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Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.38 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Congenital myaesthenic syndrome v2.40 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Congenital myasthenic syndrome; Plectin deficiency; Congenital myasthenic syndrome associatedwith epidermolysis bullosa (EBS) to Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Congenital muscular dystrophy v2.28 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Muscular dystrophy with epidermolysis bullosa simplex, 226670; Muscular dystrophy, limb-girdle autosomal recessive 17, 613723; Epidermolysis bullosa simplex with muscular dystrophy, 226670 to Muscular dystrophy, limb-girdle, autosomal recessive 17, OMIM:613723; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670
Familial cicatricial alopecia v1.4 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from PLEC-related Epidermolysis Bullosa; Epidermolysis bullosa simplex with pyloric atresia, 612138; Epidermolysis bullosa simplex with muscular dystrophy, 226670; Epidermolysis bullosa simplex, Ogna type, 131950; scarring alopecia to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Ectodermal dysplasia v1.40 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from PLEC-related Epidermolysis Bullosa; Epidermolysis bullosa simplex, Ogna type, 131950; scarring alopecia; Epidermolysis bullosa simplex with muscular dystrophy, 226670; Epidermolysis bullosa simplex with pyloric atresia, 612138 to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Epidermolysis bullosa v1.8 PLEC Arina Puzriakova Phenotypes for gene: PLEC were changed from Epidermolysis bullosa simplex, Ogna type (AD), 131950; Epidermolysis bullosa simplex including Ogna variant; Epidermolysis Bullosa Simplex, Ogna Type; Epidermolysis bullosa simplex with pyloric atresia (AR), 612138; Epidermolysis bullosa simplex with pyloric atresia; Epidermolysis Bullosa Simplex With Pyloric Atresia; Muscular dystrophy with epidermolysis bullosa simplex (AR), 226670; Epidermolysis Bullosa with Muscular Dystrophy; Epidermolysis Bullosa Simplex With Muscular Dystrophy to Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive , OMIM:616487; Epidermolysis bullosa simplex 5A, Ogna type, OMIM:131950; Epidermolysis bullosa simplex 5B, with muscular dystrophy, OMIM:226670; Epidermolysis bullosa simplex 5C, with pyloric atresia, OMIM:612138
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams edited their review of gene: TTC21B: Added comment: Looking at the mode of inheritance for this gene. It is reported as both AD and AR in OMIM for Nephronophthisis 12, OMIM:613820.

There are many biallelic cases reported e.g.

PMID: 21258341 - Davis et al 2011 - report 5 families with isolated nephronophthisis (NPHP). Patients in 3 families had compound heterozygous variants (P209L/C552X, c.2758-2A>G/P209L, W150R/c.3264-3C>G) in TTC21B and 2 families with a milder phenotype were homozygous for the P209L variant. They observed the same haplotype at coding regions spanning the locus in all P209L homozygotes. In all 5 families individuals heterozygous for the variants were unaffected. They also report one case with compound het variants (R411X/L795P) with a syndromic Jeune Asphyxiating Thoracic Dystrophy phenotype.

PMID: 26940125 - Bullich et al 2017 - TTC21B variants and nephrotic proteinuria with FSGS and tubulointerstitial lesions were identified in 2 families with homozygous (p.P209L) variants (both families from Morocco, high blood pressure noted in individuals from each), and in 1 family with compound het variants (p.P209L and p.H426D)(family from Spain).

PMID:34957165 - Gambino et al 2021 - patient from a North African family with severe hypertension and chronic kidney disease at age 20. Several cases of hypertension, myopia, and severe kidney disease were reported in the extended family. A homozygous p.P209L variant was identified in TTC21B.

PMID:34805047 - Bezdíčka et al 2021 - 2.5 yo patient presenting with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis. She was hypertensive on admission. Compound het variants in TTC21B were identified p.Pro209Leu and p.Cys14Arg. The mother was a healthy carrier of the c.626C>T, p.Pro209Leu heterozygous variant.

PMID:35289079 - Olinger et al 2022 - 2 siblings with extreme early-onset HTN, proteinuria, and progressive CKD leading to kidney failure. Compound het variants in TTC21B were identified (p.(Gln834Ter) and p.(Pro209Leu)).

However, there are also reports of heterozygous variants in TTC21B in patients with kidney disease but it is thought that these may be modifier variants

PMID: 26940125 - Bullich et al 2017 - rare heterozygous variants in TTC21B were found in 5 patients, 4 with glomerular disease and 1 with cystic disease, but in addition to other likely pathogenic variants in other renal disease related genes (PKD1 , COL4A3, COL4A5 and NPHS2) suggesting a modifier role of TTC21B alleles. 2 patients presented a more severe phenotype than expected. A similar frequency for the total set of rare TTC21B variants predicted to be pathogenic was found between renal patients and controls

PMID: 21258341 - Davis et al 2011 - found an enrichment of pathogenic TTC21B alleles in ciliopathy patients (∼5%) and suggest that TTC21B might be a common contributor to the total mutational load in ciliopathies.; Changed publications to: 21258341, 26940125, 34957165, 34805047, 35289079
Intellectual disability v3.1547 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Dyskeratosis congenita, autosomal recessive 6, 616353 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353
Familial pulmonary fibrosis v1.29 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, 616371 to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Cytopenia - NOT Fanconi anaemia v1.64 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4; 616353 Dyskeratosis congenita, autosomal recessive 6; 616353 Dyskeratosis congenita, autosomal recessive 6 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Haematological malignancies cancer susceptibility v2.27 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Adult solid tumours cancer susceptibility v2.20 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616353 Dyskeratosis congenita, autosomal recessive 6; 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Childhood solid tumours v2.33 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from 616353 Dyskeratosis congenita, autosomal recessive 6; 616371 Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4 to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Haematological malignancies for rare disease v1.11 PARN Arina Puzriakova Phenotypes for gene: PARN were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal recessive 6, OMIM:616353; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 4, OMIM:616371
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams Tag Q2_22_MOI tag was added to gene: TTC21B.
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams Phenotypes for gene: TTC21B were changed from Short-rib thoracic dysplasia 4 with or without polydactyly, MIM 613819; Nephronopthisis 12 MIM 613820 to Nephronopthisis 12, OMIM:613820
Extreme early-onset hypertension v1.18 TTC21B Eleanor Williams Phenotypes for gene: TTC21B were changed from Hypertension; focal segmental glomerulosclerosis; nephronopthisis; myopia to Hypertension; focal segmental glomerulosclerosis; nephronopthisis; myopia; Nephronophthisis 12, OMIM:613820
Extreme early-onset hypertension v1.17 TTC21B Eleanor Williams Publications for gene: TTC21B were set to 24876116; 26940125; 34957165; 34805047
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Classified gene: TTC21B as Green List (high evidence)
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Added comment: Comment on list classification: Promoting this gene to green as there are sufficient cases in which hypertension is a characteristic of the disease phenotype.
Extreme early-onset hypertension v1.16 TTC21B Eleanor Williams Gene: ttc21b has been classified as Green List (High Evidence).
Extreme early-onset hypertension v1.15 TTC21B Eleanor Williams reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.156 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Behr syndrome, 210000; Optic atrophy plus syndrome, 125250 to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Optic neuropathy v2.67 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Optic neuropathy v2.66 OPA1 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. Biallelic variants cause Behr syndrome (MIM# 210000) in which early-onset optic atrophy is a main clinical feature of the phenotype (PMID: 20157015; 21636302; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Optic neuropathy v2.66 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Optic neuropathy v2.65 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Optic neuropathy v2.64 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1 165500; Optic atrophy plus syndrome 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Optic neuropathy v2.63 OPA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: OPA1.
Hereditary neuropathy v1.450 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Hereditary neuropathy or pain disorder v1.98 OPA1 Arina Puzriakova Publications for gene: OPA1 were set to
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Classified gene: OPA1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Added comment: Comment on list classification: It has now been agreed that all genes causing neuropathy as a key feature of a phenotype, even if in the context of other syndromic symptoms, should be included on this panel to minimise the risk of missing cases. For this reason it would now be appropriate to rate this gene as Green on R78.
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Gene: opa1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.96 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause Behr syndrome (MIM# 210000) which is also associated with axonal sensorimotor peripheral neuropathy (PMID: 20157015; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Hereditary neuropathy or pain disorder v1.96 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.95 OPA1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: OPA1.
Hereditary neuropathy v1.449 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause Behr syndrome (MIM# 210000) which is also associated with axonal sensorimotor peripheral neuropathy (PMID: 20157015; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Hereditary neuropathy v1.449 OPA1 Arina Puzriakova Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.95 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic neuropathy, PEO, deafness, myelopathy, sensory-motor axonal neuropathy; Optic atrophy plus syndrome, 125250 to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Hereditary neuropathy v1.448 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250; Optic neuropathy, PEO, deafness, myelopathy, sensory-motor axonal neuropathy to Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Unexplained kidney failure in young people v1.113 CFHR5 Eleanor Williams Phenotypes for gene: CFHR5 were changed from Haematuria; C3 glomerulopathy; kidney failure; macroscopic haematuria to C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency, OMIM:614809; Immune-complex-mediated MPGN; CFHR5 nephropathy; Haematuria; Chronic Kidney Disease; Proteinuria; End stage renal disease
Unexplained kidney failure in young people v1.112 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to PubMed: 20800271; 24067434
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Classified gene: CFHR5 as Green List (high evidence)
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Added comment: Comment on list classification: Promoting to green in light of external review and the fact that it is already green on the 'Unexplained paediatric onset end-stage renal disease' panel.
Unexplained kidney failure in young people v1.111 CFHR5 Eleanor Williams Gene: cfhr5 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.110 CFHR5 Eleanor Williams Mode of pathogenicity for gene: CFHR5 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
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Tag Q2_22_NHS_review tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Daniel Gale confirms that the mode of inheritance should be monoallelic only.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.26 CFHR5 Eleanor Williams Mode of inheritance for gene: CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.25 CFHR5 Eleanor Williams Phenotypes for gene: CFHR5 were changed from C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency,614809; Immune-complex-mediated MPGN; CFHR5 nephropathy to C3 glomerulopathy; C3G; Immune complex MPGN; IC-MPGN; Nephropathy due to CFHR5 deficiency, OMIM:614809; Immune-complex-mediated MPGN; CFHR5 nephropathy; Haematuria; Chronic Kidney Disease; Proteinuria; End stage renal disease
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.24 CFHR5 Eleanor Williams Publications for gene: CFHR5 were set to 24172683; 20800271; 24067434; 23728178; 27458560; 21566112; 32928961; 22503529
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Added comment: Comment on mode of pathogenicity: Updating as per reviewer suggestion
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.23 CFHR5 Eleanor Williams Mode of pathogenicity for gene: CFHR5 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 disorders v2.99 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Likely inborn error of metabolism v2.245 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Possible mitochondrial disorder, nuclear genes v1.74 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Undiagnosed metabolic disorders v1.527 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Optic atrophy 1, 165500; {Glaucoma, normal tension, susceptibility to}, 606657; Optic atrophy plus syndrome, 125250; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Mitochondrial DNA maintenance disorder v1.8 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Optic atrophy plus syndrome, 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Monogenic hearing loss v2.242 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from #125250:Optic atrophy plus syndrome; #165500:Optic atrophy 1; #606657:{Glaucoma, normal tension, susceptibility to} to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Auditory Neuropathy Spectrum Disorde v1.9 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from 125250 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Ataxia and cerebellar anomalies - childhood onset v2.293 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858 to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Behr syndrome, OMIM:210000
Retinal disorders v2.256 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Eye Disorders to Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250
Structural eye disease v1.122 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from Optic atrophy 1, 165500; Glaucoma, normal tension, susceptibility to, 210000; Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to} 606657; Behr syndrome to {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Optic atrophy 1, OMIM:165500; Optic atrophy plus syndrome, OMIM:125250; Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type), OMIM:616896; Behr syndrome, OMIM:210000
Glaucoma (developmental) v1.42 OPA1 Arina Puzriakova Phenotypes for gene: OPA1 were changed from {Glaucoma, normal tension, susceptibility to} 606657 to {Glaucoma, normal tension, susceptibility to}, OMIM:606657
Retinal disorders v2.255 MYO7A Arina Puzriakova Phenotypes for gene: MYO7A were changed from Eye Disorders to Usher syndrome, type 1B, OMIM:276900
Structural eye disease v1.121 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1, 267750 to Knobloch syndrome, type 1, OMIM:267750
Monogenic hearing loss v2.241 MYO7A Arina Puzriakova Phenotypes for gene: MYO7A were changed from hearing loss; Usher syndrome, type 1B, 276900; Nonsyndromic Hearing Loss, Dominant; #600060:Deafness, autosomal recessive 2; Nonsyndromic Hearing Loss, Recessive; #601317:Deafness, autosomal dominant 11 to Deafness, autosomal dominant 11, OMIM:601317; Deafness, autosomal recessive 2, OMIM:600060; Usher syndrome, type 1B, OMIM:276900
Retinal disorders v2.254 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch Syndrome Type I, 267750 to Knobloch syndrome, type 1, OMIM:267750
Structural eye disease v1.120 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 17546652; 22399687
Retinal disorders v2.253 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to
DDG2P v2.71 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I 267750 to Knobloch syndrome, type 1, OMIM:267750
Fetal anomalies v1.854 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I to Knobloch syndrome, type 1, OMIM:267750
Bilateral congenital or childhood onset cataracts v2.106 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome; high myopia; cataracts; vitreoretinal degeneration; retinal detachment to Knobloch syndrome, type 1, OMIM:267750
Early onset or syndromic epilepsy v2.511 COL18A1 Sarah Leigh Phenotypes for gene: COL18A1 were changed from Knobloch syndrome, type 1 267750 to Knobloch syndrome, type 1, OMIM:267750
Early onset or syndromic epilepsy v2.510 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 19160445; 28602933; 28950998
Fetal anomalies v1.853 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to
DDG2P v2.70 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to 10942434
Bilateral congenital or childhood onset cataracts v2.105 COL18A1 Sarah Leigh Publications for gene: COL18A1 were set to Aldahmesh et al (2011) J Genet Med 48(9):597-601; Williams et al (2008) Ophthal Genet 29:85-86; Suzuki et al (2002) Am J Hum Genet 71:1320-1329
Hydrocephalus v2.129 CLIC2 Sarah Leigh Classified gene: CLIC2 as Red List (low evidence)
Hydrocephalus v2.129 CLIC2 Sarah Leigh Gene: clic2 has been classified as Red List (Low Evidence).
Intellectual disability v3.1546 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.128 CLIC2 Sarah Leigh Publications for gene: CLIC2 were set to 22814392
Hydrocephalus v2.127 CLIC2 Sarah Leigh reviewed gene: CLIC2: Rating: RED; Mode of pathogenicity: None; Publications: 28333917, 31349857, 22814392; Phenotypes: ; Mode of inheritance: None
Cytopenia - NOT Fanconi anaemia v1.63 MPL Arina Puzriakova Added comment: Comment on mode of inheritance: The MOI on this panel should be reviewed at the next GMS panel update to determine the pertinent inheritance pattern (currently set to both AD/AR).

