenotypes: Joubert syndrome 12; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.132 EP300 Samantha Malka gene: EP300 was added
gene: EP300 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EP300 were set to PMID: 26279656
Phenotypes for gene: EP300 were set to Rubinstein-Taybi syndrome 2
Penetrance for gene: EP300 were set to unknown
Mode of pathogenicity for gene: EP300 was set to Other
Review for gene: EP300 was set to RED
Added comment: One reported case of Rubinstein-Taybi syndrome 2 with an EP300 genetic diagnosis, having a phenotype including coloboma.
Sources: Literature
Structural eye disease v1.132 NR2F1 Samantha Malka gene: NR2F1 was added
gene: NR2F1 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: NR2F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR2F1 were set to PMID: 34787370
Phenotypes for gene: NR2F1 were set to Bosch-Boonstra-Schaaf optic atrophy syndrome
Penetrance for gene: NR2F1 were set to Complete
Mode of pathogenicity for gene: NR2F1 was set to Other
Review for gene: NR2F1 was set to RED
Added comment: One report in literature of a phenotype including coloboma
Sources: Literature
Intellectual disability v3.1701 ANK3 Rachel Challis reviewed gene: ANK3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 28687526, 34218362; Phenotypes: Intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova commented on gene: RPS15: This gene has been flagged for GMS expert review as published evidence linking germline variants to haematological malignancies is limited, which may warrant a rating downgrade from Green, subject to review.
RPS15 somatic variants are enriched within chronic lymphocytic leukemia, particularly in aggressive cases - however, the contribution of germline variants is not well-defined.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Tag somatic tag was added to gene: RPS15.
Haematological malignancies for rare disease v1.14 RPS15 Arina Puzriakova Tag somatic tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Tag Q3_22_rating tag was added to gene: RPS15.
Tag Q3_22_expert_review tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.36 RPS15 Arina Puzriakova Phenotypes for gene: RPS15 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia; Chronic lymphocytic leukemia
Haematological malignancies for rare disease v1.14 RPS15 Arina Puzriakova Phenotypes for gene: RPS15 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia; Chronic lymphocytic leukemia
Haematological malignancies cancer susceptibility v2.35 RPS15 Arina Puzriakova Publications for gene: RPS15 were set to 28297620
Haematological malignancies for rare disease v1.13 RPS15 Arina Puzriakova Publications for gene: RPS15 were set to 28297620
Haematological malignancies for rare disease v1.12 RPS15 Arina Puzriakova Tag watchlist tag was added to gene: RPS15.
Haematological malignancies cancer susceptibility v2.34 RPS15 Arina Puzriakova reviewed gene: RPS15: Rating: ; Mode of pathogenicity: None; Publications: 19061985, 26466571, 26675346, 30181176, 34251413; Phenotypes: Diamond-Blackfan anemia, Chronic lymphocytic leukemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies for rare disease v1.12 RPS15 Arina Puzriakova reviewed gene: RPS15: Rating: ; Mode of pathogenicity: None; Publications: 19061985, 26466571, 26675346, 30181176, 34251413; Phenotypes: Diamond-Blackfan anemia, Chronic lymphocytic leukemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v2.158 STUB1 James Polke reviewed gene: STUB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32713943, 33564152, 35493319, 34906452; Phenotypes: Cerebellar Ataxia, Dementia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Adult onset neurodegenerative disorder v2.284 STUB1 James Polke reviewed gene: STUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32713943, 33564152, 35493319, 34906452; Phenotypes: Cerebellar Ataxia, Dementia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.284 STUB1 James Polke Deleted their review
Adult onset neurodegenerative disorder v2.284 STUB1 James Polke reviewed gene: STUB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32713943, 33564152; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: FASTKD2.
Mitochondrial disorder with complex IV deficiency v1.24 FASTKD2 Arina Puzriakova Publications for gene: FASTKD2 were set to 28499982
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: FASTKD2.
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova reviewed gene: FASTKD2: Rating: RED; Mode of pathogenicity: None; Publications: 31944455; Phenotypes: Combined oxidative phosphorylation deficiency 44, OMIM:618855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Early onset or syndromic epilepsy v2.590 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.148 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.148 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Childhood onset hereditary spastic paraplegia v2.148 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.147 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that the number of unrelated families presenting the relevant phenotype meets the criteria for an Amber rating at this time.
Optic neuropathy v2.75 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
White matter disorders and cerebral calcification - narrow panel v1.244 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.244 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that a Green rating on this panel is justified given the number of unrelated families presenting a relevant phenotype meets the criteria.
White matter disorders and cerebral calcification - narrow panel v1.244 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Classified gene: BLOC1S1 as Amber List (moderate evidence)
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Added comment: Comment on list classification: After seeking consultation from the Helen Brittain (Genomics England Clinical Team) due to the limited details provided in the paper as well as lack of additional support albeit with a sufficient number of total cases with a consistent phenotype (PMID:33875846), it was decided that a Green rating on this panel is justified given the number of unrelated families presenting a relevant phenotype meets the criteria.
Intellectual disability v3.1701 BLOC1S1 Arina Puzriakova Gene: bloc1s1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.243 BLOC1S1 Arina Puzriakova Tag watchlist was removed from gene: BLOC1S1.
Tag Q3_22_rating tag was added to gene: BLOC1S1.
Intellectual disability v3.1700 BLOC1S1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: BLOC1S1.
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Optic neuropathy v2.74 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Optic neuropathy. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Childhood onset hereditary spastic paraplegia v2.147 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Childhood onset hereditary spastic paraplegia v2.147 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
White matter disorders and cerebral calcification - narrow panel v1.243 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
White matter disorders and cerebral calcification - narrow panel v1.243 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova Entity copied from Intellectual disability v3.1700
Early onset or syndromic epilepsy v2.589 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Genetic epilepsy syndromes. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Intellectual disability v3.1700 BLOC1S1 Arina Puzriakova Publications for gene: BLOC1S1 were updated from PMID: 33875846 to 33875846
Early onset or syndromic epilepsy v2.588 FASTKD2 Arina Puzriakova Publications for gene: FASTKD2 were set to
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: FASTKD2.
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova reviewed gene: FASTKD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18771761, 28499982, 31944455, 35729327; Phenotypes: Combined oxidative phosphorylation deficiency 44, OMIM:618855; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset dystonia, chorea or related movement disorder v1.174 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.256 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Childhood onset dystonia, chorea or related movement disorder v1.255 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Dystonia
Childhood onset dystonia, chorea or related movement disorder v1.254 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.79 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Mitochondrial disorders v2.177 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Adult onset dystonia, chorea or related movement disorder v1.173 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Early onset or syndromic epilepsy v2.587 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Early onset or syndromic epilepsy v2.586 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.319 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency; Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency; Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors) to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Possible mitochondrial disorder - nuclear genes v1.160 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Undiagnosed metabolic disorders v1.562 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Complex IV (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS assembly factors); Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110; Mitochondrial Diseases; Mitochondrial Respiratory Chain Complex IV Deficiency to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Adult onset neurodegenerative disorder v2.284 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Adult onset neurodegenerative disorder v2.283 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.23 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from ?Mitochondrial complex IV deficiency, 220110 to Combined oxidative phosphorylation deficiency 44, OMIM:618855
Early onset dystonia v1.122 FASTKD2 Arina Puzriakova Mode of inheritance for gene: FASTKD2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.121 FASTKD2 Arina Puzriakova Phenotypes for gene: FASTKD2 were changed from Dystonia to Combined oxidative phosphorylation deficiency 44, OMIM:618855; Dystonia
Likely inborn error of metabolism v2.318 UQCRC2 Arina Puzriakova Mode of inheritance for gene: UQCRC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.317 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorders v2.176 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Possible mitochondrial disorder - nuclear genes v1.159 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorder with complex III deficiency v1.17 UQCRC2 Arina Puzriakova Publications for gene: UQCRC2 were set to 28275242; 23281071
Mitochondrial disorders v2.175 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Isolated complex III deficiency; Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Likely inborn error of metabolism v2.316 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160; Isolated complex III deficiency to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Possible mitochondrial disorder - nuclear genes v1.158 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Mitochondrial disorder with complex III deficiency v1.16 UQCRC2 Arina Puzriakova Phenotypes for gene: UQCRC2 were changed from Mitochondrial complex III deficiency, nuclear type 5, 615160 to Mitochondrial complex III deficiency, nuclear type 5, OMIM:615160
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Likely inborn error of metabolism v2.315 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Mitochondrial disorders v2.174 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v2.282 UQCRC1 Arina Puzriakova Tag watchlist tag was added to gene: UQCRC1.
Adult onset neurodegenerative disorder v2.282 UQCRC1 Arina Puzriakova Classified gene: UQCRC1 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v2.282 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804)
Adult onset neurodegenerative disorder v2.282 UQCRC1 Arina Puzriakova Gene: uqcrc1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.314 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Adult onset neurodegenerative disorder v2.281 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to 33141179; 33248804
Mitochondrial disorders v2.173 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Possible mitochondrial disorder - nuclear genes v1.157 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Mitochondrial disorder with complex III deficiency v1.15 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to 30788857; 33141179; 33779694; 33248804
Mitochondrial disorder with complex III deficiency v1.14 UQCRC1 Arina Puzriakova Publications for gene: UQCRC1 were set to
Likely inborn error of metabolism v2.313 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.172 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v1.156 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.312 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Mitochondrial disorder with complex III deficiency v1.13 UQCRC1 Arina Puzriakova Mode of inheritance for gene: UQCRC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.171 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Adult onset neurodegenerative disorder v2.280 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from 33141179; 33248804 to Parkinsonism with polyneuropathy, OMIM:619279
Possible mitochondrial disorder - nuclear genes v1.155 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Mitochondrial disorder with complex III deficiency v1.12 UQCRC1 Arina Puzriakova Phenotypes for gene: UQCRC1 were changed from No OMIM phenotype to Parkinsonism with polyneuropathy, OMIM:619279
Likely inborn error of metabolism v2.311 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from lesions in the medulla oblongata to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Mitochondrial disorders v2.170 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Mitochondrial disorder with complex IV deficiency v1.22 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Possible mitochondrial disorder - nuclear genes v1.154 PET117 Arina Puzriakova Phenotypes for gene: PET117 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 19, OMIM:619063
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Classified gene: NFS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS review - associated with relevant phenotype in OMIM (MIM#619386) but not yet in G2P. At least one variant reported in six cases from two unrelated families, together with supportive functional studies.
Likely inborn error of metabolism v2.310 NFS1 Arina Puzriakova Gene: nfs1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NFS1.
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova reviewed gene: NFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24498631, 33457206; Phenotypes: Combined oxidative phosphorylation deficiency 52, OMIM: 619386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.309 NFS1 Arina Puzriakova Mode of inheritance for gene: NFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.153 NFS1 Arina Puzriakova Classified gene: NFS1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.153 NFS1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS review - associated with relevant phenotype in OMIM (MIM#619386) but not yet in G2P. At least one variant reported in six cases from two unrelated families, together with supportive functional studies.