Biallelic variants cause thrombocytopenia (MIM# 604498) which in severe forms can present with pancytopenia, a phenotype that is within the scope of this panel. On the other hand, monoallelic variants are associated with thrombocythemia (MIM# 601977) which does not include features that may be relevant here. Therefore it may be appropriate to update the MOI to 'biallelic' only.
Cytopenia - NOT Fanconi anaemia v1.63 MPL Arina Puzriakova Mode of inheritance for gene: MPL was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.62 MPL Arina Puzriakova Tag Q2_22_MOI tag was added to gene: MPL.
Tag Q2_22_expert_review tag was added to gene: MPL.
Thrombocythaemia v1.3 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Thrombocythemia 2, 601977 to Thrombocythemia 2, OMIM:601977
Cytopenia - NOT Fanconi anaemia v1.62 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from 601977 Thrombocythemia 2; 604498 Thrombocytopenia, congenital amegakaryocytic; Thrombocytopenia, congenital amegakaryocytic, 604498 to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Bleeding and platelet disorders v1.38 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from 604498 Thrombocytopenia, congenital amegakaryocytic to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Cytopenias and congenital anaemias v1.106 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Inherited Bone Marrow Failure Syndromes - Thrombocytopenia; Congenital amegkaryocytic thrombocytopenia; Congenital Amegakaryocytic Thrombocytopenia; Amegakaryocytic Thrombocytopenia, Congenital; Thrombocytopenia, congenital amegakaryocytic, 604498 to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Inherited bleeding disorders v1.167 MPL Arina Puzriakova Phenotypes for gene: MPL were changed from Congenital amegakaryocytic thrombocytopenia (CAMT) to Thrombocytopenia, congenital amegakaryocytic, OMIM:604498
Structural eye disease v1.119 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, type 2A2, 609260; Eye Disorders to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Structural eye disease v1.118 MFN2 Arina Puzriakova Mode of inheritance for gene: MFN2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.63 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Optic Atrophy; Hereditary motor and sensory neuropathy VIA; Charcot-Marie-Tooth disease, axonal, type 2A2A (AD), 609260; Charcot-Marie-Tooth disease, axonal, type 2A2B (AR), 617087; Hereditary motor and sensory neuropathy VIA (AD), 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary neuropathy or pain disorder v1.94 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot Marie Tooth disease, type 2A2, 609260; Charcot-Marie-Tooth, Type 2 (Dominant); Hereditary motor and sensory neuropathy VI, 601152; MFN2 axonal neuropathy; Hereditary Motor and Sensory Neuropathy (Recessive) to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Mitochondrial disorders v2.98 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Charcot-Marie-Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary neuropathy v1.447 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth, Type 2 (Dominant); MFN2 axonal neuropathy; MFN2 axonal neuropathy; Charcot-Marie-Tooth, Type 2 (Dominant); Charcot Marie Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152; Hereditary motor and sensory neuropathy VI, 601152; Hereditary Motor and Sensory Neuropathy (Recessive); Hereditary Motor and Sensory Neuropathy (Recessive) to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Likely inborn error of metabolism v2.244 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Charcot-Marie-Tooth disease, type 2A2, 609260; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Possible mitochondrial disorder, nuclear genes v1.73 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Mitochondrial DNA depletion syndrome; Optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Undiagnosed metabolic disorders v1.526 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Disorders of mitochondrial DNA maintenance and integrity; Charcot-Marie-Tooth disease, type 2A2, 609260; Hereditary motor and sensory neuropathy VI, 601152 to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Mitochondrial DNA maintenance disorder v1.7 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Mitochondrial DNA depletion syndrome; Optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260; Charcot-Marie-Tooth disease, axonal, type 2A2B, OMIM:617087; Hereditary motor and sensory neuropathy VIA, OMIM:601152
Hereditary ataxia, adult onset v2.155 MFN2 Arina Puzriakova Phenotypes for gene: MFN2 were changed from Dominant optic atrophy plus to Charcot-Marie-Tooth disease, axonal, type 2A2A, OMIM:609260
Inherited ovarian cancer (without breast cancer) v2.26 BRIP1 Sarah Leigh Added comment: Comment on phenotypes: Association of BRIP1 and breast cancer has been refuted (https://search.clinicalgenome.org/kb/gene-validity/CGGCIEX:assertion_9910)
{Breast cancer, early-onset, susceptibility to}, OMIM:114480;Hereditary breast carcinoma, MONDO:0016419
Inherited ovarian cancer (without breast cancer) v2.26 BRIP1 Sarah Leigh Phenotypes for gene: BRIP1 were changed from {Breast cancer, early-onset, susceptibility to}, OMIM:114480; Hereditary breast carcinoma, MONDO:0016419 to ovarian epithelial tumor, MONDO:0002229
Renal tubulopathies v2.50 CLCNKA Sarah Leigh Phenotypes for gene: CLCNKA were changed from Bartter syndrome, type 4b, digenic 613090 to Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.49 CLCNKA Sarah Leigh Publications for gene: CLCNKA were set to 18310267
Renal tubulopathies v2.48 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267; 32506365; 32488762; 30999883
Renal tubulopathies v2.47 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224; 32506365
Renal tubulopathies v2.46 SLC12A1 Sarah Leigh Publications for gene: SLC12A1 were set to 8640224
Renal tubulopathies v2.45 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267
Intellectual disability v3.1546 AFF3 Arina Puzriakova commented on gene: AFF3
Intellectual disability v3.1546 AFF3 Arina Puzriakova Tag watchlist was removed from gene: AFF3.
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Classified gene: AFF3 as Amber List (moderate evidence)
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Skeletal dysplasia v2.194 AFF3 Arina Puzriakova Gene: aff3 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: AFF3.
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova reviewed gene: AFF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18616733, 31388108, 33961779; Phenotypes: KINSSHIP syndrome, OMIM:619297; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.193 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to
Intellectual disability v3.1546 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Early onset or syndromic epilepsy v2.509 AFF3 Arina Puzriakova Publications for gene: AFF3 were set to https://doi.org/10.1101/693937; 18616733; 21677750; 25660031; 31388108
Skeletal dysplasia v2.192 AFF3 Arina Puzriakova Mode of inheritance for gene: AFF3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1545 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures to KINSSHIP syndrome, OMIM:619297
Early onset or syndromic epilepsy v2.508 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from Intellectual disability; Seizures; KINSSHIP syndrome to KINSSHIP syndrome, OMIM:619297
Skeletal dysplasia v2.191 AFF3 Arina Puzriakova Phenotypes for gene: AFF3 were changed from No OMIM or G2P phenotype to KINSSHIP syndrome, OMIM:619297
Renal tubulopathies v2.44 CLCNKB Sarah Leigh Added comment: Comment on phenotypes: Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria
Renal tubulopathies v2.44 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090 to Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.43 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936; 18310267
Early onset or syndromic epilepsy v2.507 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to 31271740; 34918187; 35346037
Phenotypes for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Intellectual disability v3.1544 DTYMK Konstantinos Varvagiannis gene: DTYMK was added
gene: DTYMK was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest
Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037
Penetrance for gene: DTYMK were set to Complete
Review for gene: DTYMK was set to GREEN
Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported.

Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc].

Relevant studies are summarized below.
----
Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants.

The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y.

Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib.

There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway.

Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS).

Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood).

This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%.
----
Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem.

CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction).

WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu.

In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect.

Variants were both ultrarare without homozygotes in ExAC,.

The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells.

dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested.

In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase).

Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain.

Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage).

In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides).

Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks.

mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency.

Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents.

Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents.

Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction.