Possible mitochondrial disorder - nuclear genes v1.153 NFS1 Arina Puzriakova Gene: nfs1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.308 NFS1 Arina Puzriakova Publications for gene: NFS1 were set to
Possible mitochondrial disorder - nuclear genes v1.152 NFS1 Arina Puzriakova Publications for gene: NFS1 were set to 24498631
Possible mitochondrial disorder - nuclear genes v1.151 NFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NFS1.
Possible mitochondrial disorder - nuclear genes v1.151 NFS1 Arina Puzriakova edited their review of gene: NFS1: Added comment: Also now additional paper - PMID 33457206: reporting a second family (consanguineous) with three affected children and supportive functional data. Homozygous for the same missense variant as reported in the 2014 paper - this family of Christian Arab descent; the family in the previous report of Mennonite background. Suggests this is a mutation hotspot.; Changed rating: GREEN; Changed publications to: 24498631, 33457206
Possible mitochondrial disorder - nuclear genes v1.151 NFS1 Arina Puzriakova changed review comment from: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; to: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on evidence provided in PMID:24498631
Likely inborn error of metabolism v2.307 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Mitochondrial disorders v2.169 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Possible mitochondrial disorder - nuclear genes v1.151 NFS1 Arina Puzriakova Phenotypes for gene: NFS1 were changed from Infantile mitochondrial complex II/III deficiency to Combined oxidative phosphorylation deficiency 52, OMIM:619386
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IRF7 Dmitrijs Rots reviewed gene: IRF7: Rating: AMBER; Mode of pathogenicity: None; Publications: 35986347; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IFNAR2 Dmitrijs Rots changed review comment from: In review 35986347 report on family with severe COVID and biallelic IFNAR2 variant.; to: In review 35986347 report on study + family with severe COVID and biallelic IFNAR2 variant.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 IFNAR2 Dmitrijs Rots reviewed gene: IFNAR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35986347; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.168 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Likely inborn error of metabolism v2.306 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Disorders of mitochondrial DNA maintenance and integrity; Mitochondrial DNA Depletion Syndrome (biallelic); Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Undiagnosed metabolic disorders v1.561 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia, autosomal dominant, 3, 609286; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions (monoallelic); Mitochondrial Membrane Protein-Associated Neurodegeneration (biallelic); Mitochondrial DNA Depletion Syndrome (biallelic) to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Mitochondrial liver disease, including transient infantile liver failure v1.8 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Possible mitochondrial disorder - nuclear genes v1.150 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Mitochondrial DNA maintenance disorder v1.24 TWNK Arina Puzriakova Phenotypes for gene: TWNK were changed from Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), 271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, 609286 to Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286; Perrault syndrome 5, OMIM:616138
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.25 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Hereditary Paraganglioma-Pheochromocytoma Syndrome; Leigh syndrome, 256000Mitochondrial respiratory chain complex II deficiency, 252011Cardiomyopathy, dilated, 1GG, 613642Paragangliomas 5, 614165 to Paragangliomas 5, OMIM:614165
Inherited phaeochromocytoma and paraganglioma v1.11 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000Mitochondrial respiratory chain complex II deficiency, 252011Cardiomyopathy, dilated, 1GG, 613642Paragangliomas 5, 614165; Hereditary Paraganglioma-Pheochromocytoma Syndrome to Paragangliomas 5, OMIM:614165
Neuroendocrine cancer pertinent cancer susceptibility v1.4 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Neuroendocrine cancer to Paragangliomas 5, OMIM:614165
Likely inborn error of metabolism v2.305 SDHA Arina Puzriakova Publications for gene: SDHA were set to 27604308
Undiagnosed metabolic disorders v1.560 SDHA Arina Puzriakova Publications for gene: SDHA were set to 27604308
Mitochondrial disorders v2.167 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Possible mitochondrial disorder - nuclear genes v1.149 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Likely inborn error of metabolism v2.304 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Leigh syndrome, 256000; Paragangliomas 5, 614165; Cardiomyopathy, dilated, 1GG, 613642; Isolated complex II deficiency; Mitochondrial respiratory chain complex II deficiency, 252011; Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorder with complex II deficiency v1.9 SDHA Arina Puzriakova Publications for gene: SDHA were set to
Undiagnosed metabolic disorders v1.559 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex II deficiency; Leigh syndrome, 256000; Mitochondrial respiratory chain complex II deficiency, 252011; Cardiomyopathy, dilated, 1GG, 613642; Paragangliomas 5, 614165; Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorders v2.166 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Isolated complex II deficiency; Leigh syndrome, 256000; Mitochondrial respiratory chain complex II deficiency, 252011; Cardiomyopathy, dilated, 1GG, 613642; Paragangliomas 5, 614165; Mitochondrial Respiratory Chain Complex II Deficiency to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Possible mitochondrial disorder - nuclear genes v1.148 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, 252011; Leigh syndrome, 256000 to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Mitochondrial disorder with complex II deficiency v1.8 SDHA Arina Puzriakova Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, 252011; Leigh syndrome, 256000 to Mitochondrial complex II deficiency, nuclear type 1, OMIM:252011; Neurodegeneration with ataxia and late-onset optic atrophy, OMIM:619259; Cardiomyopathy, dilated, 1GG, OMIM:613642
Likely inborn error of metabolism v2.303 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Mitochondrial disorders v2.165 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Likely inborn error of metabolism v2.302 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 29440775; 26741492
Possible mitochondrial disorder - nuclear genes v1.147 QRSL1 Arina Puzriakova Phenotypes for gene: QRSL1 were changed from Mitochondrial cardiomyopathy; Combined oxidative phosphorylation deficiency 40, 618835 to Combined oxidative phosphorylation deficiency 40, OMIM:618835
Mitochondrial disorders v2.164 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 29440775; 26741492
Possible mitochondrial disorder - nuclear genes v1.146 QRSL1 Arina Puzriakova Publications for gene: QRSL1 were set to 30283131; 26741492
Early onset or syndromic epilepsy v2.585 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Fetal anomalies v1.964 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16 (hepatic type), MONDO:0032799; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MONDO:0012415 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Likely inborn error of metabolism v2.301 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 27604308
Mitochondrial liver disease, including transient infantile liver failure v1.7 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Possible mitochondrial disorder - nuclear genes v1.145 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Mitochondrial DNA maintenance disorder v1.23 POLG2 Arina Puzriakova Publications for gene: POLG2 were set to 30157269
Mitochondrial disorders v2.163 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Likely inborn error of metabolism v2.300 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Disorders of mitochondrial DNA maintenance and integrity; Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Undiagnosed metabolic disorders v1.558 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Required for mtDNA maintenance (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4,610131; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Mitochondrial liver disease, including transient infantile liver failure v1.6 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Possible mitochondrial disorder - nuclear genes v1.144 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Mitochondrial DNA maintenance disorder v1.22 POLG2 Arina Puzriakova Phenotypes for gene: POLG2 were changed from Mitochondrial DNA depletion syndrome, NA; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM:618528; Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM:619425; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Childhood onset dystonia, chorea or related movement disorder v1.253 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Intellectual disability v3.1699 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Early onset or syndromic epilepsy v2.584 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Cytopenia - NOT Fanconi anaemia v1.72 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Likely inborn error of metabolism v2.299 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Undiagnosed metabolic disorders v1.557 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Primary immunodeficiency or monogenic inflammatory bowel disease v2.574 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Mitochondrial disorders v2.162 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Possible mitochondrial disorder - nuclear genes v1.143 CLPB Arina Puzriakova Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813
Possible mitochondrial disorder - nuclear genes v1.142 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 26916670; 28687938; 34140661
Cytopenia - NOT Fanconi anaemia v1.71 CLPB Arina Puzriakova Publications for gene: CLPB were set to 25597510; 25597511; 25650066; 26916670; 28687938; 34140661
Likely inborn error of metabolism v2.298 UQCRFS1 Arina Puzriakova Classified gene: UQCRFS1 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.298 UQCRFS1 Arina Puzriakova Gene: uqcrfs1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.161 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Mitochondrial disorders v2.160 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Likely inborn error of metabolism v2.297 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Likely inborn error of metabolism v2.296 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Possible mitochondrial disorder - nuclear genes v1.141 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Mitochondrial disorder with complex III deficiency v1.11 UQCRFS1 Arina Puzriakova Phenotypes for gene: UQCRFS1 were changed from No OMIM phenotype to Mitochondrial complex III deficiency, nuclear type 10, OMIM:618775
Mitochondrial disorders v2.159 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.140 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Mitochondrial disorder with complex III deficiency v1.10 UQCRFS1 Arina Puzriakova Publications for gene: UQCRFS1 were set to
Likely inborn error of metabolism v2.295 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex III deficiency v1.9 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.158 UQCRFS1 Arina Puzriakova Classified gene: UQCRFS1 as Amber List (moderate evidence)
Mitochondrial disorders v2.158 UQCRFS1 Arina Puzriakova Gene: uqcrfs1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v1.139 UQCRFS1 Arina Puzriakova Mode of inheritance for gene: UQCRFS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.157 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Likely inborn error of metabolism v2.294 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Possible mitochondrial disorder - nuclear genes v1.138 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to
Mitochondrial disorders v2.156 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Likely inborn error of metabolism v2.293 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Possible mitochondrial disorder - nuclear genes v1.137 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Mitochondrial disorder with complex I deficiency v1.30 TIMMDC1 Arina Puzriakova Phenotypes for gene: TIMMDC1 were changed from Mitochondrial complex I deficiency, nuclear type 31, 618251 to Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251
Mitochondrial disorder with complex I deficiency v1.29 TIMMDC1 Arina Puzriakova Publications for gene: TIMMDC1 were set to 28604674
Likely inborn error of metabolism v2.292 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial disorders v2.155 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Possible mitochondrial disorder - nuclear genes v1.136 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial DNA maintenance disorder v1.21 TFAM Arina Puzriakova Publications for gene: TFAM were set to 27448789
Mitochondrial disorders v2.154 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial liver disease, including transient infantile liver failure v1.5 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME 15 (HEPATOCEREBRAL TYPE), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Likely inborn error of metabolism v2.291 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Possible mitochondrial disorder - nuclear genes v1.135 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial DNA maintenance disorder v1.20 TFAM Arina Puzriakova Phenotypes for gene: TFAM were changed from ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156 to Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM:617156
Mitochondrial disorders v2.153 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Likely inborn error of metabolism v2.290 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Possible mitochondrial disorder - nuclear genes v1.134 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from Combined oxidative phosphorylation deficiency 21 OMIM:615918; combined oxidative phosphorylation defect type 21 MONDO:0014398 to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Childhood onset dystonia, chorea or related movement disorder v1.252 TARS2 Arina Puzriakova Phenotypes for gene: TARS2 were changed from to Combined oxidative phosphorylation deficiency 21, OMIM:615918
Possible mitochondrial disorder - nuclear genes v1.133 TARS2 Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: TARS2.
Inherited white matter disorders v1.160 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Mitochondrial Leukoencephalopathy; Succinate dehydrogenase-deficient leukoencephalopathy; complex II deficiency to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
White matter disorders and cerebral calcification - narrow panel v1.242 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Succinate dehydrogenase-deficient leukoencephalopathy; complex II deficiency; Mitochondrial Leukoencephalopathy to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Childhood solid tumours v2.35 SDHB Arina Puzriakova Mode of inheritance for gene: SDHB was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Adult solid tumours cancer susceptibility v2.22 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Familial Paraganglioma and Pheochromocytoma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Childhood solid tumours v2.34 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Adult solid tumours for rare disease v1.34 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Familial Paraganglioma and Pheochromocytoma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864; Gastrointestinal stromal tumor, OMIM:606764
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.24 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paraganglioma and Gastric Stromal Sarcoma; Paragangliomas 4, 115310Pheochromocytoma, 171300Paraganglioma and gastric stromal sarcoma, 606864Cowden syndrome 2, 612359Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Inherited phaeochromocytoma and paraganglioma v1.10 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paraganglioma and Gastric Stromal Sarcoma; Paragangliomas 4, 115310Pheochromocytoma, 171300Paraganglioma and gastric stromal sarcoma, 606864Cowden syndrome 2, 612359Gastrointestinal stromal tumor, 606764 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Multiple endocrine tumours v1.14 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Endocrine Cancer; familial paraganglioma to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Inherited renal cancer v1.22 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, OMIM:115310; Renal cell carcinoma (disease), MONDO:0005086 to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Renal cancer pertinent cancer susceptibility v1.2 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Renal cancer to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Neuroendocrine cancer pertinent cancer susceptibility v1.3 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Neuroendocrine cancer to Paragangliomas 4, OMIM:115310; Pheochromocytoma, OMIM:171300; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Genodermatoses with malignancies v1.7 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764 to Gastrointestinal stromal tumor, OMIM:606764; Paraganglioma and gastric stromal sarcoma, OMIM:606864
Likely inborn error of metabolism v2.289 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Mitochondrial Diseases; Gastrointestinal stromal tumor, 606764; Pheochromocytoma, 171300; Paragangliomas 4, 115310; Isolated complex II deficiency; Cowden syndrome 2, 612359; Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Paraganglioma and gastric stromal sarcoma, 606864 to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Undiagnosed metabolic disorders v1.556 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Complex II (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); Isolated complex II deficiency; Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Gastrointestinal stromal tumor, 606764; Mitochondrial Diseases to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorders v2.152 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from Isolated complex II deficiency; Paragangliomas 4, 115310; Pheochromocytoma, 171300; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 2, 612359; Gastrointestinal stromal tumor, 606764; Mitochondrial Diseases to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Possible mitochondrial disorder - nuclear genes v1.133 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from No OMIM phenotype to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorder with complex II deficiency v1.7 SDHB Arina Puzriakova Phenotypes for gene: SDHB were changed from No OMIM phenotype to Mitochondrial complex II deficiency, nuclear type 4, OMIM:619224
Mitochondrial disorders v2.151 SDHB Arina Puzriakova Publications for gene: SDHB were set to 26925370; 22972948
Possible mitochondrial disorder - nuclear genes v1.132 SDHB Arina Puzriakova Publications for gene: SDHB were set to 22972948
Mitochondrial disorder with complex II deficiency v1.6 SDHB Arina Puzriakova Publications for gene: SDHB were set to 22972948
Likely inborn error of metabolism v2.288 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from Combined mitochondrial respiratory chain complex deficiency to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Mitochondrial disorders v2.150 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Possible mitochondrial disorder - nuclear genes v1.131 NSUN3 Arina Puzriakova Phenotypes for gene: NSUN3 were changed from No OMIM phenotype to Combined oxidative phosphorylation deficiency 48, OMIM:619012
Mitochondrial disorders v2.149 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Likely inborn error of metabolism v2.287 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Possible mitochondrial disorder - nuclear genes v1.130 NSUN3 Arina Puzriakova Publications for gene: NSUN3 were set to 27356879
Mitochondrial disorders v2.148 NDUFC2 Arina Puzriakova Publications for gene: NDUFC2 were set to
Mitochondrial disorders v2.147 NDUFC2 Arina Puzriakova Phenotypes for gene: NDUFC2 were changed from Isolated complex I deficiency; No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 36, OMIM:619170
Mitochondrial disorders v2.146 NDUFC2 Arina Puzriakova Classified gene: NDUFC2 as Amber List (moderate evidence)
Mitochondrial disorders v2.146 NDUFC2 Arina Puzriakova Gene: ndufc2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.145 NDUFC2 Arina Puzriakova Mode of inheritance for gene: NDUFC2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.129 SSBP1 Arina Puzriakova Classified gene: SSBP1 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v1.129 SSBP1 Arina Puzriakova Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Mitochondrial DNA maintenance disorder v1.19 SSBP1 Arina Puzriakova Classified gene: SSBP1 as Amber List (moderate evidence)
Mitochondrial DNA maintenance disorder v1.19 SSBP1 Arina Puzriakova Gene: ssbp1 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v1.128 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 was changed from Other to Other
Possible mitochondrial disorder - nuclear genes v1.127 SSBP1 Arina Puzriakova Publications for gene: SSBP1 were set to 29182774
Mitochondrial DNA maintenance disorder v1.18 SSBP1 Arina Puzriakova Publications for gene: SSBP1 were set to 29182774
Possible mitochondrial disorder - nuclear genes v1.126 SSBP1 Arina Puzriakova Phenotypes for gene: SSBP1 were changed from No OMIM phenotype to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Mitochondrial DNA maintenance disorder v1.17 SSBP1 Arina Puzriakova Phenotypes for gene: SSBP1 were changed from No OMIM phenotype to Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510
Likely inborn error of metabolism v2.286 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.286 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.285 NDUFB10 Arina Puzriakova Mode of inheritance for gene: NDUFB10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.144 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Mitochondrial disorders v2.144 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.284 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to
Mitochondrial disorders v2.143 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Possible mitochondrial disorder - nuclear genes v1.125 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Likely inborn error of metabolism v2.283 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorder with complex I deficiency v1.28 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to 28040730
Possible mitochondrial disorder - nuclear genes v1.124 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorders v2.142 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from Isolated complex I deficiency; No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Mitochondrial disorder with complex I deficiency v1.27 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 35, OMIM:619003
Possible mitochondrial disorder - nuclear genes v1.123 NDUFB10 Arina Puzriakova changed review comment from: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; to: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. Three individuals from two unrelated families now reported with convincing functional studies that support mitochondrial disease (PMID: 28040730; 33169436)
Likely inborn error of metabolism v2.282 NDUFA8 Arina Puzriakova Classified gene: NDUFA8 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.282 NDUFA8 Arina Puzriakova Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.141 NDUFA8 Arina Puzriakova Classified gene: NDUFA8 as Amber List (moderate evidence)
Mitochondrial disorders v2.141 NDUFA8 Arina Puzriakova Gene: ndufa8 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.281 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial Diseases; No OMIM phenotype; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorders v2.140 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Isolated complex I deficiency; No OMIM phenotype; Mitochondrial Diseases to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Likely inborn error of metabolism v2.280 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to
Possible mitochondrial disorder - nuclear genes v1.123 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272 to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorder with complex I deficiency v1.26 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272 to Mitochondrial complex I deficiency, nuclear type 37, OMIM:619272
Mitochondrial disorders v2.139 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to 15576045
Possible mitochondrial disorder - nuclear genes v1.122 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272
Mitochondrial disorder with complex I deficiency v1.25 NDUFA8 Arina Puzriakova Phenotypes for gene: NDUFA8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272
Likely inborn error of metabolism v2.279 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.138 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.121 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to
Possible mitochondrial disorder - nuclear genes v1.120 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.24 NDUFA8 Arina Puzriakova Publications for gene: NDUFA8 were set to 15576045
Mitochondrial disorder with complex I deficiency v1.23 NDUFA8 Arina Puzriakova Mode of inheritance for gene: NDUFA8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.137 NDUFA13 Arina Puzriakova Classified gene: NDUFA13 as Amber List (moderate evidence)
Mitochondrial disorders v2.137 NDUFA13 Arina Puzriakova Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.278 NDUFA13 Arina Puzriakova Classified gene: NDUFA13 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.278 NDUFA13 Arina Puzriakova Gene: ndufa13 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.277 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from Mitochondrial Diseases; {Thyroid carcinoma, Hurthle cell}, 607464; Isolated complex I deficiency to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Mitochondrial disorders v2.136 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from Isolated complex I deficiency; Mitochondrial Diseases; ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Possible mitochondrial disorder - nuclear genes v1.119 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Mitochondrial disorder with complex I deficiency v1.22 NDUFA13 Arina Puzriakova Phenotypes for gene: NDUFA13 were changed from ?Mitochondrial complex I deficiency, nuclear type 28, 618249 to Mitochondrial complex I deficiency, nuclear type 28, OMIM:618249
Likely inborn error of metabolism v2.276 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Mitochondrial disorders v2.135 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Possible mitochondrial disorder - nuclear genes v1.118 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to
Mitochondrial disorder with complex I deficiency v1.21 NDUFA13 Arina Puzriakova Publications for gene: NDUFA13 were set to 25901006
Possible mitochondrial disorder - nuclear genes v1.117 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Intellectual disability v3.1698 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Likely inborn error of metabolism v2.275 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Adult onset dystonia, chorea or related movement disorder v1.172 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244; Leigh syndrome due to mitochondrial complex 1 deficiency to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Mitochondrial disorders v2.134 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Adult onset neurodegenerative disorder v2.279 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Mitochondrial disorder with complex I deficiency v1.20 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Intellectual disability v3.1697 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to
Likely inborn error of metabolism v2.274 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Adult onset dystonia, chorea or related movement disorder v1.171 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Adult onset neurodegenerative disorder v2.278 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Mitochondrial disorders v2.133 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 33715266
Possible mitochondrial disorder - nuclear genes v1.116 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to
Mitochondrial disorder with complex I deficiency v1.19 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Undiagnosed metabolic disorders v1.555 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Undiagnosed metabolic disorders v1.554 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Undiagnosed metabolic disorders v1.553 LYRM4 Arina Puzriakova Classified gene: LYRM4 as Green List (high evidence)
Undiagnosed metabolic disorders v1.553 LYRM4 Arina Puzriakova Gene: lyrm4 has been classified as Green List (High Evidence).