The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD.
------
In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed]
Sources: Literature
Renal tubulopathies v2.42 CLCNKB Sarah Leigh Added comment: Comment on phenotypes: Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria
Renal tubulopathies v2.42 CLCNKB Sarah Leigh Phenotypes for gene: CLCNKB were changed from Hypokalaemic alkalosis with hypomagnesaemia & hypocalciuria; Bartter syndrome, type 3, 607394 to Bartter syndrome, type 3, OMIM:607364; Bartter syndrome, type 4b, digenic, OMIM:613090
Renal tubulopathies v2.41 CLCNKB Sarah Leigh Publications for gene: CLCNKB were set to 9326936
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh Deleted their comment
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh commented on gene: CFI: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel.
Unexplained young onset end-stage renal disease v1.36 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923; Complement factor I deficiency, OMIM:610984
Unexplained young onset end-stage renal disease v1.35 CFI Sarah Leigh Publications for gene: CFI were set to 16621965; 15173250
Unexplained young onset end-stage renal disease v1.34 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Unexplained young onset end-stage renal disease v1.34 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.109 CFI Sarah Leigh Mode of inheritance for gene: CFI was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh Tag Q2_22_MOI was removed from gene: CFI.
Atypical haemolytic uraemic syndrome v2.15 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.14 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.13 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Atypical haemolytic uraemic syndrome v2.12 CFI Sarah Leigh Publications for gene: CFI were set to 16621965; 17597211; 15173250; 23685748
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in this panel.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh changed review comment from: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; to: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.
Unexplained kidney failure in young people v1.108 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923; Complement factor I deficiency, OMIM:610984
Unexplained kidney failure in young people v1.107 CFI Sarah Leigh Publications for gene: CFI were set to 15173250; 16621965;
Unexplained kidney failure in young people v1.106 CFI Sarah Leigh edited their review of gene: CFI: Added comment: Renal insufficiency, glomerulonephritis and pyelonephritis has been reported in Complement factor I deficiency (OMIM:610984)(PMID:17018561; 10352206), therefore it would be appropriate for the mode of inheritance to be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 17018561, 10352206; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.106 CFI Sarah Leigh Tag Q2_22_MOI tag was added to gene: CFI.
Atypical haemolytic uraemic syndrome v2.11 CFI Sarah Leigh Phenotypes for gene: CFI were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 3 612923 to Hemolytic uremic syndrome, atypical, susceptibility to, 3, OMIM:612923
COVID-19 research v1.123 CFI Sarah Leigh Mode of inheritance for gene: CFI was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood solid tumours v2.32 CDKN1C Sarah Leigh Publications for gene: CDKN1C were set to 10424812
Childhood solid tumours v2.31 CDKN1C Sarah Leigh Tag Q2_22_MOI tag was added to gene: CDKN1C.
Childhood solid tumours v2.31 CDKN1C Sarah Leigh reviewed gene: CDKN1C: Rating: ; Mode of pathogenicity: None; Publications: 7550351, 7729684, 8610162).; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Familial rhabdomyosarcoma v1.5 CDKN1C Sarah Leigh Mode of inheritance for gene: CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Childhood solid tumours cancer susceptibility v1.20 CDKN1C Sarah Leigh Mode of inheritance for gene: CDKN1C was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 CFHR5 Daniel Gale reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 20800271, 21566112, 30844074, 28729035, 32928961, 24067434, 27490940, 33753502, 30197990, 24067434; Phenotypes: Haematuria, C3 glomerulopathy, Chronic Kidney Disease, Proteinuria, End stage renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Unexplained kidney failure in young people v1.106 CFHR5 Daniel Gale reviewed gene: CFHR5: 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: 20800271, 21566112, 30844074, 28729035, 32928961, 24067434, 27490940, 33753502, 30197990, 24067434; Phenotypes: Haematuria, C3 glomerulopathy, Chronic Kidney Disease, Proteinuria, End stage renal disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh edited their review of gene: C19orf12: Added comment: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed publications to: 29295770, 31087512; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Undiagnosed metabolic disorders v1.525 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.108 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Parkinson Disease and Complex Parkinsonism v1.108 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.62 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Optic neuropathy v2.62 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders, adult onset v2.272 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Neurodegenerative disorders, adult onset v2.272 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset dystonia v1.117 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Early onset dystonia v1.117 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.292 C19orf12 Sarah Leigh Added comment: Comment on mode of inheritance: Monfrini et al (PMID: 29295770) and Gregory et al (PMID: 31087512) have reported heterozygous pathogenic C19ORF12 variants in patients with neurodegeneration with brain iron accumulation 4 (OMIM: 614298). Therefore, the mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary spastic paraplegia v1.292 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.133 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Hereditary spastic paraplegia, childhood onset v2.133 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.97 C19orf12 Sarah Leigh reviewed gene: C19orf12: Rating: ; Mode of pathogenicity: None; Publications: 29295770, 31087512; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.97 C19orf12 Sarah Leigh Tag Q2_22_MOI tag was added to gene: C19orf12.
Likely inborn error of metabolism v2.243 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Neurodegeneration with brain iron accumulation 4, 614298; Mitochondrial Membrane Protein-Associated Neurodegeneration to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Dystonia, chorea or related movement disorder, childhood onset v1.227 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from neurodegeneration with brain iron accumulation-4, 614298; mitochondrial membrane protein-associated neurodegeneration; Dystonia to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Undiagnosed metabolic disorders v1.524 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation (NBIA) (Disorder of iron metabolism); Neurodegeneration with brain iron accumulation 4, 614298; Mitochondrial Membrane Protein-Associated Neurodegeneration to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Neurodegenerative disorders, adult onset v2.272 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation 4, OMIM: 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Neurodegenerative disorders, adult onset v2.271 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; neurodegeneration with brain iron accumulation-4, OMIM:614298 to Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Hereditary spastic paraplegia, adult onset v1.97 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Hereditary spastic paraplegia, childhood onset v2.133 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Optic neuropathy v2.62 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from SPASTIC PARAPLEGIA 43, AUTOSOMAL RECESSIVE, 615043; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Hereditary spastic paraplegia v1.291 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Structural basal ganglia disorders v1.32 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Early onset dystonia v1.116 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; mitochondrial membrane protein-associated neurodegeneration; neurodegeneration with brain iron accumulation-4 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Parkinson Disease and Complex Parkinsonism v1.107 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Dystonia; mitochondrial membrane protein-associated neurodegeneration; Neurodegeneration with brain iron accumulation 4 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Early onset dystonia v1.115 C19orf12 Sarah Leigh Mode of inheritance for gene: C19orf12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.106 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Early onset dystonia v1.114 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Structural basal ganglia disorders v1.31 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Hereditary spastic paraplegia v1.290 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to Landoure (2013)
Optic neuropathy v2.61 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27772766; 26187298; 24209434; 22584950
Hereditary spastic paraplegia, childhood onset v2.132 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Hereditary spastic paraplegia, adult onset v1.96 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23857908; 26539891
Neurodegenerative disorders, adult onset v2.270 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 23278385; Landoure (2013)
Likely inborn error of metabolism v2.242 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27604308
Undiagnosed metabolic disorders v1.523 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to 27604308
Dystonia, chorea or related movement disorder, adult onset v1.169 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.226 C19orf12 Sarah Leigh Publications for gene: C19orf12 were set to
Intellectual disability v3.1544 KDM5B Arina Puzriakova Phenotypes for gene: KDM5B were changed from neurodevelopment delay and autism spectrum disorder; Mental retardation, autosomal recessive 65, 618109 to Intellectual developmental disorder, autosomal recessive 65, OMIM:618109
Monogenic hearing loss v2.240 KCNQ4 Arina Puzriakova Phenotypes for gene: KCNQ4 were changed from #600101:Deafness, autosomal dominant 2A to Deafness, autosomal dominant 2A, OMIM:600101
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.69 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Resistance to insulin-like growth factor I to Insulin-like growth factor I, resistance to, OMIM:270450
Fetal anomalies v1.852 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO to Insulin-like growth factor I, resistance to, OMIM:270450
Severe microcephaly v2.300 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-like growth factor I, resistance to 270450 to Insulin-like growth factor I, resistance to, OMIM:270450
IUGR and IGF abnormalities v1.52 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin‐likegrowthfactorI,resistanceto,270450; Insulin-Like Growth Factor I Resistance to Insulin-like growth factor I, resistance to, OMIM:270450
Intellectual disability v3.1543 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Gene2Phenotype confirmed gene with ID HPO; Insulin-like growth factor I, resistance to, 270450; developmental delay to Insulin-like growth factor I, resistance to, OMIM:270450
Silver Russell syndrome v1.12 IGF1R Arina Puzriakova Phenotypes for gene: IGF1R were changed from Insulin-like growth factor I, resistance to 270450 to Insulin-like growth factor I, resistance to, OMIM:270450
Early onset or syndromic epilepsy v2.507 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925
Intellectual disability v3.1542 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Inherited white matter disorders v1.158 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from General Leukodystrophy & Mitochondrial Leukoencephalopathy; Megalencephalic leukoencephalopathy with subcortical cysts (MLC); Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Leukodystrophy, adult onset v1.41 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2A, 613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, 613926 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
White matter disorders and cerebral calcification - childhood onset v1.236 HEPACAM Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts (MLC); General Leukodystrophy & Mitochondrial Leukoencephalopathy; Megalencephalic leukoencephalopathy with subcortical cysts 2A; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926
Cytopenias and congenital anaemias v1.105 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Hereditary persistence of fetal hemoglobin, OMIM:141749; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Rare anaemia v1.40 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Hereditary persistence of fetal hemoglobin, OMIM:141749; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Cytopenias and congenital anaemias v1.104 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from Globin Disorder; Delta-beta thalassemia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 141749; Erythremias, beta-; Heinz body anemias, beta- (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 140700; Hereditary persistence of fetal hemoglobin,(MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown),141749; Methemoglobinemias, beta-; Sickle cell anemia (BIALLELIC, autosomal or pseudoautosomal),603903; Thalassemia-beta, dominant inclusion-body, 603902; Thalassemias, beta-,(BIALLELIC, autosomal or pseudoautosomal), 613985 to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Rare anaemia v1.39 HBB Arina Puzriakova Phenotypes for gene: HBB were changed from 603902 Dominand inclusion body beta thalassaemia; Erythremias, beta-; Heinz body anemias, beta- (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 140700; Globin Disorder; 141749 Delta-beta thalassaemia; 613985 Beta thalassaemia; Methemoglobinemias, beta-; Thalassemias, beta-,(BIALLELIC, autosomal or pseudoautosomal), 613985; 603903 Sickle cell disease; 603902 Thalassemia-beta, dominant inclusion-body; Sickle cell anemia (BIALLELIC, autosomal or pseudoautosomal),603903; Hereditary persistence of fetal hemoglobin,(MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown),141749; Thalassemia-beta, dominant inclusion-body, 603902; Delta-beta thalassemia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown), 141749; 613985 Thalassemia, beta to Delta-beta thalassemia, OMIM:141749; Heinz body anemia, OMIM:140700; Methemoglobinemia, beta type, OMIM:617971; Thalassemia, beta, OMIM:613985; Thalassemia-beta, dominant inclusion-body, OMIM:603902; Sickle cell anemia, OMIM:603903
Corneal dystrophy v1.12 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120 to Amyloidosis, Finnish type, OMIM:105120
Periodic fever syndromes v1.30 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis; Amyloidosis, Finnish type, 105120 to Amyloidosis, Finnish type, OMIM:105120
Hereditary systemic amyloidosis v1.13 GSN Arina Puzriakova Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120 to Amyloidosis, Finnish type, OMIM:105120
Corneal dystrophy v1.11 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from Corneal dystrophy, posterior polymorphous, 4 618031 to Corneal dystrophy, posterior polymorphous, 4, OMIM:618031
Monogenic hearing loss v2.239 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from hearing loss; Deafness, autosomal dominant 28, 608641; #616029: Ectodermal dysplasia/short stature syndrome to Deafness, autosomal dominant 28, OMIM:608641; Ectodermal dysplasia/short stature syndrome, OMIM:616029
Ectodermal dysplasia v1.39 GRHL2 Arina Puzriakova Phenotypes for gene: GRHL2 were changed from to Ectodermal dysplasia/short stature syndrome, OMIM:616029
Ectodermal dysplasia v1.38 GRHL2 Arina Puzriakova Publications for gene: GRHL2 were set to 25152456
Ectodermal dysplasia v1.37 GRHL2 Arina Puzriakova Tag Q2_22_rating tag was added to gene: GRHL2.
Tag Q2_22_expert_review tag was added to gene: GRHL2.
Ectodermal dysplasia v1.37 GRHL2 Arina Puzriakova reviewed gene: GRHL2: Rating: ; Mode of pathogenicity: None; Publications: 27612988; Phenotypes: Ectodermal dysplasia/short stature syndrome, OMIM:616029; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.292 PEX6 Sarah Leigh Tag Q2_22_MOI was removed from gene: PEX6.
Tag Q2_22_rating tag was added to gene: PEX6.
Ataxia and cerebellar anomalies - childhood onset v2.292 PEX6 Sarah Leigh Added comment: 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, in order to highlight that unaffected parents may also carry rs61753230.
Ataxia and cerebellar anomalies - childhood onset v2.292 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.291 PEX6 Sarah Leigh Classified gene: PEX6 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - childhood onset v2.291 PEX6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for PEX6 to be green on this panel.
Ataxia and cerebellar anomalies - childhood onset v2.291 PEX6 Sarah Leigh Gene: pex6 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - childhood onset v2.290 PEX6 Sarah Leigh gene: PEX6 was added
gene: PEX6 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Q2_22_MOI tags were added to gene: PEX6.
Mode of inheritance for gene: PEX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PEX6 were set to 25655951; 29220678
Phenotypes for gene: PEX6 were set to Peroxisome biogenesis disorder 4B, OMIM:614863
Penetrance for gene: PEX6 were set to Incomplete
Mode of pathogenicity for gene: PEX6 was set to Other
Review for gene: PEX6 was set to GREEN
Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).
Sources: Literature
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova edited their review of gene: NCAPD3: Changed rating: GREEN
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Classified gene: NCAPD3 as Amber List (moderate evidence)
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Added comment: Comment on list classification: Given the discovery of a third patient in the NHS presenting a phenotype consistent with previous reports and functional studies providing a plausible disease mechanism, this gene should now be promoted to Green at the next GMS panel update to ensure detection of cases.
Severe microcephaly v2.299 NCAPD3 Arina Puzriakova Gene: ncapd3 has been classified as Amber List (Moderate Evidence).
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Tag Q2_21_MOI was removed from gene: SLURP1.
Tag Q2_22_MOI tag was added to gene: SLURP1.
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: NCAPD3.
Tag Q2_22_NHS_review tag was added to gene: NCAPD3.
Severe microcephaly v2.298 NCAPD3 Arina Puzriakova Phenotypes for gene: NCAPD3 were changed from Microcephaly 22, primary, autosomal recessive, 617984 to Microcephaly 22, primary, autosomal recessive, OMIM:617984
Severe microcephaly v2.297 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Severe microcephaly v2.297 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Severe microcephaly. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Intellectual disability v3.1541 NAPB Arina Puzriakova Entity copied from Genetic epilepsy syndromes v2.506
Intellectual disability v3.1541 NAPB Arina Puzriakova gene: NAPB was added
gene: NAPB was added to Intellectual disability. Sources: Expert Review Amber,NHS GMS
Q2_22_rating, Q2_22_NHS_review tags were added to gene: NAPB.
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Classified gene: NAPB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.506 NAPB 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 3 unrelated families (4 affected individuals) with distinct homozygous variants in this gene, universally presenting seizures, profound ID and microcephaly. Pathogenicity is supported by a complimentary knockout mouse model demonstrating recurrent post-natal epileptic seizures which were lethal in some mice.
Early onset or syndromic epilepsy v2.506 NAPB Arina Puzriakova Gene: napb has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.505 NAPB Arina Puzriakova Tag Q2_22_rating tag was added to gene: NAPB.
Tag Q2_22_NHS_review tag was added to gene: NAPB.
Pulmonary Fibrosis, Familial v0.8 RPA1 Arina Puzriakova changed review comment from: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerge.; to: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerges.
Pulmonary Fibrosis, Familial v0.8 RPA1 Arina Puzriakova edited their review of gene: RPA1: Changed rating: AMBER
Pulmonary Fibrosis, Familial v0.8 RPA1 Arina Puzriakova Classified gene: RPA1 as Amber List (moderate evidence)
Pulmonary Fibrosis, Familial v0.8 RPA1 Arina Puzriakova Added comment: Comment on list classification: Heterogenous phenotypes have been recorded and only two individuals presented with pulmonary fibrosis (associated with post-transplant complications in one). At present this is sufficient to rate as amber but this may be reviewed if further evidence emerge.
Pulmonary Fibrosis, Familial v0.8 RPA1 Arina Puzriakova Gene: rpa1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Classified gene: RPA1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Added comment: Comment on list classification: Despite the heterogenous phenotypes observed, there are sufficient cases (3) with hematopoietic manifestations to warrant a green rating on this panel at the next GMS review.
Cytopenia - NOT Fanconi anaemia v1.61 RPA1 Arina Puzriakova Gene: rpa1 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.60 RPA1 Arina Puzriakova Tag Q2_22_rating tag was added to gene: RPA1.
Pulmonary Fibrosis, Familial v0.7 RPA1 Arina Puzriakova Entity copied from Cytopenia - NOT Fanconi anaemia v1.60
Pulmonary Fibrosis, Familial v0.7 RPA1 Arina Puzriakova gene: RPA1 was added
gene: RPA1 was added to Pulmonary fibrosis familial. Sources: Literature
Mode of inheritance for gene: RPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPA1 were set to 34767620
Phenotypes for gene: RPA1 were set to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
Penetrance for gene: RPA1 were set to Incomplete
Mode of pathogenicity for gene: RPA1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Cytopenia - NOT Fanconi anaemia v1.60 RPA1 Arina Puzriakova Penetrance for gene RPA1 was set from to unknown
Cytopenia - NOT Fanconi anaemia v1.59 RPA1 Arina Puzriakova Publications for gene: RPA1 were set to
Cytopenia - NOT Fanconi anaemia v1.58 RPA1 Arina Puzriakova reviewed gene: RPA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34767620; Phenotypes: Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.58 RPA1 Arina Puzriakova Phenotypes for gene: RPA1 were changed from bone marrow failure; T- and B-cell lymphopenia; pulmonary fibrosis; skin manifestations. to Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, OMIM:619767
Intellectual disability v3.1540 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Hereditary neuropathy or pain disorder v1.93 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from motor neuropathy to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Early onset or syndromic epilepsy v2.505 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Likely inborn error of metabolism v2.241 SLC5A6 Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from SLC5A6-related Neurodevelopmental Disorder to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973
Intellectual disability v3.1539 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Fetal anomalies v1.851 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Fetal anomalies v1.850 RAC3 Arina Puzriakova Classified gene: RAC3 as Amber List (moderate evidence)
Fetal anomalies v1.850 RAC3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update.
Fetal anomalies v1.850 RAC3 Arina Puzriakova Gene: rac3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.849 RAC3 Arina Puzriakova Tag Q2_22_rating tag was added to gene: RAC3.
Retinal disorders v2.252 CTNNB1 Arina Puzriakova Publications for gene: CTNNB1 were set to 28575650; 28514307
White matter disorders and cerebral calcification - childhood onset v1.235 NDUFV2 Arina Puzriakova Classified gene: NDUFV2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.235 NDUFV2 Arina Puzriakova Gene: ndufv2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.234 NDUFV2 Arina Puzriakova gene: NDUFV2 was added
gene: NDUFV2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
watchlist tags were added to gene: NDUFV2.
Mode of inheritance for gene: NDUFV2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFV2 were set to 33811136
Phenotypes for gene: NDUFV2 were set to Mitochondrial complex I deficiency, nuclear type 7, OMIM:618229; Progressive cavitating leukoencephalopathy, MONDO:0015349
Review for gene: NDUFV2 was set to AMBER
Added comment: Liu et al., 2022 (PMID: 33811136) report on two sibling pairs of two unrelated Chinese families presenting with progressive cavitating leukoencephalopathy associated with distinct biallelic variants in this gene. Functional analyses demonstrated impaired structural stability and function of the NDUFV2 protein and complex I deficiency was confirmed in affected individuals' fibroblasts and a muscle biopsy.