Mitochondrial disorders v2.132 LYRM4 Arina Puzriakova Classified gene: LYRM4 as Amber List (moderate evidence)
Mitochondrial disorders v2.132 LYRM4 Arina Puzriakova Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.273 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Mitochondrial disorders v2.131 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Mitochondrial disorders v2.130 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to
Possible mitochondrial disorder - nuclear genes v1.115 LYRM4 Arina Puzriakova Phenotypes for gene: LYRM4 were changed from ?Combined oxidative phosphorylation deficiency 19, 615595 to Combined oxidative phosphorylation deficiency 19, OMIM:615595
Likely inborn error of metabolism v2.272 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Possible mitochondrial disorder - nuclear genes v1.114 LYRM4 Arina Puzriakova Publications for gene: LYRM4 were set to 23814038
Possible mitochondrial disorder - nuclear genes v1.113 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Mitochondrial disorder with complex IV deficiency v1.21 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Possible mitochondrial disorder - nuclear genes v1.112 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v1.20 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.111 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Mitochondrial disorder with complex IV deficiency v1.19 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Adult onset neurodegenerative disorder v2.277 SPTLC1 James Polke gene: SPTLC1 was added
gene: SPTLC1 was added to Neurodegenerative disorders - adult onset. Sources: NHS GMS
Mode of inheritance for gene: SPTLC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTLC1 were set to 34059824; 34459874; 35627278; 35900868
Phenotypes for gene: SPTLC1 were set to Juvenile ALS
Penetrance for gene: SPTLC1 were set to Incomplete
Mode of pathogenicity for gene: SPTLC1 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: SPTLC1 was set to GREEN
Added comment: SPTLC1 previously associated with HSN1A but variants in these two publications associated with juvenile ALS. 34059824 and 35900868 propose a distinct pathomechanism of juvenile ALS variants (increased sphinganine systhesis) compared to HSN1A variants (shift to deoxysphinganine synthesis). At least 5 different variants now reported, almost all de-novo, but one family in 34059824 with p.Leu39del inherited from father with mild sensorimotor axonal neuropathy. Juvenile onset but inclusion on this adult panel in-line with current inclusion of ALS2 and SETX which also cause early onset ALS.

No evidence that LoF variants cause HSN1A or juvenile ALS - GOF mechanisms demonstrated.
Sources: NHS GMS
Likely inborn error of metabolism v2.271 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.271 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.129 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Mitochondrial disorders v2.129 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.270 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v2.128 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.269 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorders v2.127 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Possible mitochondrial disorder - nuclear genes v1.110 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v1.109 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorder with complex V deficiency v1.15 ATP5G3 Arina Puzriakova Publications for gene: ATP5G3 were set to
Mitochondrial disorders v2.126 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Likely inborn error of metabolism v2.268 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Possible mitochondrial disorder - nuclear genes v1.108 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Mitochondrial disorder with complex V deficiency v1.14 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from No OMIM phenotype to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Mitochondrial disorder with complex V deficiency v1.13 ATP5G3 Arina Puzriakova Mode of inheritance for gene: ATP5G3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.583 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Likely inborn error of metabolism v2.267 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to PMID: 23599390 (two siblings with a severe neonatal encephalopathy caused by complex V deficiency); PMID: 23596069 (newborn female with failure to thrive, microcephaly, encephalopathy, IUGR, hypotonia, bacteremia, pulmonary hypertension, heart failure, and mitchondrial depletion).
Mitochondrial disorders v2.125 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23599390; 23596069
Likely inborn error of metabolism v2.266 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22; Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228; ?Combined oxidative phosphorylation deficiency 22 616045 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Mitochondrial disorder with complex V deficiency v1.12 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23596069; 23599390
Mitochondrial disorders v2.124 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Mitochondrial disorder with complex V deficiency v1.11 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22, 616045; ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Possible mitochondrial disorder - nuclear genes v1.107 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from ?Combined oxidative phosphorylation deficiency 22, 616045; ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, 615228 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228; Combined oxidative phosphorylation deficiency 22, OMIM: 616045
Possible mitochondrial disorder - nuclear genes v1.106 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 23596069; 23599390
Possible mitochondrial disorder - nuclear genes v1.105 CLPB Arina Puzriakova edited their review of gene: CLPB: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the MOI update on this panel from biallelic to both based on current evidence.; Changed rating: GREEN; Changed publications to: 34140661, 34115842; Changed phenotypes to: 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271, 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM: 619835, Neutropenia, severe congenital, 9, autosomal dominant, OMIM: 619813; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.105 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23281071, 33865955, 28275242; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.8 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23281071, 33865955, 28275242; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 UQCRC1 Arina Puzriakova reviewed gene: UQCRC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30788857, 33141179; Phenotypes: Parkinsonism with polyneuropathy, OMIM: 619279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.8 UQCRC1 Arina Puzriakova reviewed gene: UQCRC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30788857, 33141179; Phenotypes: Parkinsonism with polyneuropathy, OMIM: 619279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 PET117 Arina Puzriakova reviewed gene: PET117: Rating: AMBER; Mode of pathogenicity: ; Publications: 28386624; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 19, OMIM: 619063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 NFS1 Arina Puzriakova reviewed gene: NFS1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24498631; Phenotypes: Combined oxidative phosphorylation deficiency 52, OMIM: 619386; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 TWNK Arina Puzriakova reviewed gene: TWNK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM: 609286, Perrault syndrome 5, OMIM: 616138, Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM 271245; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.16 TWNK Arina Puzriakova reviewed gene: TWNK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM: 609286, Perrault syndrome 5, OMIM: 616138, Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM 271245; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 33471299, 10976639, 27683074; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259, Cardiomyopathy, dilated, 1GG, OMIM: 613642; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex II deficiency v1.5 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 33471299, 10976639, 27683074; Phenotypes: Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259, Cardiomyopathy, dilated, 1GG, OMIM: 613642; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 QRSL1 Arina Puzriakova reviewed gene: QRSL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29440775, 30283131, 26741492; Phenotypes: Combined oxidative phosphorylation deficiency 40, OMIM: 618835; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.105 POLG2 Arina Puzriakova reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31778857, 21555342, 27592148, 16685652; Phenotypes: ?Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM: 618528, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM: 610131, ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM: 619425; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.16 POLG2 Arina Puzriakova reviewed gene: POLG2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31778857, 21555342, 27592148, 16685652; Phenotypes: ?Mitochondrial DNA depletion syndrome syndrome 16 (hepatic type), OMIM: 618528, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM: 610131, ?Mitochondrial DNA depletion syndrome 16B (neuroophthalmic type), OMIM: 619425; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.104 COX16 Arina Puzriakova edited their review of gene: COX16: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; Changed rating: AMBER; Set current diagnostic: yes
Mitochondrial disorder with complex IV deficiency v1.18 COX16 Arina Puzriakova edited their review of gene: COX16: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the Amber rating of this gene on this panel based on current evidence.; Changed rating: AMBER; Set current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.103 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex III deficiency v1.7 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.103 TIMMDC1 Arina Puzriakova edited their review of gene: TIMMDC1: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed publications to: 33278652, 28604674
Mitochondrial disorder with complex I deficiency v1.18 TIMMDC1 Arina Puzriakova edited their review of gene: TIMMDC1: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed publications to: 33278652, 28604674
Possible mitochondrial disorder - nuclear genes v1.103 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 31785789, 32399598, 27448789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial DNA maintenance disorder v1.15 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 31785789, 32399598, 27448789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.102 POLRMT Arina Puzriakova edited their review of gene: POLRMT: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, supporting the rating upgrade from Amber to Green on this panel.; Changed rating: GREEN; Changed publications to: 33602924; Changed phenotypes to: Combined oxidative phosphorylation deficiency 55, OMIM: 619743; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.102 TARS2 Arina Puzriakova reviewed gene: TARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153448, 24827421, 34508595; Phenotypes: Combined oxidative phosphorylation deficiency 21, OMIM: 615918; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.102 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 22972948, 32124427, 26925370, 27604842; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex II deficiency v1.4 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 22972948, 32124427, 26925370, 27604842; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.101 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32488845, 27356879; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.100 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.17 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.99 SSBP1 Arina Puzriakova commented on gene: SSBP1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from unknown to both mono- and biallelic inline with this review. Carl Fratter mentions additional cases have been seen within NHS GMS (not published).
Mitochondrial DNA maintenance disorder v1.14 SSBP1 Arina Puzriakova commented on gene: SSBP1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from unknown to both mono- and biallelic inline with this review. Carl Fratter mentions additional cases have been seen within NHS GMS (not published).
Possible mitochondrial disorder - nuclear genes v1.99 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.17 NDUFB10 Arina Puzriakova commented on gene: NDUFB10: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder - nuclear genes v1.99 NDUFA8 Arina Puzriakova commented on gene: NDUFA8: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA8 Arina Puzriakova commented on gene: NDUFA8: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder - nuclear genes v1.99 NDUFA13 Arina Puzriakova commented on gene: NDUFA13: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA13 Arina Puzriakova commented on gene: NDUFA13: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder - nuclear genes v1.99 NDUFA12 Arina Puzriakova commented on gene: NDUFA12: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Mitochondrial disorder with complex I deficiency v1.17 NDUFA12 Arina Puzriakova commented on gene: NDUFA12: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder - nuclear genes v1.99 LYRM4 Arina Puzriakova commented on gene: LYRM4: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.
Possible mitochondrial disorder - nuclear genes v1.99 COX6A2 Arina Puzriakova edited their review of gene: COX6A2: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 31155743, 23460811, 32744742; Changed phenotypes to: Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Mitochondrial disorder with complex IV deficiency v1.17 COX6A2 Arina Puzriakova edited their review of gene: COX6A2: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 31155743, 23460811, 32744742; Changed phenotypes to: Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Set current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.99 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes
Mitochondrial disorder with complex V deficiency v1.10 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.99 ATP5A1 Arina Puzriakova commented on gene: ATP5A1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from biallelic to both mono- and biallelic inline with this review.
Mitochondrial disorder with complex V deficiency v1.10 ATP5A1 Arina Puzriakova commented on gene: ATP5A1: Gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) in August 2022 on behalf of the three GMS Mitochondrial providers, indicating that this gene requires a rating upgrade from Amber to Green. MOI has also been updated from biallelic to both mono- and biallelic inline with this review.