This is the first report linking NDUFV2 with a leukoencephalopathy phenotype and therefore rating as Amber for now until further cases emerge.
Sources: Literature
Rare genetic inflammatory skin disorders v1.54 GJB4 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both monoallelic and biallelic' to just 'monoallelic' as the literature only reports heterozygous (monoallelic) variants associated with EKVP. Rare biallelic forms of EKVP have so far only been reported for GJB3 (OMIM:133200).
Rare genetic inflammatory skin disorders v1.54 GJB4 Arina Puzriakova Mode of inheritance for gene: GJB4 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v1.53 GJB4 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: GJB4.
Pigmentary skin disorders v1.50 GJB4 Arina Puzriakova Phenotypes for gene: GJB4 were changed from Erythrokeratodermia variabilis; EKVP2; ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2 to Erythrokeratodermia variabilis et progressiva 2, OMIM:617524
Palmoplantar keratoderma and erythrokeratodermas v1.24 GJB4 Arina Puzriakova Phenotypes for gene: GJB4 were changed from Erythrokeratodermia variabilis et progressiva 2, 617524 to Erythrokeratodermia variabilis et progressiva 2, OMIM:617524
Intellectual disability v3.1538 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.92 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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
Hereditary neuropathy v1.446 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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
Possible mitochondrial disorder, nuclear genes v1.72 GDAP1 Arina Puzriakova Mode of inheritance for gene: GDAP1 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
Hereditary neuropathy or pain disorder v1.91 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease, recessive intermediate, A, 608340; Charcot-Marie-Tooth with Vocal Cord Paresis (recessive); Charcot Marie Tooth disease, type 4A, 214400; Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth, Intermediate (Dominant) to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Intellectual disability v3.1537 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth; disease, axonal, with vocal cord paresis, 607706; Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive; intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Mitochondrial disorders v2.97 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, type 4A to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Hereditary neuropathy v1.445 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot Marie Tooth disease, type 4A, 214400; Charcot-Marie-Tooth, Intermediate (Dominant); Charcot Marie Tooth disease, type 4A, 214400; Charcot Marie Tooth disease, recessive intermediate, A, 608340; Charcot Marie Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth, Intermediate (Dominant); Charcot-Marie-Tooth with Vocal Cord Paresis (recessive); Charcot Marie Tooth disease, recessive intermediate, A, 608340 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Likely inborn error of metabolism v2.240 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, type 4A; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, axonal, type 2K to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Possible mitochondrial disorder, nuclear genes v1.71 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot-Marie-Tooth disease, axonal, type 2K, 607831; Charcot-Marie-Tooth disease, recessive intermediate, A, 608340; Charcot-Marie-Tooth disease, type 4A, 214400; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, 607706 to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Undiagnosed metabolic disorders v1.522 GDAP1 Arina Puzriakova Phenotypes for gene: GDAP1 were changed from Charcot Marie Tooth disease (CMT4A); Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, type 4A to Charcot-Marie-Tooth disease, axonal, type 2K, OMIM:607831; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, OMIM:607706; Charcot-Marie-Tooth disease, recessive intermediate, A, OMIM:608340; Charcot-Marie-Tooth disease, type 4A, OMIM:214400
Adult solid tumours cancer susceptibility v2.19 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Lynch syndrome to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
GI tract tumours v1.19 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Gastrointestinal and Colorectal Cancer; High Risk Colorectal Cancer to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
Adult solid tumours for rare disease v1.32 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Lynch syndrome to Colorectal cancer, hereditary nonpolyposis, type 8, OMIM:613244
COVID-19 research v1.122 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Primary immunodeficiency or monogenic inflammatory bowel disease v2.542 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Gastrointestinal epithelial barrier disorders v1.72 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital 613217; Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8, 613244; Diarrhea 5, with tufting enteropathy, congenital, 613217 to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Infantile enterocolitis & monogenic inflammatory bowel disease v1.38 EPCAM Arina Puzriakova Phenotypes for gene: EPCAM were changed from Diarrhea 5, with tufting enteropathy, congenital 613217 to Diarrhea 5, with tufting enteropathy, congenital, OMIM:613217
Hereditary neuropathy or pain disorder v1.90 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Hereditary neuropathy v1.444 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Paroxysmal central nervous system disorders v1.44 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Neuropathy, Hereditary Sensory and Autonomic, Type III; Familial dysautonomia; Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Pain syndromes v1.12 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Familial dysautonomia; NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; Dysautonomia, familial, 223900 to Dysautonomia, familial, OMIM:223900
Familial dysautonomia v1.17 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Familial Dysautonomia; Neuropathy, hereditary sensory and autonomic, type 3; Riley-Day Syndrome 223900 to Dysautonomia, familial, OMIM:223900
Childhood solid tumours cancer susceptibility v1.19 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Paediatric medulloblastoma Sonic Hedgehog subtype to Medulloblastoma, OMIM:155255
Childhood solid tumours v2.31 ELP1 Arina Puzriakova Phenotypes for gene: ELP1 were changed from Medulloblastoma predisposition to Medulloblastoma, OMIM:155255
Palmoplantar keratodermas v1.13 CDSN Arina Puzriakova Tag Q2_22_rating tag was added to gene: CDSN.
Tag Q2_22_expert_review tag was added to gene: CDSN.
Palmoplantar keratodermas v1.13 CDSN Arina Puzriakova commented on gene: CDSN
Peeling skin syndrome v1.4 CDSN Arina Puzriakova Phenotypes for gene: CDSN were changed from Peeling skin syndrome 1, 270300; PSS1; OMIM:#270300; Peeling skin HP:0040189; Pruritus HP:0000989; Allergy HP:0012393; Increased IgE level HP:0003212; Generalised erythroderma HP:0001019; erythema HP:0010783; Hyperkeratosis HP:0000962. to Peeling skin syndrome 1, OMIM:270300; Peeling skin HP:0040189; Pruritus HP:0000989; Allergy HP:0012393; Increased IgE level HP:0003212; Generalised erythroderma HP:0001019; erythema HP:0010783; Hyperkeratosis HP:0000962.
Intellectual disability v3.1536 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Gene2Phenotype confirmed gene with ID HPO to Fanconi anemia, complementation group J, OMIM:609054
Fetal anomalies v1.849 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from FANCONI ANEMIA, COMPLEMENTATION GROUP J to Fanconi anemia, complementation group J, OMIM:609054
Fanconi anaemia or Bloom syndrome v1.16 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from 609054 Fanconi anemia, complementation group J; Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Severe microcephaly v2.296 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Haematological malignancies cancer susceptibility v2.26 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Class: BM failure FA, (typ AR); AML; leukaemia; breast; Fanconi anaemia J; breast cancer susceptiblity; MDS; Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar to Fanconi anemia, complementation group J, OMIM:609054
Childhood solid tumours cancer susceptibility v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J 609054 to Fanconi anemia, complementation group J, OMIM:609054
Cytopenias and congenital anaemias v1.103 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J 609054 to Fanconi anemia, complementation group J, OMIM:609054
Pigmentary skin disorders v1.49 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from FANCJ; FANCONI ANEMIA, COMPLEMENTATION GROUP J to Fanconi anemia, complementation group J, OMIM:609054
Limb disorders v2.77 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Radial Ray abnormality; Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054; Radial ray abnormality
Childhood solid tumours v2.30 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054; Fanconi anemia, complementation group J, 609054; Fanconi Anaemia; ?Breast cancer, early-onset, 114480; Fanconi Anemia to Fanconi anemia, complementation group J, OMIM:609054
COVID-19 research v1.121 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Neurofibromatosis Type 1 v1.29 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from ?Breast cancer, early-onset, 114480; Fanconi anemia, complementation group J, 609054; Fanconi Anemia; Fanconi Anaemia to Fanconi anemia, complementation group J, OMIM:609054
Haematological malignancies for rare disease v1.10 BRIP1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: "Class: BM failure FA, (typ AR);AML; leukaemia; breast;Fanconi anaemia J; breast cancer susceptiblity;MDS; Leukaemia;Bone marrow failure;Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar"
Haematological malignancies for rare disease v1.10 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Class: BM failure FA, (typ AR); AML; leukaemia; breast; Fanconi anaemia J; breast cancer susceptiblity; MDS; Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer, Squamous cell carcinoma oral, GI, vulvar to Fanconi anemia, complementation group J, OMIM:609054
Radial dysplasia v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from Fanconi anemia, complementation group J, 609054 to Fanconi anemia, complementation group J, OMIM:609054
Adult solid tumours cancer susceptibility v2.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from predisposition to ovarian cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Adult solid tumours for rare disease v1.31 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from predisposition to ovarian cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Ovarian cancer pertinent cancer susceptibility v1.9 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Familial breast cancer v1.18 BRIP1 Arina Puzriakova Phenotypes for gene: BRIP1 were changed from ?Breast cancer, early-onset, 114480; Fanconi anemia, complementation group J, 609054; Breast and Ovarian Cancer; Breast Cancer to {Breast cancer, early-onset, susceptibility to}, OMIM:114480
Osteogenesis imperfecta v2.45 P4HB Eleanor Williams Tag Q2_22_MOI tag was added to gene: P4HB.
Osteogenesis imperfecta v2.45 P4HB Eleanor Williams Phenotypes for gene: P4HB were changed from Cole-Carpenter Syndrome; Osteogenesis Imperfecta; Cole Carpenter syndrome to Cole-Carpenter syndrome 1, OMIM:112240; Cole-Carpenter syndrome 1, MONDO:000720
Osteogenesis imperfecta v2.44 P4HB Eleanor Williams Added comment: Comment on mode of inheritance: Cole-Carpenter syndrome 1 is due to heterozygous variants in P4HB and so the mode of inheritance should be changed to monoallelic at the next review.
Osteogenesis imperfecta v2.44 P4HB Eleanor Williams Mode of inheritance for gene: P4HB was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 CFHR5 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic just now, but only monoallelic cases confirmed so recommending a change to this mode of inheritance.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.22 CFHR5 Eleanor Williams Mode of inheritance for gene: CFHR5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFHR5 Eleanor Williams Tag Q2_22_MOI tag was added to gene: CFHR5.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.21 CFHR5 Eleanor Williams reviewed gene: CFHR5: Rating: ; Mode of pathogenicity: None; Publications: 20800271, 22503529, 23402027, 24334459, 24067434, 34566977; Phenotypes: Nephropathy due to CFHR5 deficiency, OMIM:614809; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to Fanconi anemia, complementation group D1, OMIM:605724; Wilms tumor, OMIM:194070; {Glioblastoma 3}, OMIM:613029; {Medulloblastoma}, OMIM:155255
Childhood solid tumours v2.29 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Wilms tumor, 194070; Fanconi Anaemia; {Breast cancer, male, susceptibility to}, 114480; Prostate cancer, 176807; {Medulloblastoma}, 155255; {Glioblastoma 3}, 613029; Fanconi Anemia; Hereditary Breast and Ovarian Cancer; Fanconi anemia, complementation group D1, 605724; {Breast-ovarian cancer, familial, 2}, 612555; Pancreatic cancer, 613347 to Fanconi anemia, complementation group D1, OMIM:605724; Wilms tumor, OMIM:194070; {Glioblastoma 3}, OMIM:613029; {Medulloblastoma}, OMIM:155255
Primary immunodeficiency or monogenic inflammatory bowel disease v2.541 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type D1 to Fanconi anemia, complementation group D1, OMIM:605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
COVID-19 research v1.120 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type D1 to Fanconi anemia, complementation group D1, OMIM:605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
Intellectual disability v3.1535 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1: FANCD1 OMIM: 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Fanconi anaemia or Bloom syndrome v1.15 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from 605724 Fanconi anemia, complementation group D1; Fanconi anemia, complementation group D1, 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Severe microcephaly v2.295 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724 (Microcephaly) to Fanconi anemia, complementation group D1, OMIM:605724
Haematological malignancies cancer susceptibility v2.25 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; breast, ovarian, pancreatic, leukaemia (FANCB, FANCD1); hereditary breast, ovarian cancer; MDS; AML, Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer ,Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group D1, OMIM:605724
Cytopenias and congenital anaemias v1.102 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Pigmentary skin disorders v1.48 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from FANCD1; FANCONI ANEMIA, COMPLEMENTATION GROUP D1 to Fanconi anemia, complementation group D1, OMIM:605724
Limb disorders v2.76 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724; Radial Ray abnormality to Fanconi anemia, complementation group D1, OMIM:605724
Neurofibromatosis Type 1 v1.28 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from {Breast-ovarian cancer, familial, 2}, 612555; Fanconi anemia, complementation group D1, 605724; Prostate cancer, 176807; {Breast cancer, male, susceptibility to}, 114480; Wilms tumor, 194070; {Medulloblastoma}, 155255; {Glioblastoma 3}, 613029; Pancreatic cancer, 613347; {Glioblastoma 3},; Fanconi Anemia; Fanconi Anaemia to Fanconi anemia, complementation group D1, OMIM:605724
Haematological malignancies for rare disease v1.9 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; breast, ovarian, pancreatic, leukaemia (FANCB, FANCD1); hereditary breast, ovarian cancer; MDS; AML, Leukaemia; Bone marrow failure; Head and neck and anogenital squamous cell cancers, liver cancer, esophageal cancer ,Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group D1, OMIM:605724
Radial dysplasia v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Fanconi anemia, complementation group D1, 605724 to Fanconi anemia, complementation group D1, OMIM:605724
Prostate cancer pertinent cancer susceptibility v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Prostate cancer to {Prostate cancer}, OMIM:176807
Familial prostate cancer v1.3 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from male breast cancer and prostate cancer; {Prostate cancer} 176807 to {Prostate cancer}, OMIM:176807
Additional findings health related - CNV analysis adult specific v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Additional findings health related - adult specific v1.2 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Adult solid tumours cancer susceptibility v2.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; {Prostate cancer}, OMIM:176807
Adult solid tumours for rare disease v1.30 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; {Prostate cancer}, OMIM:176807
Ovarian cancer pertinent cancer susceptibility v1.8 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Ovarian cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555
Breast cancer pertinent cancer susceptibility v1.6 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Breast cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480
Additional findings health related v0.114 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from Breast and ovarian cancer predisposition; Adult only to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480; Adult only
Familial breast cancer v1.17 BRCA2 Arina Puzriakova Phenotypes for gene: BRCA2 were changed from {Breast-ovarian cancer, familial, 2}, 612555; Fanconi anemia, complementation group D1, 605724; Prostate cancer, 176807; {Breast cancer, male, susceptibility to}, 114480; Wilms tumor, 194070; {Medulloblastoma}, 155255; {Glioblastoma 3},; Hereditary Breast and Ovarian Cancer ; Hereditary Breast and Ovarian Cancer Syndrome; Breast and Ovarian Cancer; High Risk Breast Cancer ; Breast cancer to {Breast-ovarian cancer, familial, 2}, OMIM:612555; {Breast cancer, male, susceptibility to}, OMIM:114480
Primary immunodeficiency or monogenic inflammatory bowel disease v2.540 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia, complementation group S, 617883; normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type S to Fanconi anemia, complementation group S, OMIM:617883; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
COVID-19 research v1.119 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia, complementation group S, 617883; normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure; Fanconi Anemia Type S to Fanconi anemia, complementation group S, OMIM:617883; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure
Fanconi anaemia or Bloom syndrome v1.14 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia; 617883 Fanconi anemia, complementation group S to Fanconi anemia, complementation group S, OMIM:617883
Haematological malignancies cancer susceptibility v2.24 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group S, OMIM:617883
Cytopenias and congenital anaemias v1.101 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Fanconi anemia to Fanconi anemia, complementation group S, OMIM:617883
Pigmentary skin disorders v1.47 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from FANCS; FANCONI ANEMIA, COMPLEMENTATION GROUP S to Fanconi anemia, complementation group S, OMIM:617883
Haematological malignancies for rare disease v1.8 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group S, OMIM:617883
Ovarian cancer pertinent cancer susceptibility v1.7 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Ovarian cancer pertinent cancer susceptibility v1.7 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Ovarian cancer pertinent cancer susceptibility v1.6 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Breast cancer pertinent cancer susceptibility v1.5 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Tag watchlist was removed from gene: F12.
Tag watchlist_moi tag was added to gene: F12.
Familial breast cancer v1.16 BRCA1 Arina Puzriakova Tag watchlist_moi tag was added to gene: BRCA1.
Inherited breast cancer and ovarian cancer v0.17 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic germline BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Inherited breast cancer and ovarian cancer v0.17 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited breast cancer and ovarian cancer v0.16 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: BRCA1.
Tag Q2_22_expert_review tag was added to gene: BRCA1.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Although more rare, biallelic BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375). There are at least two unrelated individuals in literature who were diagnosed with ovarian carcinoma in association with biallelic germline BRCA1 variants.

This may warrant an MOI change from 'monoallelic' to 'both mono- and biallelic' to ensure these rarer cases are not missed; however this will be flagged for further review to confirm whether the GMS expert group agrees with the change.
Inherited ovarian cancer (without breast cancer) v2.25 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Additional findings health related - CNV analysis adult specific v1.1 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Adult only
Additional findings health related - adult specific v1.1 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Adult only; Breast and ovarian cancer predisposition to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Adult only
Adult solid tumours for rare disease v1.29 BRCA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI from 'monoallelic' to 'both mono- and biallelic' to align with the MOI set on the GMS Adult solid tumours cancer susceptibility (v2.2) panel. Although more rare, biallelic BRCA1 variants have been shown to also confer breast and ovarian cancer susceptibility (with or without FA‐like features), and multiple such cases have been reported worldwide (PMIDs: 23269703; 25472942; 31347298; 33477375).
Adult solid tumours for rare disease v1.29 BRCA1 Arina Puzriakova Mode of inheritance for gene: BRCA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult solid tumours for rare disease v1.28 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Fanconi anemia, complementation group S, OMIM:617883
Adult solid tumours cancer susceptibility v2.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Fanconi anemia, complementation group S, OMIM:617883
Childhood solid tumours cancer susceptibility v1.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Childhood solid tumours v2.28 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Hereditary Breast and Ovarian Cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Ovarian cancer pertinent cancer susceptibility v1.6 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Ovarian cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Breast cancer pertinent cancer susceptibility v1.4 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Breast cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Additional findings health related v0.113 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from Breast and ovarian cancer predisposition; Adult only to {Breast-ovarian cancer, familial, 1}, OMIM:604370; Breast and ovarian cancer predisposition; Adult only
Familial breast cancer v1.16 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from {Breast-ovarian cancer, familial, 1}, 604370; {Pancreatic cancer, susceptibility to, 4}, 614320; Hereditary Breast and Ovarian Cancer ; Hereditary Breast and Ovarian Cancer Syndrome; Breast and Ovarian Cancer; High Risk Breast Cancer ; Breast cancer to {Breast-ovarian cancer, familial, 1}, OMIM:604370
Familial prostate cancer v1.2 BRCA1 Arina Puzriakova Phenotypes for gene: BRCA1 were changed from to Prostate cancer, MONDO:0008315
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Tag watchlist tag was added to gene: F12.
Inherited bleeding disorders v1.166 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Coagulaton disorder; Angioedema, hereditary, type 3 (AD); Angioedema, hereditary, type III; Factor 12 deficiency (AR); Factor XII deficiency to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Bleeding and platelet disorders v1.37 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from 234000 Factor XII deficiency; 234000 Factor XII deficiency, hereditary Angioedema type III; 610618 Hereditary Angioedema type III to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: F12.
Tag Q2_22_phenotype tag was added to gene: F12.
Tag Q2_22_expert_review tag was added to gene: F12.
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova changed review comment from: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.; to: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or whether this gene should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.
Bleeding and platelet disorders v1.36 F12 Arina Puzriakova changed review comment from: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.; to: This gene will be flagged for GMS review regarding the pertinence of monoallelic variants to this panel and whether the MOI should remain as 'both mono- and biallelic' or changed to 'biallelic' only or should be demoted on this panel altogether.

Monoallelic variants are associated with hereditary angioedema (MIM# 610618) characterised clinically by recurrent skin swelling, abdominal pain attacks, and episodes of upper airway obstruction but otherwise patients do not display any strong evidence of abnormal bleeding or clotting phenotypes. Biallelic variants cause a separate disorder, factor XII deficiency (MIM# 234000) associated with hypercoagulation which in some cases has been linked to thrombus formation.
Vascular skin disorders v1.49 F12 Arina Puzriakova Tag Q2_22_MOI tag was added to gene: F12.
Tag Q2_22_expert_review tag was added to gene: F12.
Vascular skin disorders v1.49 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Angioedema, hereditary, type III, OMIM:610618 to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000
Intellectual disability v3.1534 ZBTB7A Konstantinos Varvagiannis gene: ZBTB7A was added
gene: ZBTB7A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB7A were set to 31645653; 34515416
Phenotypes for gene: ZBTB7A were set to Global developmental delay; Intellectual disability; Macrocephaly; Abnormality of the lymphatic system; Sleep apnea; Increased body weight; Autism; Persistence of hemoglobin F; Abnormal leukocyte count; Recurrent infections; Umbilical hernia
Penetrance for gene: ZBTB7A were set to unknown
Review for gene: ZBTB7A was set to AMBER
Added comment: Monoallelic pathogenic ZBTB7A variants cause Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (#619769).
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Ohishi et al (2020 - PMID: 31645653) described the phenotype of a 6y5m-old male harboring a heterozygous, de novo ZBTB7A missense variant. Features included macrocephaly, mild intellectual disability (tIQ 65) and sleep apnea. Available hemoglobin levels (in the 1st month) supported high Hb and HbF levels. Other features included PDA and an umbilical hernia.

Initial investigations incl. karyotype and CMA were normal.

The ZBTB7A variant (NM_015898.3:c.1152C>G / p.Cys384Tyr) was identified following trio WES with a list of additional findings (in suppl.) not explaining the phenotype. This SNV, confirmed by Sanger sequencing, was absent from public db with several in silico predictions in favor of a deleterious effect.

ZBTB7A on 19p encodes zinc finger- and BTB domain-containing protein 7 (or Pokemon).

The authors performed a review of 19p13.3 microdeletion cases supporting a minimum region of overlap spanning PIAS4, ZBTB7A and MAP2K2 and common features of DD and ID, macrocephaly with prominent forehead, sleep apnea. The authors argue that loss of ZBTB7A explains part of - but probably not all - features of 19p13.3 microdeletions.

ZBTB7A is known to repress expression of HBG1 and HBG2 (γ-globin), with the few available HbF patient measurements in line with this role.

Based on the structure of the protein, Cys384 (along with 3 other residues) forms a coordinate bond with the Zn+2 ion, this bond predicted to be disrupted by Tyr. Further they favor a dominant negative effect given that ZBTB7A protein is known to form dimer via interaction at the BTB domain [hetero (variant+wt) and homodimers (variant+variant) having compromised function]. To support this notion, 3 previously reported somatic variants within the zinc-finger domain have been shown to exert a dominant-negative effect (PMID cited: 26455326).
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In a collaborative study, von der Lippe et al (2022 - PMID: 34515416) identified 12 additional individuals (from 10 families) harboring monoallelic ZBTB7A missense/pLoF variants most commonly as de novo events.

The authors describe a consistent phenotype with motor (9/11) and speech delay (9/12), cognitive impairment/ID (12/12 - commonly mild, ranged from specific learning difficulties to severe ID), macrocephaly (>90%le in 11/12, >97% in 7/12), lymphoid hypertrophy of pharyngeal tissue/adenoid overgrowth (12/12), sleep apnea (9/12). Autistic features were observed in 7/12. Other phenotypes included frequent upper airway infections (10/11), weight above 97th percentile (7/11). HbF levels were elevated in 4/5 individuals with available measurements (range: 2.2% to 11.2% - ref. for subjects above 6m of age : <2% ). Other hematological issues were observed in few individuals (abn. monocyte/neutrophil counts in 3-4). Cardiovascular issues were reported in 4 (2 fam). 3 subjects had umbilical hernia. There was no common dysmorphic feature.

Various initial investigations were normal or did not appear to explain the NDD phenotype and incl. standard karyotype, CMA, targeted testing for genes/disorders previously considered (PTEN, FMR1, NSD1, BWS and PWS methylation studies, CFTR, etc). One male had a maternally inherited chrX dup not thought to explain his complex phenotype, while another had a concurrent diagnosis of thalassemia.

Individuals were investigated with singleton (or trio) WES. Of note some individuals were DDD study participants.

8 had de novo ZBTB7A variants, incl. one who harbored 2 de novo missense SNVs several residues apart. 2 sibs had inherited a fs variant from their affected parent. For the latter as well as for another subject parental samples were unavailable.

There were no other variants of interest upon exome analysis.

5 different missense, 2 nonsense and 3 fs variants were identified with pLoF all predicted to lead to NMD.

All variants were absent from gnomAD (pLI of 0.96, LOEUF 0.33 and missense Z-score of 4.04) which lists one individual with htz LoF, likely not an artifact.

Given this individual (and the familial case) the authors discuss on the mild phenotype and/or eventual reduced penetrance or underdiagnosis of the disorder.

There was no difference in severity between those with missense/truncating variants.

ZBTB7A transcription factor (or pokemon or lymphoma/leukemia-related factor) is widely expressed. It is involved in several activities being among others required to block Notch signaling which in turn drives T-cell at the expense of B-cell development. Notch pathway activation has been demonstrated in Zbtba7 ko mouse models. Finally, the authors discuss the role of notch signaling in thymus and the nervous system, as well as that ZBTB7A up/down-regulation known to repress/increase respectively HbF expression (several refs in text).
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MGI (1335091) for Zbtb7a : "Mice homozygous for a knock-out allele die around E16.5 due to anemia and exhibit a cell autonomous defect in early B cell development". (Phenotypes from nervous system not commented on).
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Apart from OMIM (#619769), ZBTB7A is included in the DD panel of G2P (ZBTB7A-associated developmental disorder / monoallelic_autosomal / absent gene product / confidence limited) as well as among the primary ID genes in SysID. In PanelApp Australia the gene is incl. with green rating in the ID and Macrocephaly gene panels.
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Consider inclusion with amber or green rating (several individuals/families/variants, highly consistent phenotype, overlap with 19p microdeletions || variant effect not studied, animal models supporting contribution of the gene to the phenotype though no data on associated NDD ones).