Mitochondrial disorders v2.123 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28275242, 23281071, 33865955; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 UQCRC2 Arina Puzriakova reviewed gene: UQCRC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28275242, 23281071, 33865955; Phenotypes: Mitochondrial complex III deficiency, nuclear type 5, OMIM: 615160; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 27683074, 10976639, 33471299; Phenotypes: Cardiomyopathy, dilated, 1GG, OMIM: 613642, Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 SDHA Arina Puzriakova reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: ; Publications: 27683074, 10976639, 33471299; Phenotypes: Cardiomyopathy, dilated, 1GG, OMIM: 613642, Mitochondrial complex II deficiency, nuclear type 1, OMIM: 252011, Neurodegeneration with ataxia and late-onset optic atrophy, OMIM: 619259; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 UQCRFS1 Arina Puzriakova reviewed gene: UQCRFS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31883641; Phenotypes: Mitochondrial complex III deficiency, nuclear type 10, OMIM: 618775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 TIMMDC1 Arina Puzriakova reviewed gene: TIMMDC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28604674, 33278652; Phenotypes: Mitochondrial complex I deficiency, nuclear type 31, OMIM:618251; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 32399598, 27448789, 31785789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 TFAM Arina Puzriakova reviewed gene: TFAM: Rating: GREEN; Mode of pathogenicity: ; Publications: 32399598, 27448789, 31785789, 34647195; Phenotypes: Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), OMIM: 617156; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 SDHB Arina Puzriakova reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: ; Publications: 27604842, 32124427, 22972948, 26925370; Phenotypes: Mitochondrial complex II deficiency, nuclear type 4, OMIM: 619224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NSUN3 Arina Puzriakova reviewed gene: NSUN3: Rating: GREEN; Mode of pathogenicity: ; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, OMIM: 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFC2 Arina Puzriakova reviewed gene: NDUFC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32969598; Phenotypes: Mitochondrial complex I deficiency, nuclear type 36, OMIM: 619170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 SSBP1 Arina Puzriakova reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34905022, 31550240, 31550237, 31298765, 31479473; Phenotypes: Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial DNA maintenance disorder v1.13 SSBP1 Arina Puzriakova reviewed gene: SSBP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34905022, 31550240, 31550237, 31298765, 31479473; Phenotypes: Optic atrophy 13 with retinal and foveal abnormalities, OMIM:165510; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.16 NDUFB10 Arina Puzriakova reviewed gene: NDUFB10: Rating: GREEN; Mode of pathogenicity: ; Publications: 28040730, 32025618, 33169436; Phenotypes: Mitochondrial complex I deficiency, nuclear type 35, OMIM: 619003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA8 Arina Puzriakova reviewed gene: NDUFA8: Rating: GREEN; Mode of pathogenicity: ; Publications: 33153867, 32385911; Phenotypes: Mitochondrial complex I deficiency, nuclear type 37, OMIM: 619272; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism v2.265 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA13 Arina Puzriakova reviewed gene: NDUFA13: Rating: GREEN; Mode of pathogenicity: ; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, OMIM: 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Possible mitochondrial disorder - nuclear genes v1.98 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: ; Publications: 33715266, 21617257, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex I deficiency v1.16 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: ; Publications: 33715266, 21617257, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Undiagnosed metabolic disorders v1.552 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.265 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 LYRM4 Arina Puzriakova reviewed gene: LYRM4: Rating: GREEN; Mode of pathogenicity: ; Publications: 31497476, 23814038; Phenotypes: Combined oxidative phosphorylation deficiency 19, OMIM: 615595; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.123 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the rating should be upgraded from Amber to Green on Mitochondrial panels (R357 and R63). As there is sufficient supporting evidence, the rating should also be updated to Green on this panel at the next GMS review.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.265 ATP5G3 Arina Puzriakova edited their review of gene: ATP5G3: Added comment: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the rating should be upgraded from Amber to Green on Mitochondrial panels (R357 and R63). As there is sufficient supporting evidence, the rating should also be updated to Green on this panel at the next GMS review.; Changed rating: GREEN; Changed publications to: 34636445, 34954817; Changed phenotypes to: Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.265 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.123 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.98 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorder with complex V deficiency v1.9 ATP5A1 Arina Puzriakova reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: ; Publications: 34483339, 23596069, 23599390, 34954817; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228, Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.582 SLC32A1 Helen Lord reviewed gene: SLC32A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34038384, Platzer et al, 2022 - not on pubmed curently; Phenotypes: developmental and epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset dystonia v1.120 HPRT1 Eldar Dedic changed review comment from: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.384+1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.; to: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.486-1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.
Early onset dystonia v1.120 HPRT1 Eldar Dedic changed review comment from: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, all variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.; to: Jinnah, et al. (2006) studied 44 Lesch–Nyhan disease patients (age range between 2 and 38 years; only one of them was female; all experienced severe dystonia). Multiple rare HPRT1 variants (including at least 2 splice site variants (IVS6-1G>A (also known as c.486-1G>A), and IVS4+1G>A (also known as c.384+1G>A)), as well as exon 1 deletion, and exon 9 deletion) in patients (the majority of which were under 31 years of age when they were first seen by a clinician) with hypoxanthine-guanine phosphoribosyltransferase activity below 1% have been reported. As of August 2022, the c.384+1G>A and c.384+1G>A variants were absent from gnomAD version 2.1.1, and no high-frequency structural variants have been reported in gnomAD SVs v2.1 either.
Early onset dystonia v1.120 HPRT1 Eldar Dedic reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16549399; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1696 DOCK8 Tracy Lester reviewed gene: DOCK8: Rating: RED; Mode of pathogenicity: None; Publications: 18060736, 1764478, 27891178, 19776401; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.122 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Likely inborn error of metabolism v2.264 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Possible mitochondrial disorder - nuclear genes v1.97 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Tag Q3_22_NHS_review tag was added to gene: UQCRC2.
Mitochondrial disorder with complex III deficiency v1.6 UQCRC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRC2.
Tag Q3_22_NHS_review tag was added to gene: UQCRC2.
Paediatric or syndromic cardiomyopathy v1.78 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'biallelic' only to 'both mono- and biallelic' as cardiomyopathy has also been shown to be a feature associated with heterozygous variants in this gene (PMID: 27683074)
Paediatric or syndromic cardiomyopathy v1.78 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Added comment: Comment on mode of inheritance: This gene was recently included on a gene list provided by Carl Fratter (Oxford University Hospitals NHS Trust) on behalf of GMS Mitochondrial providers, indicating that the MOI should be updated from 'biallelic' only to 'both mono- and biallelic' on Mitochondrial GMS panels (R354 and R63). As there was sufficient supporting evidence for the change, the MOI has also been updated to 'both' on this panel to ensure all panels reflect correct knowledge. Heterozygous variants can be associated with abnormal mitochondrial accumulation and therefore also within the scope of the panel.
Undiagnosed metabolic disorders v1.551 SDHA Arina Puzriakova Mode of inheritance for gene: SDHA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.97 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Tag Q3_22_NHS_review tag was added to gene: SDHA.
Mitochondrial disorder with complex II deficiency v1.3 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Tag Q3_22_NHS_review tag was added to gene: SDHA.
Likely inborn error of metabolism v2.264 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Mitochondrial disorders v2.122 SDHA Arina Puzriakova Tag Q3_22_MOI tag was added to gene: SDHA.
Possible mitochondrial disorder - nuclear genes v1.97 CLPB Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: CLPB.
Mitochondrial disorders v2.122 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Likely inborn error of metabolism v2.264 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Possible mitochondrial disorder - nuclear genes v1.97 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Tag Q3_22_NHS_review tag was added to gene: UQCRFS1.
Mitochondrial disorder with complex III deficiency v1.6 UQCRFS1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: UQCRFS1.
Tag Q3_22_NHS_review tag was added to gene: UQCRFS1.
Mitochondrial disorders v2.122 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Likely inborn error of metabolism v2.264 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Possible mitochondrial disorder - nuclear genes v1.97 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Tag Q3_22_NHS_review tag was added to gene: TIMMDC1.
Mitochondrial disorder with complex I deficiency v1.15 TIMMDC1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TIMMDC1.
Tag Q3_22_NHS_review tag was added to gene: TIMMDC1.
Mitochondrial disorders v2.122 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Likely inborn error of metabolism v2.264 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Possible mitochondrial disorder - nuclear genes v1.97 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Tag Q3_22_NHS_review tag was added to gene: TFAM.
Mitochondrial DNA maintenance disorder v1.12 TFAM Arina Puzriakova Tag Q3_22_rating tag was added to gene: TFAM.
Tag Q3_22_NHS_review tag was added to gene: TFAM.
Possible mitochondrial disorder - nuclear genes v1.97 TARS2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: TARS2.
Mitochondrial disorders v2.122 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Possible mitochondrial disorder - nuclear genes v1.97 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Tag Q3_22_NHS_review tag was added to gene: SDHB.
Mitochondrial disorder with complex II deficiency v1.3 SDHB Arina Puzriakova Tag Q3_22_rating tag was added to gene: SDHB.
Tag Q3_22_NHS_review tag was added to gene: SDHB.
Possible mitochondrial disorder - nuclear genes v1.97 POLRMT Arina Puzriakova Tag Q3_22_NHS_review tag was added to gene: POLRMT.
Mitochondrial disorders v2.122 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Likely inborn error of metabolism v2.264 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Possible mitochondrial disorder - nuclear genes v1.97 NSUN3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NSUN3.
Tag Q3_22_NHS_review tag was added to gene: NSUN3.
Mitochondrial disorders v2.122 NDUFC2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFC2.
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Tag Q2_21_rating was removed from gene: NDUFC2.
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Classified gene: NDUFC2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.550 NDUFC2 Arina Puzriakova Gene: ndufc2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.582 FBXO28 Sarah Leigh Mode of inheritance for gene: FBXO28 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1696 FBXO28 Sarah Leigh Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy 100 (# 619777) to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695
Early onset or syndromic epilepsy v2.581 FBXO28 Sarah Leigh Phenotypes for gene: FBXO28 were changed from Developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 100, OMIM:619777; developmental and epileptic encephalopathy 100, MONDO:0030695
Early onset or syndromic epilepsy v2.580 FBXO28 Sarah Leigh Publications for gene: FBXO28 were set to 33280099
Intellectual disability v3.1695 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh edited their review of gene: FBXO28: Added comment: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least six variants have been reported in at least six cases. In one of these cases the variant was inherited from the unanaffected mother, who was mosaic (PMID: 33280099), otherwise the variants were de novo heterozygotes (PMIDs: 30160831; 33280099).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXO28.
Tag Q3_22_MOI tag was added to gene: FBXO28.
Intellectual disability v3.1695 FBXO28 Sarah Leigh Tag Q3_22_rating tag was added to gene: FBXO28.
Tag Q3_22_MOI tag was added to gene: FBXO28.
Intellectual disability v3.1695 FBXO28 Sarah Leigh Classified gene: FBXO28 as Amber List (moderate evidence)
Intellectual disability v3.1695 FBXO28 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 v3.1695 FBXO28 Sarah Leigh Gene: fbxo28 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Classified gene: FBXO28 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.579 FBXO28 Sarah Leigh Gene: fbxo28 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1694 CDK9 Sarah Leigh edited their review of gene: CDK9: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least four variants have been reported in unrelated cases with a CHARGE-like syndrome:
NM_001261:c.280C>T, p.Arg94Cys (PMID: 29302074)
NM_001261.3:c.673C>T / p.Arg225Cys (PMID: 26633546, 30237576)
NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys (PMID: 33640901).
Supportive functional studies have also been reported (PMID: 33640901).; Changed rating: GREEN
Intellectual disability v3.1694 CDK9 Sarah Leigh Tag Q3_22_rating tag was added to gene: CDK9.