Please also consider inclusion in other relevant panels (macrocephaly, lymphatic disorders, ASD, etc).
Sources: Literature, Other
Early onset or syndromic epilepsy v2.504 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 33057194
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to AMBER
Added comment: At least 12 individuals with NDD due to monoallelic missense/pLoF ATP2B1 variants have been reported to date. Seizures were observed in 5 of them.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with amber rating.
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Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Intellectual disability v3.1534 ATP2B1 Konstantinos Varvagiannis gene: ATP2B1 was added
gene: ATP2B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2B1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2B1 were set to 35358416; 35358416
Phenotypes for gene: ATP2B1 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck
Penetrance for gene: ATP2B1 were set to unknown
Review for gene: ATP2B1 was set to GREEN
Added comment: Monoallelic missense/pLoF ATP2B1 variants have been reported in 12 unrelated individuals with DD/ID making this gene relevant to the current panel.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with green (rather than amber) rating.
---
Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature
Retinal disorders v2.251 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595; 29220678; 21937992
Retinal disorders v2.250 PEX6 Sarah Leigh commented on gene: PEX6: Retinal involvement is mentioned in Peroxisome biogenesis disorder 4B (OMIM:614863)(PMID:21937992; 22871920).
Retinal disorders v2.250 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595; 29220678
Retinal disorders v2.249 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Retinal disorders v2.248 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v2.248 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Heimler syndrome 2, OMIM:616617, MONDO:0014709 to Heimler syndrome 2, OMIM:616617; MONDO:0014709; Peroxisome biogenesis disorder 4B, OMIM:614863
Retinal disorders v2.247 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 32866347; 31884617; 29676688; 26387595
Retinal disorders v2.246 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Retinal disorders v2.246 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.245 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Arthrogryposis v3.158 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Arthrogryposis v3.157 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: Arthrogryposis maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. If this is the case, for Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) have identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.157 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Arthrogryposis v3.157 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Arthrogryposis v3.156 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 20301621
Arthrogryposis v3.155 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Arthrogryposis v3.155 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.233 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
White matter disorders and cerebral calcification - childhood onset v1.232 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4B 614863; Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
White matter disorders and cerebral calcification - childhood onset v1.231 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 25655951
White matter disorders and cerebral calcification - childhood onset v1.230 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
White matter disorders and cerebral calcification - childhood onset v1.230 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.229 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
White matter disorders and cerebral calcification - childhood onset v1.229 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.521 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Undiagnosed metabolic disorders v1.520 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Disorders of peroxisome biogenesis; Peroxisome biogenesis disorder 4A (Zellweger) 614862; Peroxisome biogenesis disorder 4B 614863 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Undiagnosed metabolic disorders v1.519 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Undiagnosed metabolic disorders v1.518 PEX6 Sarah Leigh Added comment: 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, in order to highlight that unaffected parents may also carry rs61753230.
Undiagnosed metabolic disorders v1.518 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.517 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Peroxisomal disorders v1.19 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Peroxisomal disorders v1.18 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Peroxisomal disorders v1.18 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Peroxisomal disorders v1.17 PEX6 Sarah Leigh Added comment: 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, in order to highlight that unaffected parents may also carry rs61753230.
Peroxisomal disorders v1.17 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v2.141 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Malformations of cortical development v2.140 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Malformations of cortical development v2.140 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Malformations of cortical development v2.140 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Malformations of cortical development v2.140 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.139 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Disorders of peroxisome biogenesis; Peroxisome biogenesis disorder 4A (Zellweger), 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Malformations of cortical development v2.138 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Intellectual disability v3.1534 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Intellectual disability v3.1533 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Intellectual disability v3.1533 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1532 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger), 614862Peroxisome biogenesis disorder 4B, 614863; ZELLWEGER SYNDROME (ZWS) to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Intellectual disability v3.1531 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Intellectual disability v3.1530 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Intellectual disability v3.1530 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.239 PEX6 Sarah Leigh Mode of pathogenicity for gene PEX6 was changed from to Other
Penetrance for gene PEX6 was set from to None
Likely inborn error of metabolism v2.238 PEX6 Sarah Leigh commented on gene: PEX6: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).
Likely inborn error of metabolism v2.238 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Likely inborn error of metabolism v2.238 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.237 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Hereditary ataxia, adult onset v2.154 PEX6 Sarah Leigh Mode of pathogenicity for gene PEX6 was changed from to Other
Penetrance for gene PEX6 was set from to None
Hereditary ataxia, adult onset v2.153 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.153 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Hereditary ataxia, adult onset v2.153 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Hereditary ataxia, adult onset v2.153 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.152 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A, 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Hereditary ataxia, adult onset v2.151 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Fetal hydrops v1.55 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Fetal hydrops v1.54 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal hydrops v1.54 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 20033294; 23137060
Fetal hydrops v1.53 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Fetal hydrops v1.53 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.52 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Fetal hydrops v1.52 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Zellweger, peroxisome biogenesis disorder 4A, 4B; Peroxisome biogenesis disorder 4A (Zellweger), 614862; Peroxisome biogenesis disorder 4B, 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Fetal hydrops v1.51 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
DDG2P v2.69 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Fetal anomalies v1.848 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to None
Fetal anomalies v1.847 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.847 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from PEROXISOME BIOGENESIS DISORDER COMPLEMENTATION GROUP 4; ZELLWEGER SYNDROME to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Fetal anomalies v1.846 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Fetal anomalies v1.845 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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, in order to highlight that unaffected parents may also carry rs61753230.
Fetal anomalies v1.845 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.844 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
DDG2P v2.68 PEX6 Sarah Leigh changed review comment from: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; to: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).
DDG2P v2.68 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
DDG2P v2.67 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed phenotypes to: 29220678; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.67 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
DDG2P v2.67 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.66 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
DDG2P v2.66 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from ZELLWEGER SYNDROME 214100; PEROXISOME BIOGENESIS DISORDER COMPLEMENTATION GROUP 4 601498 to Heimler syndrome 2, OMIM:616617; Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Amelogenesis imperfecta v2.19 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).; Changed mode of pathogenicity: Other; Changed publications to: 29220678
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Tag Q1_22_MOI tag was added to gene: PEX6.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. 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. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.
Amelogenesis imperfecta v2.18 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.17 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27302843; 26387595; 16530715
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh edited their review of gene: PEX6: Added comment: The review by Claire Smith (University of Leeds)(below), states that amelogenesis imperfecta maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. With this in mind the Peroxisome biogenesis disorder 4B (OMIM:614863) could be relevant to this panel and such the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect variants resulting in allelic expression imbalance and dominant-negative effect (PMID: 29220678).; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.16 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Heimler syndrome 2, OMIM:616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bilateral congenital or childhood onset cataracts v2.104 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger); Confirmed DD gene for ZELLWEGER SYNDROME; Peroxisome biogenesis disorder to Heimler syndrome 2, OMIM:616617
Bilateral congenital or childhood onset cataracts v2.103 PEX6 Sarah Leigh Publications for gene: PEX6 were set to
Bilateral congenital or childhood onset cataracts v2.102 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: ; Mode of pathogenicity: None; Publications: 26387595; Phenotypes: Heimler syndrome 2 OMIM:616617; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.157 PEX6 Sarah Leigh Penetrance for gene PEX6 was set from to Complete
Inherited white matter disorders v1.156 PEX6 Sarah Leigh Added comment: Comment on mode of inheritance: For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230.
Inherited white matter disorders v1.156 PEX6 Sarah Leigh Mode of inheritance for gene: PEX6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inherited white matter disorders v1.155 PEX6 Sarah Leigh Mode of pathogenicity for gene: PEX6 was changed from None to Other
Inherited white matter disorders v1.154 PEX6 Sarah Leigh Added comment: Comment on mode of pathogenicity: Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678).
Inherited white matter disorders v1.154 PEX6 Sarah Leigh Mode of pathogenicity for gene: PEX6 was changed from to None
Inherited white matter disorders v1.153 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862; Peroxisome biogenesis disorder 4B 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Inherited white matter disorders v1.152 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 25655951
White matter disorders and cerebral calcification - childhood onset v1.229 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.229 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.228 PNPT1 Arina Puzriakova gene: PNPT1 was added
gene: PNPT1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Q1_22_rating tags were added to gene: PNPT1.
Mode of inheritance for gene: PNPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPT1 were set to 28594066; 30046113; 33199448
Phenotypes for gene: PNPT1 were set to Combined oxidative phosphorylation deficiency 13, OMIM:614932
Review for gene: PNPT1 was set to GREEN
Added comment: White matter abnormalities can be observed in some patients with PNPT1-related mitochondrial disease caused by biallelic variants. Overall at 6 least unrelated cases reported in literature with diminished white matter and/or delayed myelination which is sufficient to justify a Green rating on this panel.
Sources: Literature
Dystonia, chorea or related movement disorder, childhood onset v1.225 PNPT1 Arina Puzriakova edited their review of gene: PNPT1: Changed rating: GREEN
Dystonia, chorea or related movement disorder, childhood onset v1.225 PNPT1 Arina Puzriakova Publications for gene: PNPT1 were set to 23084291; 33199448
Primary ciliary disorders v1.40 XPNPEP3 Sarah Leigh commented on gene: XPNPEP3: Helen Brittain (GEL Clinical Fellow) agrees with the review from Ian Berry (below) that this gene is not relevant for Primary ciliary disorders. XPNPEP3 is recommended to be green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/XPNPEP3/#!review).
Dystonia, chorea or related movement disorder, childhood onset v1.224 PNPT1 Arina Puzriakova Classified gene: PNPT1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.224 PNPT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate this gene as Green at the next GMS review.
Dystonia, chorea or related movement disorder, childhood onset v1.224 PNPT1 Arina Puzriakova Gene: pnpt1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, childhood onset v1.223 PNPT1 Arina Puzriakova Publications for gene: PNPT1 were set to
Dystonia, chorea or related movement disorder, childhood onset v1.222 PNPT1 Arina Puzriakova Tag Q1_22_rating tag was added to gene: PNPT1.
Dystonia, chorea or related movement disorder, childhood onset v1.222 PNPT1 Arina Puzriakova reviewed gene: PNPT1: Rating: ; Mode of pathogenicity: None; Publications: 33199448; Phenotypes: Combined oxidative phosphorylation deficiency 13, OMIM:614932; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.222 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Dystonia
Dystonia, chorea or related movement disorder, adult onset v1.168 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Dystonia to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Dystonia
Monogenic hearing loss v2.238 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934
Mitochondrial disorders v2.96 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; respiratory chain disorder; hearing loss to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Likely inborn error of metabolism v2.237 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Deafness, autosomal recessive 70, 614934; Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; respiratory chain disorder; hearing loss; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Possible mitochondrial disorder, nuclear genes v1.70 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Deafness, autosomal recessive 70, 614934; Combined oxidative phosphorylation deficiency 13, 614932 to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Undiagnosed metabolic disorders v1.517 PNPT1 Arina Puzriakova Phenotypes for gene: PNPT1 were changed from Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 13, 614932; Deafness, autosomal recessive 70, 614934; respiratory chain disorder; hearing loss to Combined oxidative phosphorylation deficiency 13, OMIM:614932; Deafness, autosomal recessive 70, OMIM:614934; Disorders of mitochondrial protein import (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Intellectual disability v3.1530 MAN2C1 Konstantinos Varvagiannis gene: MAN2C1 was added
gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2C1 were set to 35045343
Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly
Penetrance for gene: MAN2C1 were set to unknown
Review for gene: MAN2C1 was set to GREEN
Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder.
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Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam).

While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4).

All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs).

There were no putative pathogenic variants in known disease genes.

MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation.

Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3]

Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect.

For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg.

Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT.

Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg.

In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects.

The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation.

Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides.
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G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels.

Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals).

Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc).
Sources: Literature, Other
Intellectual disability v3.1530 TLK2 Arina Puzriakova Publications for gene: TLK2 were set to 27479843; https://doi.org/10.1016/j.ajhg.2018.04.014
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.68 SIX1 Arina Puzriakova Publications for gene: SIX1 were set to
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Classified gene: ZNF423 as Amber List (moderate evidence)
Cystic kidney disease v2.41 ZNF423 Arina Puzriakova Gene: znf423 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.40 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to
Neurological ciliopathies v1.31 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.30 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Rare multisystem ciliopathy disorders v1.160 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19, 614844; Nephronophthisis 14, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Neurological ciliopathies v1.30 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Dystonia, chorea or related movement disorder, childhood onset v1.221 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19; Nephronophthisis 14; Nephronophthisis 14, 614844; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Unexplained young onset end-stage renal disease v1.34 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Cystic kidney disease v2.39 ZNF423 Arina Puzriakova Mode of inheritance for gene: ZNF423 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v1.19 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Joubert syndrome 19 MIM 614844; Nephronopthisis 14 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Cystic kidney disease v2.38 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Unexplained kidney failure in young people v1.106 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Ciliopathy genes associated with cystic kidney disease to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Renal ciliopathies v1.63 ZNF423 Arina Puzriakova Phenotypes for gene: ZNF423 were changed from Nephronophthisis 14; Joubert syndrome 19, 614844; Joubert syndrome with oculorenal defect; Joubert syndrome 19; Nephronophthisis 14, 614844 to Joubert syndrome 19, OMIM:614844; Nephronophthisis 14, OMIM:614844
Renal ciliopathies v1.62 ZNF423 Arina Puzriakova Publications for gene: ZNF423 were set to 22863007
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova commented on gene: ZNF423: There are now two unrelated families with homozygous variants and two cases with heterozygous variants in this gene associated with nephronophthisis or Joubert syndrome. Zfp423-mutant mice harbouring some variants (but not all - including one patient variant) displayed neuroanatomical abnormalities that were consistent with the human phenotype. Overall the evidence is borderline and therefore this gene will be flagged for GMS expert review to determine whether it should be upgraded to green at this stage.
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova Tag Q1_22_expert_review tag was added to gene: ZNF423.
Early onset or syndromic epilepsy v2.504 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Intellectual disability v3.1529 SLC38A3 Konstantinos Varvagiannis gene: SLC38A3 was added
gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC38A3 were set to 34605855
Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia
Penetrance for gene: SLC38A3 were set to Complete
Review for gene: SLC38A3 was set to GREEN
Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Renal ciliopathies v1.61 ZNF423 Arina Puzriakova reviewed gene: ZNF423: Rating: ; Mode of pathogenicity: None; Publications: 22863007, 32925911, 33323469; Phenotypes: Joubert syndrome 19, OMIM:614844, Nephronophthisis 14, OMIM:614844; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.190 ANO5 Sarah Leigh Tag Q1_22_MOI tag was added to gene: ANO5.
DDG2P v2.65 ANO5 Sarah Leigh reviewed gene: ANO5: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.65 ALPL Sarah Leigh reviewed gene: ALPL: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cystic kidney disease v2.37 ALG8 Sarah Leigh Publications for gene: ALG8 were set to 30135240; 28375157
Cystic kidney disease v2.36 ALG8 Sarah Leigh reviewed gene: ALG8: Rating: ; Mode of pathogenicity: None; Publications: 15235028; Phenotypes: ; Mode of inheritance: None
Polycystic liver disease v1.23 ALG8 Sarah Leigh reviewed gene: ALG8: Rating: ; Mode of pathogenicity: None; Publications: 15235028; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1529 ALG8 Sarah Leigh Publications for gene: ALG8 were set to 0
Likely inborn error of metabolism v2.236 SPTLC1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SPTLC1.
Likely inborn error of metabolism v2.236 SPTLC1 Sarah Leigh Added comment: Comment on mode of inheritance: There is no data to support that homozygous variants of SPTLC1 are associated with Neuropathy, hereditary sensory and autonomic, type IA, OMIM:162400. Therefore the MOI for this gene should be MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism v2.236 SPTLC1 Sarah Leigh Mode of inheritance for gene: SPTLC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.516 SPTLC1 Sarah Leigh Mode of inheritance for gene: SPTLC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.515 SPTLC1 Sarah Leigh Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Likely inborn error of metabolism v2.235 SPTLC1 Sarah Leigh Publications for gene: SPTLC1 were set to 27604308; 20097765; 21618344; 20097765; 30420926
Likely inborn error of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Likely inborn error of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Likely inborn error of metabolism v2.234 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.514 SPTLC1 Sarah Leigh Deleted their comment
Intellectual disability v3.1528 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286; MRT36 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Early onset or syndromic epilepsy v2.504 ADAT3 Arina Puzriakova Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36 615286 to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, OMIM:615286
Extreme early-onset hypertension v1.15 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300; Pseudohypoaldosteronism, type IIC, OMIM:614492
Renal tubulopathies v2.40 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Pseudohypoaldosteronism, type IIC, 614492 to Pseudohypoaldosteronism, type IIC, OMIM:614492
Hereditary neuropathy or pain disorder v1.89 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Hereditary neuropathy v1.443 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary Sensory and Autonomic Neuropathy, Type II; Pseudohypoaldosteronism, type IIC, 614492; Hereditary Sensory and Autonomic Neuropathy, Type II ; Neuropathy, hereditary sensory and autonomic, type II, 201300; Pseudohypoaldosteronism, type IIC, 614492 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Paroxysmal central nervous system disorders v1.43 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from HSAN 2; Neuropathy, hereditary sensory and autonomic, type II, 201300; Hereditary sensory and autonomic neuropathy type IIA to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Familial dysautonomia v1.16 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Neuropathy, hereditary sensory and autonomic, type II 201300 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Pain syndromes v1.11 WNK1 Arina Puzriakova Phenotypes for gene: WNK1 were changed from Hereditary sensory and autonomic neuropathy type IIA; HSAN 2; Neuropathy, hereditary sensory and autonomic, type II, 201300 to Neuropathy, hereditary sensory and autonomic, type II, OMIM:201300
Early onset dystonia v1.113 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, OMIM:128100; Dystonic disorder, MONDO:0003441 to Dystonia-1, torsion, OMIM:128100; Arthrogryposis multiplex congenita 5, OMIM:618947
Dystonia, chorea or related movement disorder, childhood onset v1.220 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Dystonia-1, torsion, OMIM:128100; Dystonic disorder, MONDO:0003441 to Dystonia-1, torsion, OMIM:128100; Arthrogryposis multiplex congenita 5, OMIM:618947
Early onset dystonia v1.112 TOR1A Arina Puzriakova Added comment: Comment on mode of inheritance: Dystonia association with monoallelic variants is well-established with multiple cases reported worldwide (OMIM:128100). Biallelic variants cause a more severe phenotype of congenital arthrogryposis (OMIM:618947) and movement impairments including dystonia are also common (PMIDs: 29053766, 30244176). For this reason the MOI was updated from 'monoallelic' only to 'both mono- and biallelic (biallelic more severe)'.
Early onset dystonia v1.112 TOR1A Arina Puzriakova Mode of inheritance for gene: TOR1A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Dystonia, chorea or related movement disorder, childhood onset v1.219 TOR1A Arina Puzriakova Publications for gene: TOR1A were set to 20301334; 11523564; 17503336; 20301665; 9288096; 16537570
Dystonia, chorea or related movement disorder, childhood onset v1.218 TOR1A Arina Puzriakova Tag Q1_22_MOI tag was added to gene: TOR1A.
Dystonia, chorea or related movement disorder, childhood onset v1.218 TOR1A Arina Puzriakova reviewed gene: TOR1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia-1, torsion, OMIM:128100, Arthrogryposis multiplex congenita 5, OMIM:618947; Mode of inheritance: None
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, OMIM:231095 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Intellectual disability v3.1527 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal hematodiaphyseal syndrome, 231095; ?Thromboxane synthase; deficiency, 614158 to Ghosal hematodiaphyseal syndrome, OMIM:231095
Inherited bleeding disorders v1.165 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal syndrome to Ghosal hematodiaphyseal syndrome, OMIM:231095; ?Thromboxane synthase deficiency, OMIM:614158; Bleeding disorder, platelet-type, 14, OMIM:614158
Bleeding and platelet disorders v1.36 TBXAS1 Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from 231095 Ghosal hematodiaphyseal syndrome; 614158 ?Thromboxane synthase deficiency; 614158 ?Thromboxane synthase deficiency, 231095 Ghosal hematodiaphyseal syndrome to Ghosal hematodiaphyseal syndrome, OMIM:231095; ?Thromboxane synthase deficiency, OMIM:614158; Bleeding disorder, platelet-type, 14, OMIM:614158
Hereditary ataxia, adult onset v2.150 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar Ataxia, Dominant; Autosomal recessive spinocerebellar ataxia 14, 615386; Spinocerebellar ataxia, autosomal recessive 14; Spinocerebellar ataxia 5; Spinocerebellar ataxia 5, 600224; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Neurodegenerative disorders, adult onset v2.269 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14; Spinocerebellar Ataxia, Dominant; Spinocerebellar ataxia, autosomal recessive 14; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); Spinocerebellar ataxia 5 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Cerebellar hypoplasia v1.62 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5 (AD); Spinocerebellar ataxia, autosomal recessive 14 (AR) to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Hereditary ataxia v1.300 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5; Spinocerebellar ataxia, autosomal recessive 14; Spinocerebellar Ataxia, Dominant; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant); SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14 to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Intellectual disability v3.1526 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia, autosomal recessive 14; MIM:615386; Developmental delay to Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Tag Q2_21_MOI tag was added to gene: SLURP1.
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova reviewed gene: SLURP1: Rating: ; Mode of pathogenicity: None; Publications: 14756676; Phenotypes: Meleda disease, OMIM:248300; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Palmoplantar keratodermas v1.13 SLURP1 Arina Puzriakova Phenotypes for gene: SLURP1 were changed from Mal de Meleda to Meleda disease, OMIM:248300
Peroxisomal disorders v1.16 SCP2 Zornitza Stark reviewed gene: SCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 16685654, 26497993; Phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.503 CACNA2D1 Konstantinos Varvagiannis reviewed gene: CACNA2D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35293990, 28097321; Phenotypes: Abnormal muscle tone, Feeding difficulties, Global developmental delay, Intellectual disability, Seizures, Microcephaly, Abnormality of the corpus callosum, Cerebral atrophy, Abnormality of movement, Cortical visual impairment, Pain insensitivity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1525 CACNA2D1 Konstantinos Varvagiannis gene: CACNA2D1 was added
gene: CACNA2D1 was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990; 28097321
Phenotypes for gene: CACNA2D1 were set to Abnormal muscle tone; Feeding difficulties; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of movement; Cortical visual impairment; Pain insensitivity
Penetrance for gene: CACNA2D1 were set to Complete
Review for gene: CACNA2D1 was set to GREEN
Added comment: Consider inclusion in the current panel with green rating.