Tag Q3_22_MOI tag was added to gene: CDK9.
Possible mitochondrial disorder - nuclear genes v1.97 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 was changed from to Other
Mitochondrial DNA maintenance disorder v1.12 SSBP1 Arina Puzriakova Mode of pathogenicity for gene: SSBP1 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
Mitochondrial DNA maintenance disorder v1.11 SSBP1 Arina Puzriakova Mode of inheritance for gene: SSBP1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1694 CDK9 Sarah Leigh Classified gene: CDK9 as Amber List (moderate evidence)
Intellectual disability v3.1694 CDK9 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 v3.1694 CDK9 Sarah Leigh Gene: cdk9 has been classified as Amber List (Moderate Evidence).
Mitochondrial DNA maintenance disorder v1.10 SSBP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SSBP1.
Tag Q3_22_NHS_review tag was added to gene: SSBP1.
Possible mitochondrial disorder - nuclear genes v1.96 SSBP1 Arina Puzriakova Mode of inheritance for gene: SSBP1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.95 SSBP1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: SSBP1.
Tag Q3_22_NHS_review tag was added to gene: SSBP1.
Intellectual disability v3.1693 CCDC32 Sarah Leigh Tag Q3_22_rating tag was added to gene: CCDC32.
Intellectual disability v3.1693 CCDC32 Sarah Leigh edited their review of gene: CCDC32: Added comment: Associated with relevant phenotype in OMIM and as strong Gen2Phen gene for CCDC32-associated neurodevelopmental syndrome. At least three variants have been reported in three unrelated cases (PMIDS: 32307552 & 35451546), together with supportive functional studies.; Changed rating: GREEN
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh reviewed gene: CCDC32: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.264 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Mitochondrial disorders v2.122 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Possible mitochondrial disorder - nuclear genes v1.95 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Tag Q3_22_NHS_review tag was added to gene: NDUFB10.
Mitochondrial disorder with complex I deficiency v1.15 NDUFB10 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFB10.
Tag Q3_22_NHS_review tag was added to gene: NDUFB10.
Intellectual disability v3.1693 CCDC32 Sarah Leigh Classified gene: CCDC32 as Amber List (moderate evidence)
Intellectual disability v3.1693 CCDC32 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 v3.1693 CCDC32 Sarah Leigh Gene: ccdc32 has been classified as Amber List (Moderate Evidence).
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh Classified gene: CCDC32 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.163 CCDC32 Sarah Leigh Gene: ccdc32 has been classified as Green List (High Evidence).
Mitochondrial disorders v2.122 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Likely inborn error of metabolism v2.264 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Possible mitochondrial disorder - nuclear genes v1.95 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Tag Q3_22_NHS_review tag was added to gene: NDUFA8.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA8 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA8.
Tag Q3_22_NHS_review tag was added to gene: NDUFA8.
Rare multisystem ciliopathy disorders v1.162 CCDC32 Sarah Leigh Phenotypes for gene: CCDC32 were changed from Craniofacial, cardiac, laterality and neurodevelopmental anomalies to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Intellectual disability v3.1692 CCDC32 Sarah Leigh Phenotypes for gene: CCDC32 were changed from global developmental delay to Cardiofacioneurodevelopmental syndrome, OMIM:619123; cardiofacioneurodevelopmental syndrome, MONDO:0030873
Intellectual disability v3.1691 CCDC32 Sarah Leigh Publications for gene: CCDC32 were set to 32307552
Rare multisystem ciliopathy disorders v1.161 CCDC32 Sarah Leigh Publications for gene: CCDC32 were set to 32307552
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_MOI tag was added to gene: GLRA2.
Intellectual disability v3.1690 GLRA2 Sarah Leigh Tag Q3_22_rating tag was added to gene: GLRA2.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Tag Q3_22_rating tag was added to gene: GLRA2.
Intellectual disability v3.1690 GLRA2 Sarah Leigh Classified gene: GLRA2 as Amber List (moderate evidence)
Intellectual disability v3.1690 GLRA2 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 v3.1690 GLRA2 Sarah Leigh Gene: glra2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.264 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Mitochondrial disorders v2.122 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Tag Q3_22_NHS_review tag was added to gene: NDUFA13.
Possible mitochondrial disorder - nuclear genes v1.95 NDUFA13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA13.
Tag Q3_22_NHS_review tag was added to gene: NDUFA13.
Intellectual disability v3.1689 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh edited their review of gene: GLRA2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35294868 reports eight GLRA2 variants in affected females (n=8) and males (n=5). The variants in the females were de novo and c.887C>T,
p.Thr296Met (NC_000023.10, chrX: g.14627284C>T) was present in six individuals (PMID: 35294868, table 2) and was found to have a gain-of-function effect, which is in contrast to c.754C>T, p.Arg252Cys and c.407A>G, p.Asn136Ser (PMID: 2637014). All of the 13 GLRA2 variant carriers in PMID: 35294868 had developmental delay/intellectual disability and epilepsy was evident in 7/13 of the cases (PMID: 35294868, table 2). Supportive functional studies were also presented.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Classified gene: GLRA2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.578 GLRA2 Sarah Leigh Gene: glra2 has been classified as Amber List (Moderate Evidence).
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Green List (high evidence)
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Early onset dystonia v1.120 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Green List (High Evidence).
Early onset dystonia v1.119 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset dystonia v1.119 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Undiagnosed metabolic disorders v1.549 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Early onset dystonia v1.118 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Undiagnosed metabolic disorders v1.548 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257; 27604308
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Green List (high evidence)
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Added comment: Comment on list classification: Gene was recently upgraded from Amber to Green on GMS panels and therefore also updating the rating here to ensure all panels display correct knowledge.
Undiagnosed metabolic disorders v1.547 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.546 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v2.73 NDUFA12 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.251
Optic neuropathy v2.73 NDUFA12 Arina Puzriakova gene: NDUFA12 was added
gene: NDUFA12 was added to Optic neuropathy. Sources: Expert Review Amber,PanelApp,South West GLH
Q3_22_rating tags were added to gene: NDUFA12.
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to 21617257; 33715266; 35141356
Phenotypes for gene: NDUFA12 were set to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Childhood onset hereditary spastic paraplegia v2.146 NDUFA12 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.251
Childhood onset hereditary spastic paraplegia v2.146 NDUFA12 Arina Puzriakova gene: NDUFA12 was added
gene: NDUFA12 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,PanelApp,South West GLH
Q3_22_rating tags were added to gene: NDUFA12.
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to 21617257; 33715266; 35141356
Phenotypes for gene: NDUFA12 were set to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Childhood onset dystonia, chorea or related movement disorder v1.251 NDUFA12 Arina Puzriakova Phenotypes for gene: NDUFA12 were changed from Leigh syndrome due to mitochondrial complex 1 deficiency 256000; ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Childhood onset dystonia, chorea or related movement disorder v1.250 NDUFA12 Arina Puzriakova Publications for gene: NDUFA12 were set to 21617257
Childhood onset dystonia, chorea or related movement disorder v1.249 NDUFA12 Arina Puzriakova Classified gene: NDUFA12 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.249 NDUFA12 Arina Puzriakova Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.248 NDUFA12 Arina Puzriakova reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 21617257, 33715266, 35141356; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.248 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Possible mitochondrial disorder - nuclear genes v1.95 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Tag Q3_22_NHS_review tag was added to gene: NDUFA12.
Mitochondrial disorder with complex I deficiency v1.15 NDUFA12 Arina Puzriakova Tag Q3_22_rating tag was added to gene: NDUFA12.
Tag Q3_22_NHS_review tag was added to gene: NDUFA12.
Intellectual disability v3.1689 GLRA2 Sarah Leigh Phenotypes for gene: GLRA2 were changed from Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772 to Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772
Intellectual disability v3.1689 GLRA2 Sarah Leigh Phenotypes for gene: GLRA2 were changed from autism spectrum disorder to Intellectual developmental disorder, X-linked syndromic, Pilorge type, OMIM:301076; intellectual developmental disorder, X-linked, syndromic, Pilorge type, MONDO:0024772
Intellectual disability v3.1688 GLRA2 Sarah Leigh Publications for gene: GLRA2 were set to 28588452; 26370147; 29057625
Intellectual disability v3.1687 NRCAM Sarah Leigh edited their review of gene: NRCAM: Added comment: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for NRCAM neurodevelopmental disorder with dysmorphic features, hypotonia and spasticity. At least 12 variants have been reported in PMID: 35108495 in 8 unrelated cases (table 1). Global developmental delay / intellectual disabilty was evident in 5/7 unrelated cases (individual 1 was not considered as they also had homozygous loss-of-function variant in CD55 (OMIM: 125240)(PMID: 35108495).; Changed rating: GREEN
Intellectual disability v3.1687 NRCAM Sarah Leigh Tag Q3_22_rating tag was added to gene: NRCAM.
Tag Q3_22_MOI tag was added to gene: NRCAM.
Intellectual disability v3.1687 NRCAM Sarah Leigh Classified gene: NRCAM as Amber List (moderate evidence)
Intellectual disability v3.1687 NRCAM 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 v3.1687 NRCAM Sarah Leigh Gene: nrcam has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1686 NRCAM Sarah Leigh Phenotypes for gene: NRCAM were changed from Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Primary immunodeficiency or monogenic inflammatory bowel disease v2.573 FOXI3 Boaz Palterer gene: FOXI3 was added
gene: FOXI3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FOXI3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXI3 were set to 35987349
Phenotypes for gene: FOXI3 were set to T-cell lymphopenia; low TREC; thymic hypoplasia
Penetrance for gene: FOXI3 were set to Incomplete
Review for gene: FOXI3 was set to AMBER
Added comment: Ghosh et al. described 2 unrelated patients with T cell lymphopenia, positive TREC screening and thymic hypoplasia with deleterious FOXI3 variants. FOXI3 was demonstrated in mice models to be involved in thymic development.
Sources: Literature
Rare anaemia v1.42 HEATR3 Sarah Leigh Tag Q3_22_rating tag was added to gene: HEATR3.
Tag Q3_22_MOI tag was added to gene: HEATR3.
Likely inborn error of metabolism v2.264 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Mitochondrial disorders v2.122 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Possible mitochondrial disorder - nuclear genes v1.95 LYRM4 Arina Puzriakova Tag Q3_22_rating tag was added to gene: LYRM4.
Tag Q3_22_NHS_review tag was added to gene: LYRM4.
Congenital myopathy v2.90 COX6A2 Arina Puzriakova Entity copied from Mitochondrial disorders v2.122
Congenital myopathy v2.90 COX6A2 Arina Puzriakova gene: COX6A2 was added
gene: COX6A2 was added to Congenital myopathy. Sources: Expert Review Amber,NHS GMS
Q3_22_rating tags were added to gene: COX6A2.
Mode of inheritance for gene: COX6A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX6A2 were set to 23460811; 31155743; 32744742
Phenotypes for gene: COX6A2 were set to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Mitochondrial disorder with complex IV deficiency v1.16 COX6A2 Arina Puzriakova commented on gene: COX6A2
Possible mitochondrial disorder - nuclear genes v1.95 COX6A2 Arina Puzriakova commented on gene: COX6A2
Mitochondrial disorders v2.122 COX6A2 Arina Puzriakova Classified gene: COX6A2 as Amber List (moderate evidence)
Mitochondrial disorders v2.122 COX6A2 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 two unrelated cases harbouring different biallelic variants in this gene (PMID: 31155743) and presenting with a consistent phenotype of congenital myopathy. Functional studies and two mouse models are supportive of pathogenicity (PMID: 23460811; 31155743; 32744742)
Mitochondrial disorders v2.122 COX6A2 Arina Puzriakova Gene: cox6a2 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.121 COX6A2 Arina Puzriakova Mode of inheritance for gene: COX6A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.120 COX6A2 Arina Puzriakova Publications for gene: COX6A2 were set to
Mitochondrial disorders v2.119 COX6A2 Arina Puzriakova Phenotypes for gene: COX6A2 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 18, OMIM:619062
Possible mitochondrial disorder - nuclear genes v1.95 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Tag Q3_22_NHS_review tag was added to gene: COX6A2.
Mitochondrial disorder with complex IV deficiency v1.16 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Tag Q3_22_NHS_review tag was added to gene: COX6A2.
Mitochondrial disorders v2.118 COX6A2 Arina Puzriakova Tag Q3_22_rating tag was added to gene: COX6A2.
Rare anaemia v1.42 HEATR3 Sarah Leigh edited their review of gene: HEATR3: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; Changed rating: GREEN
Rare anaemia v1.42 HEATR3 Sarah Leigh Deleted their comment
Rare anaemia v1.42 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
Rare anaemia v1.42 HEATR3 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35213692 reports five HEATR3 variants in four unrelated cases who all displayed anaemia reminiscent of Diamond-Blackfan anemia, together with bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability.
Rare anaemia v1.42 HEATR3 Sarah Leigh Entity copied from Intellectual disability v3.1685
Rare anaemia v1.42 HEATR3 Sarah Leigh gene: HEATR3 was added
gene: HEATR3 was added to Rare anaemia. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR3 were set to 35213692
Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face
Penetrance for gene: HEATR3 were set to Complete
Intellectual disability v3.1685 HEATR3 Sarah Leigh reviewed gene: HEATR3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1685 HEATR3 Sarah Leigh Classified gene: HEATR3 as Amber List (moderate evidence)
Intellectual disability v3.1685 HEATR3 Sarah Leigh Gene: heatr3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.264 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Mitochondrial disorders v2.118 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Mitochondrial disorder with complex V deficiency v1.8 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Tag Q3_22_NHS_review tag was added to gene: ATP5G3.
Possible mitochondrial disorder - nuclear genes v1.95 ATP5G3 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5G3.
Tag Q3_22_NHS_review tag was added to gene: ATP5G3.
Likely inborn error of metabolism v2.264 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Mitochondrial disorders v2.118 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Mitochondrial disorder with complex V deficiency v1.8 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Possible mitochondrial disorder - nuclear genes v1.95 ATP5G3 Arina Puzriakova commented on gene: ATP5G3
Childhood onset dystonia, chorea or related movement disorder v1.248 ATP5G3 Arina Puzriakova Classified gene: ATP5G3 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.248 ATP5G3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least four unrelated families with heterozygous variants primarily presenting with dystonia or related movement disorder (PMID: 34636445; 34954817); also supportive Drosophila model described.
Childhood onset dystonia, chorea or related movement disorder v1.248 ATP5G3 Arina Puzriakova Gene: atp5g3 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.247 ATP5G3 Arina Puzriakova Phenotypes for gene: ATP5G3 were changed from Dystonia, early-onset, and/or spastic paraplegia, MIM# 619681 to Dystonia, early-onset, and/or spastic paraplegia, OMIM:619681
Childhood onset dystonia, chorea or related movement disorder v1.246 ATP5G3 Arina Puzriakova Tag new-gene-name tag was added to gene: ATP5G3.
Tag Q3_22_rating tag was added to gene: ATP5G3.
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Intellectual disability v3.1684 TIAM1 Sarah Leigh edited their review of gene: TIAM1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. PMID: 35240055 reports six TIAM1 variants in four unrelated cases (5 cases in total) of Neurodevelopmental disorder with language delay and seizures, OMIM:619908. All of the cases displayed seizures and intellectual disability, where an assessment was made. The drospohila ortholog (still life) and funtional studies supported this gene disease association (PMID: 35240055).; Changed rating: GREEN
Intellectual disability v3.1684 TIAM1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TIAM1.
Tag Q3_22_MOI tag was added to gene: TIAM1.
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Tag Q3_22_rating tag was added to gene: TIAM1.
Tag Q3_22_MOI tag was added to gene: TIAM1.
Intellectual disability v3.1684 TIAM1 Sarah Leigh Phenotypes for gene: TIAM1 were changed from Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology to Neurodevelopmental disorder with language delay and seizures, OMIM:619908
Early onset or syndromic epilepsy v2.577 TIAM1 Sarah Leigh Phenotypes for gene: TIAM1 were changed from Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology to Neurodevelopmental disorder with language delay and seizures, OMIM:619908
Intellectual disability v3.1683 TIAM1 Sarah Leigh Classified gene: TIAM1 as Amber List (moderate evidence)
Intellectual disability v3.1683 TIAM1 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 v3.1683 TIAM1 Sarah Leigh Gene: tiam1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Classified gene: TIAM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.576 TIAM1 Sarah Leigh Gene: tiam1 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.546 ATP5A1 Arina Puzriakova Phenotypes for gene: ATP5A1 were changed from Complex V (Mitochondrial respiratory chain disorders (caused by nuclear variants only), OXPHOS structural subunits); ?Combined oxidative phosphorylation deficiency 22 616045; ?Mitochondrial complex (ATP synthase) deficiency, nuclear type 4 615228 to Combined oxidative phosphorylation deficiency 22, OMIM: 616045; Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4, OMIM: 615228
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Classified gene: ATP5A1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to support this gene-disease association and therefore ATP5A1 has been promoted to Green.
Undiagnosed metabolic disorders v1.545 ATP5A1 Arina Puzriakova Gene: atp5a1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.544 ATP5A1 Arina Puzriakova Publications for gene: ATP5A1 were set to 27604308; 23599390; 23596069
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Two families (with two affected sibs each) reported with recessive variants and supported by functional studies (PMIDs: 23599390; 23596069). Six unrelated patients have been reported with heterozygous variants; including one recurrent variant c.620G>A in four cases, c.545G>A and c.1037C>T in the remaining two, respectively (PMIDs: 34483339; 34954817).
Undiagnosed metabolic disorders v1.543 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Tag Q3_22_MOI was removed from gene: ATP5A1.
Tag Q3_22_rating tag was added to gene: ATP5A1.
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Tag Q3_22_MOI tag was added to gene: ATP5A1.
Likely inborn error of metabolism v2.264 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.118 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v2.117 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Possible mitochondrial disorder - nuclear genes v1.95 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v1.94 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Tag Q3_22_NHS_review tag was added to gene: ATP5A1.
Mitochondrial disorder with complex V deficiency v1.8 ATP5A1 Arina Puzriakova Mode of inheritance for gene: ATP5A1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorder with complex V deficiency v1.7 ATP5A1 Arina Puzriakova Tag Q3_22_rating tag was added to gene: ATP5A1.
Tag Q3_22_NHS_review tag was added to gene: ATP5A1.
Severe microcephaly v2.317 CPSF3 Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.575
Severe microcephaly v2.317 CPSF3 Sarah Leigh gene: CPSF3 was added
gene: CPSF3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: CPSF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPSF3 were set to 35121750
Phenotypes for gene: CPSF3 were set to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Penetrance for gene: CPSF3 were set to Complete
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Classified gene: CPSF3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.575 CPSF3 Sarah Leigh Gene: cpsf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1682 CPSF3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, (NM_016207.3) in two Icelandic families and c.1061T>C (NM_016207.3) in a large consanguineous Mexican family.; to: Associated with relevant phenotype in OMIM and as moderate Gen2Phen gene for CPSF3-associated neurodevelopmental disorder with seizures and microcephaly. PMID: 35121750 reports two CPSF3 variants in cases, c.1403G>A, p.Gly468Glu (NM_016207.3) in two Icelandic families and c.1061T>C, p.Ile354Thr (NM_016207.3) in a large consanguineous Mexican family. Intellectual disabililty was evident in all 8/8 cases and seizures and microcephaly was apparent 7/8 cases (PMID: 35121750).
Intellectual disability v3.1682 CPSF3 Sarah Leigh reviewed gene: CPSF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1682 CPSF3 Sarah Leigh Classified gene: CPSF3 as Amber List (moderate evidence)
Intellectual disability v3.1682 CPSF3 Sarah Leigh Gene: cpsf3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1681 CPSF3 Sarah Leigh Phenotypes for gene: CPSF3 were changed from Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Early onset or syndromic epilepsy v2.574 CPSF3 Sarah Leigh Phenotypes for gene: CPSF3 were changed from Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures to Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, OMIM:619876
Intellectual disability v3.1680 PDZD8 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; to: Not associated with a phenotype in OMIM (last edited: 02/21/2018), Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.
Intellectual disability v3.1680 PDZD8 Sarah Leigh Tag Q3_22_rating tag was added to gene: PDZD8.
Tag Q3_22_MOI tag was added to gene: PDZD8.
Intellectual disability v3.1680 PDZD8 Sarah Leigh edited their review of gene: PDZD8: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35227461 reports two PDZD8 variants in two unrelated cases with a neurodevelopmental cognitive disorder. The PDZD8 variants were biallelic in the affected cases in two unrelated families, but heterozygous or absent in the unaffected family members (figure 1 PMID: 35227461). Supportive animal models were also presented in PMID: 35227461.; Changed rating: GREEN
Intellectual disability v3.1680 PDZD8 Sarah Leigh Classified gene: PDZD8 as Amber List (moderate evidence)
Intellectual disability v3.1680 PDZD8 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 v3.1680 PDZD8 Sarah Leigh Gene: pdzd8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1679 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Severe microcephaly v2.316 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Tag Q3_22_rating tag was added to gene: CHKA.
Tag Q3_22_MOI tag was added to gene: CHKA.