Recent report of 2 unrelated individuals with DEE due to biallelic CACNA2D1 variants. Both referred to neurology/genetics for hypotonia/severe DD prior to onset of seizures.

One further individual with hypotonia and severe ID (seizures not discussed, age unknown).

Gene with established role, encoding α2δ-1 subunit of Cav channels. Studies for the variants support loss-of-function as the underlying effect.

Eventual contribution of monoallelic variants to NDD-phenotypes discussed (and put in question) in Ref [1] below.

There is currently no phenotype for CACNA2D1 in OMIM/G2P. In SysID this gene is listed among the candidates for ID, based on a previous report. CACNA2D1 is not currently included in the ID/epilepsy panels in PanelApp Australia.

See also relevant review in epilepsy panel (Dr. H. Lord).

Please consider also inclusion in other panels (e.g. microcephaly, corpus callosum, movement disorders, etc).

[1] ----
Dahimene et al (2022 - PMID: 35293990) describe the phenotype of 2 unrelated individuals with biallelic CACNA2D1 variants.

Overall, the phenotype corresponded to an early-onset DEE, characterized by abnormal muscle tone (axial hypotonia 2/2 with spasticity in extremities in 2/2), feeding difficulties (2/2), profound DD and ID (2/2), microcephaly (2/2 - approx. -2 SD in both), seizures (2/2 - 1st : onset 9m with absences and later generalized seizures, 2nd : onset 11m with hemi-clonic seizures and atypical absences). Other features included cortical visual impairment (2/2) and movement disorder (incl. choreiform movements 2/2, orofacial dyskinesia 2/2 and dystonic episodes 1/2). Brain MRI revealed corpus callosum anomalies (2/2) and cerebral atrophy (2/2). Both had echocardiography (abnormal in 1/2 - tiny PFO) and electrocardiography which was normal. Both exhibited insensibility to pain.

Presentation is relevant to the current panel as first symptoms in the first 3 months with severe hypotonia and poor head control (2/2) with evaluation in neurology/genetics preceding onset of seizures in both.

Trio ES was performed for both individuals and their (healthy) parents and revealed homozygosity for a fs variant in the first [NM_000722.3:c.818_822dup / p.(Ser275Asnfs*13)] and compound htz for a fs and a missense variant [c.13_23dup / p.(Leu9Alafs*5) and c.626G>A / p.(Gly209Asp)] in the second affected individual, respectively.

Eventual additional variants were not discussed.

Previous investigations are only provided for the 2nd and were all normal (karyotype, CMA, 15q methylation, epilepsy/neurometabolic gene panels).

Voltage-gated calcium channels are heteromultimers comprising different subunits incl. an alpha-1 (α1), α2δ (alpha-2/delta), beta (β) and gamma (γ). CACNA2D1 is one of the 4 genes (CACNA2D1-4) encoding the alpha-2/delta subunit. Its product is post-translationally processed into 2 peptides, an alpha-2 and a delta subunit, held by a disulfide bond.

Biallelic variants in CACNA2D2 - also encoding an alpha-2/delta subunit - cause cerebellar atrophy with seizures and variable developmental delay (# 618501).

Variant studies support loss-of-function effect for the studied variants, notably by NMD for the fs one, and severe impairment of the Cav2 channel function for the missense one :
- CACNA2D1 mRNA was reduced to 6-9% compared with control in fibroblasts from the 1st individual. mRNA levels for the 2nd subject were similar to control.
- Quantification of the protein in whole-cell lysates from fibroblasts revealed lower α2δ levels compared to control (10-12% and 31-38% applying to the 1st and 2nd individual).
- CACNA2D3 mRNA levels in fibroblasts from the 2nd patient were 2-7x higher compared to the 1st or controls suggesting a possible compensatory effect. CACNA2D2/4 mRNA levels were too low for quantification.
- Gly209 lies within the gabapentin and amino-acid binding pocket and this residue is invariable in CACNA2D1/CACNA2D2 in all vertebrates and paralogs.
- Transfection of tsA-201 cells with either WT or G209D HA-tagged α2δ revealed reduced cell surface expression for this missense variant (~80, for biotinylated form ~86%).
- In tsA-201 cells transfected with HA-tagged Cav2.2/β1b and either α2δ-1-WT, no α2δ-1 or α2δ-1-G209D, WT resulted in increased 13x currents with no increase applying to G209D (or in absence of α2δ). Plasma membrane expression of double (GFP/HA) tagged Cav2.2 was increased upon co-expression with WT α2δ-1 which was not the case for α2δ-1-G209D.
- In hippocampal neurons, double (GFP/HA)-tagged Cav2.2 could not be detected at the cell surface in the presence of α2δ-1-G209D (or no α2δ) in contrast with strong expression in presence of α2δ-1-WT. α2δ-1-G209D did not promote trafficking of Cav2.2 into hippocampal neurites, as indicated by reduced signals for both HA and GFP (for cell surface and total Cav2.2 respectively).
- Co-expression of double (GFP/HA) tagged Cav2.2 with β1b and either HA-α2δ-1-WT or HA-α2δ-1-G209D in tsA-201 cells, revealed reduced complex formation of G209D with Cav2.2 Co-immunoprecipitated HA-α2δ-1-G209D had higher molecular weight compared to HA-α2δ-1-WT which suggests that α2δ-1-G209D remains as the uncleaved immature form (probably in the ER).

Mouse model (several Refs in text):
Mild cardiac phenotype and reduced ventricular myocyte Ca current density was observed in hmz ko mice. Similarly to the insensibility to pain human phenotype, mice had delayed neuropathic pain-related responses. Overexpression of a2δ-1 resulted in epileptiform EEG and behavioral arrest, overall supporting a critical role of α2δ-1 for mouse brain.

The authors underscore that the parents of both patients (htz carriers) were healthy and review previous literature for association of monoallelic variants with epilepsy, ID and arrhythmogenic disorders (in suppl.) [Refs not here reviewed].

As for the NDD phenotype, CACNA2D1 is within a previously defined small region of overlap for 7q21.11 microdeletions associated with ID+/-epilepsy. The same study did not reveal de novo SNVs in any of the 3 contained genes within this SRO (HGF, CACNA2D1, PCLO) in 4293 patients with NDD [cited PMID: 28240412]. A frameshift variant (c.2625del) was identified in a 13-yo girl with infantile spasms and normal intelligence [cited PMID: 25877686]. A 1-bp insertion (c.659-2_659-1insT / not studied at the mRNA level) was identified in another 14-yo female with ID and epilepsy [cited PMID: 34356170]. The authors state that the phenotype (/differences) of these individuals as well as presence of pLoF CACNA2D1 variants in gnomAD [still pLI of 1] put in question pathogenicity of monoallelic variants for these phenotypes.

The role of heterozygous missense variants described in relation to arrhythmogenic disorders is also discussed extensively (some downgraded to LB/VUS, others having a relatively high MAF and presence of 1-2 homozygotes in gnomAD).

[2] ----
In an article cited by SysID for CACNA2D1 (2017 - PMID: 28097321), Reuter et al studied with WES and autozygosity mapping individuals with NDD belonging to consanguineous families.

As in eTables1/3, a male - single affected individual born to consanguineous parents from Turkey (MR150) - was investigated by singleton ES.

This individual was homozygous for a missense CACNA2D1 SNV [NM_000722.2:c.1514C>T;p.(Thr505Ile)].

Prior investigations are unavailable (although individuals with previously known P/LP CNVs were excluded).