Severe microcephaly v2.316 CHKA Sarah Leigh Entity copied from Genetic epilepsy syndromes v2.573
Severe microcephaly v2.316 CHKA Sarah Leigh gene: CHKA was added
gene: CHKA was added to Severe microcephaly. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Intellectual disability v3.1679 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh edited their review of gene: CHKA: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 35202461 reports five CHKA variants in five unrelated cases with a neurodevelopmental disorder, which includes intellectual disability, epileptic
encephalopathy and severe microcephaly (PMID: 35202461). Suportive functional studies are also presented in this article.; Changed rating: GREEN
Intellectual disability v3.1679 CHKA Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
Intellectual disability v3.1679 CHKA 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 v3.1679 CHKA Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Classified gene: CHKA as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.573 CHKA Sarah Leigh Gene: chka has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.248 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
DDG2P v2.79 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Intellectual Disability, Short Stature, and Facial Dysmorphism; KDM3B-related intellectual disability, short stature and facial dysmorphism to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
Intellectual disability v3.1678 KDM3B Sarah Leigh Phenotypes for gene: KDM3B were changed from Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures to Diets-Jongmans syndrome, OMIM:618846; Diets-Jongmans syndrome, MONDO:0030012
Hereditary ataxia v1.304 UCHL1 Sarah Leigh Publications for gene: UCHL1 were set to 23359680; 28007905; 29735986; 32656641; 11555633; 33159930
Ataxia and cerebellar anomalies - narrow panel v2.302 PRDM13 Arina Puzriakova Classified gene: PRDM13 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.302 PRDM13 Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update.
Ataxia and cerebellar anomalies - narrow panel v2.302 PRDM13 Arina Puzriakova Gene: prdm13 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.301 PRDM13 Arina Puzriakova Tag Q3_22_rating tag was added to gene: PRDM13.
Ataxia and cerebellar anomalies - narrow panel v2.301 PRDM13 Arina Puzriakova Entity copied from Cerebellar hypoplasia v1.64
Ataxia and cerebellar anomalies - narrow panel v2.301 PRDM13 Arina Puzriakova gene: PRDM13 was added
gene: PRDM13 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Green,Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 35390279; 34730112
Phenotypes for gene: PRDM13 were set to Pontocerebellar hypoplasia, type 17, OMIM:619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Cerebellar hypoplasia v1.64 PRDM13 Arina Puzriakova Phenotypes for gene: PRDM13 were changed from Cerebellar hypoplasia to Pontocerebellar hypoplasia, type 17, OMIM:619909; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Adult onset neurodegenerative disorder v2.277 XK Arina Puzriakova Tag Q3_22_rating tag was added to gene: XK.
Adult onset neurodegenerative disorder v2.277 XK Arina Puzriakova Classified gene: XK as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v2.277 XK Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated Green at the next major review. Neurodegenerative component resembling Huntington disease becomes apparent in older individuals.
Adult onset neurodegenerative disorder v2.277 XK Arina Puzriakova Gene: xk has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v2.276 XK Arina Puzriakova Entity copied from Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.79
Adult onset neurodegenerative disorder v2.276 XK Arina Puzriakova gene: XK was added
gene: XK was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: XK 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: XK were set to 30128557; 20301528; 8004674
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease, OMIM:300842; McLeod neuroacanthocytosis syndrome, MONDO:0018945
Penetrance for gene: XK were set to Complete
Fetal anomalies v1.963 UNC13D Arina Puzriakova Publications for gene: UNC13D were set to PMID: 33249554
Fetal anomalies v1.962 UNC13D Arina Puzriakova Classified gene: UNC13D as Amber List (moderate evidence)
Fetal anomalies v1.962 UNC13D Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.962 UNC13D Arina Puzriakova Gene: unc13d has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.961 TK2 Arina Puzriakova Phenotypes for gene: TK2 were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC FORM to Mitochondrial DNA depletion syndrome 2 (myopathic type), OMIM:609560
Fetal anomalies v1.960 TK2 Arina Puzriakova Classified gene: TK2 as Amber List (moderate evidence)
Fetal anomalies v1.960 TK2 Arina Puzriakova Added comment: Comment on list classification: Updated rating from Red to Amber inline with this recent Amber review by Rhiannon Mellis (GOSH), awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.960 TK2 Arina Puzriakova Gene: tk2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.959 TK2 Arina Puzriakova Tag watchlist tag was added to gene: TK2.
Fetal anomalies v1.959 THSD1 Arina Puzriakova Classified gene: THSD1 as Amber List (moderate evidence)
Fetal anomalies v1.959 THSD1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.959 THSD1 Arina Puzriakova Gene: thsd1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.958 THSD1 Arina Puzriakova Publications for gene: THSD1 were set to PMID: 28749478; 26036949
Fetal anomalies v1.957 ST3GAL5 Arina Puzriakova Phenotypes for gene: ST3GAL5 were changed from AMISH INFANTILE EPILEPSY SYNDROME to Infantile epilepsy
Fetal anomalies v1.956 ST3GAL5 Arina Puzriakova Publications for gene: ST3GAL5 were set to
Fetal anomalies v1.955 SERPINA11 Arina Puzriakova Publications for gene: SERPINA11 were set to PMID: 31742715; 28749478
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Classified gene: SERPINA11 as Amber List (moderate evidence)
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.954 SERPINA11 Arina Puzriakova Gene: serpina11 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.953 PIGS Arina Puzriakova Publications for gene: PIGS were set to PMID: 30269814
Fetal anomalies v1.952 PIGS Arina Puzriakova Phenotypes for gene: PIGS were changed from Developmental and epileptic encephalopathy 95 to Developmental and epileptic encephalopathy 95, OMIM:618143
Fetal anomalies v1.951 PIGS Arina Puzriakova Classified gene: PIGS as Amber List (moderate evidence)
Fetal anomalies v1.951 PIGS Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.951 PIGS Arina Puzriakova Gene: pigs has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.950 NUP88 Arina Puzriakova Publications for gene: NUP88 were set to 30543681
Fetal anomalies v1.949 NONO Arina Puzriakova Tag watchlist tag was added to gene: NONO.
Fetal anomalies v1.949 NONO Arina Puzriakova Publications for gene: NONO were set to 32397791
Fetal anomalies v1.948 NDUFB10 Arina Puzriakova Phenotypes for gene: NDUFB10 were changed from Mitochondrial complex I deficiency to Mitochondrial complex I deficiency, nuclear type 35 , OMIM:619003
Fetal anomalies v1.947 NDUFB10 Arina Puzriakova Publications for gene: NDUFB10 were set to PMID: 31130284; 28040730
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Classified gene: NDUFB10 as Amber List (moderate evidence)
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.946 NDUFB10 Arina Puzriakova Gene: ndufb10 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Classified gene: MYBPC3 as Amber List (moderate evidence)
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.

Note that the two fetal cases reported in literature harboured homozygous variants (PMID:19858127; 28749478) although expert reviewer suggests an MOI of 'both mono- and biallelic'
Fetal anomalies v1.945 MYBPC3 Arina Puzriakova Gene: mybpc3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.944 MYBPC3 Arina Puzriakova Publications for gene: MYBPC3 were set to PMID: 28749478; 19858127
Fetal anomalies v1.943 MRPS16 Arina Puzriakova Publications for gene: MRPS16 were set to PMID: 28749478
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Classified gene: MRPS16 as Amber List (moderate evidence)
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.942 MRPS16 Arina Puzriakova Gene: mrps16 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.941 MANBA Arina Puzriakova Publications for gene: MANBA were set to
Fetal anomalies v1.940 LOX Arina Puzriakova Publications for gene: LOX were set to PMID: 31742715
Fetal anomalies v1.939 LOX Arina Puzriakova Classified gene: LOX as Amber List (moderate evidence)
Fetal anomalies v1.939 LOX Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.939 LOX Arina Puzriakova Gene: lox has been classified as Amber List (Moderate Evidence).
Stickler syndrome v2.27 BMP4 martin snead reviewed gene: BMP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35979589, 30568244, 35022715, 34926457; Phenotypes: AD Stickler syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Stickler syndrome v2.27 VCAN martin snead reviewed gene: VCAN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12208278, 10729292, 11812423; Phenotypes: Ocular-only Stickler syndrome, Wagner syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Stickler syndrome v2.27 VCAN martin snead Deleted their review
Stickler syndrome v2.27 VCAN martin snead gene: VCAN was added
gene: VCAN was added to Stickler syndrome. Sources: Expert Review
Mode of inheritance for gene: VCAN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VCAN were set to Snead M, Richards A. A frame shift mutation in a tissue-specific alternatively spliced exon of collagen 2A1 in Wagner's vitreoretinal degeneration. Am J Ophthalmol. 2002 Sep; 134(3):473; author reply 473-4. doi: 10.1016/s0002-9394(02)01635-5. PMID: 12208278.
Phenotypes for gene: VCAN were set to Ocular-only Stickler syndrome; Wagner syndrome
Penetrance for gene: VCAN were set to Complete
Review for gene: VCAN was set to GREEN
Added comment: VCAN needs to be added to the Stickler panel because Ocular-only Stickler syndrome is frequently mis-diagnosed as Wagner syndrome and vice versa. Although the 2 conditions are distinguishable by vitreous phenotyping, this may not be feasible in children or any patient who has undergone previous vitrectomy surgery.
Sources: Expert Review
Fetal anomalies v1.938 FTO Arina Puzriakova Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117
Fetal anomalies v1.937 FTO Arina Puzriakova Classified gene: FTO as Amber List (moderate evidence)
Fetal anomalies v1.937 FTO Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.937 FTO Arina Puzriakova Gene: fto has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.936 FOXP2 Arina Puzriakova Phenotypes for gene: FOXP2 were changed from SPEECH-LANGUAGE DISORDER 1 to Speech-language disorder-1, OMIM:602081; Structural abnormalities of basal ganglia
Fetal anomalies v1.935 FOXP2 Arina Puzriakova Publications for gene: FOXP2 were set to
Fetal anomalies v1.934 ENG Arina Puzriakova Phenotypes for gene: ENG were changed from Telangiectasia, hereditary hemorrhagic, type 1 to Telangiectasia, hereditary hemorrhagic, type 1, OMIM:187300
Fetal anomalies v1.933 ENG Arina Puzriakova Classified gene: ENG as Amber List (moderate evidence)
Fetal anomalies v1.933 ENG Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Rhiannon Mellis (GOSH). Rating Amber inline with this review, awaiting further evidence supporting that this gene can cause a fetal phenotype.
Fetal anomalies v1.933 ENG Arina Puzriakova Gene: eng has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.932 EDA Arina Puzriakova Classified gene: EDA as Green List (high evidence)
Fetal anomalies v1.932 EDA Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update in line with the recent Red review by Rhiannon Mellis (GOSH).
Fetal anomalies v1.932 EDA Arina Puzriakova Gene: eda has been classified as Green List (High Evidence).
Fetal anomalies v1.931 EDA Arina Puzriakova Phenotypes for gene: EDA were changed from TOOTH AGENESIS SELECTIVE X-LINKED TYPE 1; ECTODERMAL DYSPLASIA TYPE 1 to Ectodermal dysplasia 1, hypohidrotic, X-linked, OMIM:305100
Fetal anomalies v1.930 EDA Arina Puzriakova Tag Q3_22_rating tag was added to gene: EDA.
Tag Q3_22_NHS_review tag was added to gene: EDA.