The phenotype - briefly reported - included hypotonia, severe ID, stereotypic behaviors, inguinal hernia and omphalocele. Presence of seizures was not commented on. The age of this individual was not reported.
Sources: Literature, Other
Intellectual disability v3.1525 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Global developmental delay; Intellectual disability to Developmental and epileptic encephalopathy 76, OMIM:618468; Intellectual developmental disorder with severe speech and ambulation defects, OMIM:618470
Early onset or syndromic epilepsy v2.503 ACTL6B Arina Puzriakova Phenotypes for gene: ACTL6B were changed from Epileptic encephalopathy, early infantile, 76, 618468; Global developmental delay; Intellectual disability; Seizures; Spasticity; epileptic encephalopathy to Developmental and epileptic encephalopathy 76, OMIM:618468
Hereditary spastic paraplegia, childhood onset v2.131 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Hereditary spastic paraplegia, childhood onset v2.131 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Dystonia, chorea or related movement disorder, childhood onset v1.218 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Dystonia, chorea or related movement disorder, childhood onset v1.218 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1524 ACER3 Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.227
Intellectual disability v3.1524 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Intellectual disability. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
White matter disorders and cerebral calcification - childhood onset v1.227 ACER3 Arina Puzriakova Classified gene: ACER3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.227 ACER3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene Green on this panel at the next GMS review - now at least 5 unrelated families reported with homozygous variants (PMIDs: 26792856; 32816236; 34281620). Phenotypes that are consistent amongst all affected individuals comprise of developmental regression (motor and cognitive), dystonia, spasticity, and leukodystrophy.
White matter disorders and cerebral calcification - childhood onset v1.227 ACER3 Arina Puzriakova Gene: acer3 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - childhood onset v1.226 ACER3 Arina Puzriakova Publications for gene: ACER3 were set to 32816236; 26792856
White matter disorders and cerebral calcification - childhood onset v1.225 ACER3 Arina Puzriakova Tag watchlist was removed from gene: ACER3.
Tag Q1_22_rating tag was added to gene: ACER3.
White matter disorders and cerebral calcification - childhood onset v1.225 ACER3 Arina Puzriakova reviewed gene: ACER3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34281620; Phenotypes: Leukodystrophy, progressive, early childhood-onset, OMIM:617762; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - childhood onset v1.225 ACER3 Arina Puzriakova Phenotypes for gene: ACER3 were changed from ?Leukodystrophy, progressive, early childhood-onset, OMIM:617762 to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Intellectual disability v3.1523 TRAPPC10 Konstantinos Varvagiannis reviewed gene: TRAPPC10: Rating: AMBER; Mode of pathogenicity: None; Publications: 35298461, 30167849; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Gait disturbance; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial pulmonary fibrosis v1.28 ACD Arina Puzriakova Tag watchlist_moi tag was added to gene: ACD.
Familial pulmonary fibrosis v1.28 ACD Arina Puzriakova Mode of inheritance for gene: ACD was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Classified gene: ACD as Green List (high evidence)
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Added comment: Comment on list classification: This gene was approved by the NHS Genomic Medicine Service, rated green on the 'Pulmonary fibrosis familial' GMS panel with 'monoallelic' inheritance. Therefore the MOI and rating on this panel was also updated accordingly and the 'watchlist' tag was removed. Added 'watchlist_MOI' tag to ensure monitoring of biallelic variants as currently no evidence linking these to PF is available but may emerge in the future.
Familial pulmonary fibrosis v1.27 ACD Arina Puzriakova Gene: acd has been classified as Green List (High Evidence).
Familial pulmonary fibrosis v1.26 ACD Arina Puzriakova Tag watchlist was removed from gene: ACD.
Pulmonary Fibrosis, Familial v0.6 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita, autosomal dominant, OMIM:6 to Dyskeratosis congenita, autosomal dominant, OMIM:616553
Pulmonary Fibrosis, Familial v0.5 ACD Arina Puzriakova Publications for gene: ACD were set to
Cholestasis v1.106 AP1S1 Ivone Leong Classified gene: AP1S1 as Red List (low evidence)
Cholestasis v1.106 AP1S1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert review by Miranda Durkie (Genetics).
Cholestasis v1.106 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Red List (Low Evidence).
Cholestasis v1.105 AP1S1 Ivone Leong Tag Q2_21_rating was removed from gene: AP1S1.
Pancreatitis v2.16 CEL Ivone Leong Classified gene: CEL as Amber List (moderate evidence)
Pancreatitis v2.16 CEL Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review by Miranda Durkie. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.
Pancreatitis v2.16 CEL Ivone Leong Gene: cel has been classified as Amber List (Moderate Evidence).
Pancreatitis v2.15 CEL Ivone Leong Phenotypes for gene: CEL were changed from to Hereditary Pancreatitis
Pancreatitis v2.14 CEL Ivone Leong Publications for gene: CEL were set to 29233499; 28881607; 28500240; 27802312; 27650499; 27773618; 26946345; 25774637; 23770712
Pancreatitis v2.13 CEL Ivone Leong Mode of inheritance for gene: CEL was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.502 RELN Sarah Leigh Phenotypes for gene: RELN were changed from {Epilepsy, familial temporal lobe, 7} 616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436
Early onset or syndromic epilepsy v2.501 RELN Sarah Leigh Publications for gene: RELN were set to 26046367
Intellectual disability v3.1523 SLC12A5 Sarah Leigh reviewed gene: SLC12A5: Rating: ; Mode of pathogenicity: None; Publications: 24928908, 24668262, 26333769; Phenotypes: Developmental and epileptic encephalopathy 34, OMIM:616645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1523 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262; 26333769
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Tag Q1_22_MOI tag was added to gene: SLC12A5.
Intellectual disability v3.1522 SLC12A5 Sarah Leigh Phenotypes for gene: SLC12A5 were changed from FEBRILE SEIZURES to Developmental and epileptic encephalopathy 34, OMIM; 616645
Intellectual disability v3.1521 SLC12A5 Sarah Leigh Publications for gene: SLC12A5 were set to 24668262
Brain channelopathy v1.78 KCNMA1 Sarah Leigh reviewed gene: KCNMA1: Rating: ; Mode of pathogenicity: None; Publications: 29545233, 27567911; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh Tag Q1_22_MOI tag was added to gene: KCNMA1.
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh reviewed gene: KCNMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29545233, 27567911; Phenotypes: Cerebellar atrophy, developmental delay, and seizures, OMIM:617643; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.42 KCNMA1 Sarah Leigh Publications for gene: KCNMA1 were set to 15937479; 26195193
Neurodegenerative disorders, adult onset v2.268 CACNA1A_CAG Louise Daugherty reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.289 CACNA1A_CAG Louise Daugherty reviewed STR: CACNA1A_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - childhood onset v2.289 ATXN10_ATTCT Louise Daugherty reviewed STR: ATXN10_ATTCT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.539 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Immunodeficiency 14,615513; Combined immunodeficiency; Unclassified antibody deficiency; Activated PI3K-delta syndrome (APDS); sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections; decreased or absent pro-B cells, EBV; Predominantly Antibody Deficiencies to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Immunodeficiency 14B, autosomal recessive, OMIM:619281; Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Predominantly Antibody Deficiencies; Sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections
COVID-19 research v1.118 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Unclassified antibody deficiency; decreased or absent pro-B cells, EBV; Predominantly Antibody Deficiencies; sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections; Immunodeficiency 14,615513 to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Immunodeficiency 14B, autosomal recessive, OMIM:619281; Combined immunodeficiency; Activated PI3K-delta syndrome (APDS); Predominantly Antibody Deficiencies; Sinopulmonary infections, dysgammaglobulinaemia, lymphadenopathy, nodular lymphoid hyperplasia and herpesviremia; Severe bacterial infections
Gastrointestinal epithelial barrier disorders v1.71 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from to Immunodeficiency 14B, autosomal recessive, OMIM:619281
Gastrointestinal epithelial barrier disorders v1.70 PIK3CD Arina Puzriakova Mode of inheritance for gene: PIK3CD was changed from to BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.56 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from Immunodeficiency 14, 615513; Bronchiectasis to Immunodeficiency 14A, autosomal dominant, OMIM:615513; Bronchiectasis
Non-CF bronchiectasis v1.27 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from to Immunodeficiency 14A, autosomal dominant, OMIM:615513
Infantile enterocolitis & monogenic inflammatory bowel disease v1.37 PIK3CD Arina Puzriakova Phenotypes for gene: PIK3CD were changed from PI3K activation syndrome; Immunodeficiency 14 615513 to Immunodeficiency 14A, autosomal dominant, OMIM:615513
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously providing a critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord changed review comment from: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS; to: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly consistent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivity to pain.

Looking at mRNA level in patient fibroblasts in both patients showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is important for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolishes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface expression or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remains largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 CACNA2D1 Helen Lord gene: CACNA2D1 was added
gene: CACNA2D1 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: CACNA2D1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA2D1 were set to 35293990
Phenotypes for gene: CACNA2D1 were set to Early onset developmental epilepsy
Review for gene: CACNA2D1 was set to AMBER
Added comment: Dahimne et al, 2022, 35293990 - two unrelated patients with biallelic CACNA2D1 variants - trio exome sequencing - identified by gene matcher.
Patient 1: homozygous fs variant c.818_821dup p.(Ser275fs) - healthy parents het carriers.
Patient 2: compound het for a fs c.13_23dup p.(Leu9fs) and a missense variant c.626G>A p.(Gly209Asp) - parents healthy carriers of each of the variants.
Both individuals show a highly conssitent phenotype, corresponding to DEE - microcephalic, severe hypotonia, absent speech, spasticity, choreiform movements, orofacial dyskinesia and cortical visual impairement. Brain imaging showed corpus callosum hypoplasia and progressive volume loss in both. Both patients also showed insensitivty to apin

Looking at mRNA level in patient fibroblasts in both pTIWNTS showed it was reduced to 6-9% compared to control fibroblasts. Also data suggest the fs variants result in LOF.

Gly209 - this Gly is importnat for maintaining a 3-strand-beta-sheet-stability and simultaneously provididn ga critial turn in the structure and is absoloutely invariant in both CACNA2D1 and CACNA2D2 orthologs in all vertebrates and paralogs and predecessors from low invertebrates.
Functional work on the missense change shows it disrupts plasma membrane a2d-1 expression by 86.2% compared to wt. It abolshes the ability of a2d-1 to promote Cav2.2 currents, it does not promote Cav2.2 cell surface exprtession or trafficking in hippocampal neurons and it shows reduced complex formation with Cav2.2 and limited proteolytic cleavage. Suggests the HA-a2b-1 with the G209D variant remians largely as the uncleaved imaature form, indicating that it probably remains in the endoplasmic reticulum - suggests LOF effect.
Sources: NHS GMS
Early onset or syndromic epilepsy v2.500 KCNC2 Helen Lord reviewed gene: KCNC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35314505; Phenotypes: epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.844 MYH6 Ivone Leong Tag Q1_22_MOI tag was added to gene: MYH6.
Corneal abnormalities v1.12 TGFBI Ivone Leong Tag Q1_22_MOI tag was added to gene: TGFBI.
Intellectual disability v3.1520 ZNF292 Rachel Challis reviewed gene: ZNF292: Rating: ; Mode of pathogenicity: None; Publications: PMID: 31723249; Phenotypes: Intellectual disability, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Bleeding and platelet disorders v1.35 F7 Arina Puzriakova commented on gene: F7
Inherited bleeding disorders v1.164 F12 Arina Puzriakova commented on gene: F12
Bleeding and platelet disorders v1.35 F12 Arina Puzriakova commented on gene: F12
Vascular skin disorders v1.48 F12 Arina Puzriakova commented on gene: F12
COVID-19 research v1.117 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from hereditary angioedema; Angioedema, Hereditary, Type III to Angioedema, hereditary, 3, OMIM:610618
Primary immunodeficiency or monogenic inflammatory bowel disease v2.538 F12 Arina Puzriakova Phenotypes for gene: F12 were changed from Angioedema, Hereditary, Type III; hereditary angioedema to Angioedema, hereditary, 3, OMIM:610618
Pancreatitis v2.12 CEL Miranda Durkie reviewed gene: CEL: Rating: AMBER; Mode of pathogenicity: Other; Publications: PMID: 16369531, PMID: 34850019; Phenotypes: Hereditary Pancreatitis, Diabetes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cholestasis v1.105 AP1S1 Miranda Durkie reviewed gene: AP1S1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 32306098; Phenotypes: Congenital diarrhoea; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.500 NAPB Tracy Lester gene: NAPB was added
gene: NAPB was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: NAPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAPB were set to 28097321; 33189936; 26235277; 21040848
Phenotypes for gene: NAPB were set to Early infantile epileptic encephalopathy
Penetrance for gene: NAPB were set to unknown
Review for gene: NAPB was set to GREEN
Added comment: Three cases reported with early infantile epileptic encepahlopathy and with homozygous LOF variants in this gene. Null mice also develop severe recurrent epileptic seizures from day 11, followed by ataxia. Sufficient evidence to be considered as green gene on the epilepsy and ID panels, autosomal recessive inheritance only.
Sources: NHS GMS
Intellectual disability v3.1520 PAN2 Konstantinos Varvagiannis gene: PAN2 was added
gene: PAN2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y
Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck
Penetrance for gene: PAN2 were set to Complete
Review for gene: PAN2 was set to AMBER
Added comment: 1.
Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2.

This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy).

As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes.

Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child).

WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)].

There were no additional studies.

Role of PAN2 and animal models discussed as below.
---
2.
Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case.

Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual.

WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'.

The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency.

Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs.

All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3].

Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19).

There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843].

Overall PAN2 loss-of-function is thought to be the underlying disease mechanism.

Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans.

In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670]

Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality.

Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening.
---
Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia.
---
Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date].

Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc.

For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment.
Sources: Literature
Hereditary neuropathy or pain disorder v1.88 PCYT2 Dmitrijs Rots gene: PCYT2 was added
gene: PCYT2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to PMID: 35243002
Review for gene: PCYT2 was set to AMBER
Added comment: Two brother with axonal neuropathy reported in PMID: 35243002. In the same study, after reviewing previously published cases, other individuals (2/10) had sensory deficit / neuropathy: "Of 5 previously reported adult patients (age range of 20–59 years),2-6 nerve conduction studies were performed in 2 of them and reported as normal.3,4 Clinically, one of them had hypopallesthesia of the ankles,4 and the other had loss of vibration sense in the lower limbs and mild loss of proprioception in the feet".
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.78 FDX2 Dmitrijs Rots reviewed gene: FDX2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35079622; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1520 HIST1H4C Konstantinos Varvagiannis reviewed gene: HIST1H4C: 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: 28920961, 35202563; Phenotypes: Tessadori-van Haaften neurodevelopmental syndrome 1, #619758; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4J Konstantinos Varvagiannis reviewed gene: HIST1H4J: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31804630, 35202563; Phenotypes: ?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1520 HIST1H4D Konstantinos Varvagiannis gene: HIST1H4D was added
gene: HIST1H4D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4D were set to 35202563
Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4D were set to Complete
Mode of pathogenicity for gene: HIST1H4D 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: HIST1H4D was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4E Konstantinos Varvagiannis gene: HIST1H4E was added
gene: HIST1H4E was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4E were set to 35202563
Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4E were set to unknown
Mode of pathogenicity for gene: HIST1H4E 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: HIST1H4E was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4F Konstantinos Varvagiannis gene: HIST1H4F was added
gene: HIST1H4F was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4F were set to 35202563
Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4F were set to unknown
Mode of pathogenicity for gene: HIST1H4F 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: HIST1H4F was set to AMBER
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Intellectual disability v3.1520 HIST1H4I Konstantinos Varvagiannis gene: HIST1H4I was added
gene: HIST1H4I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HIST1H4I were set to 35202563
Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face
Penetrance for gene: HIST1H4I were set to unknown
Mode of pathogenicity for gene: HIST1H4I 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: HIST1H4I was set to GREEN
Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair.

There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues.

Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes).

Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern :
- H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563),
- H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563),
- H4C4/HIST1H4D (1 subject - PMID:35202563),
- H4C5/HIST1H4E (17 subjects - PMID: 35202563),
- H4C6/HIST1H4F (1 subject - PMID: 35202563),
- H4C9/HIST1H4I (3 subjects - PMID: 35202563).

Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall).

Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth).

Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression).

Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one.

Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes.

Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green.

Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc).

------
Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent].

Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3).

Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature).

RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle).

Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant.

Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied.

------
In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above).

------
Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely:
- H4C3 (HIST1H4C/N=6 subjects),
- H4C11 (HIST1H4J/N=1),
- H4C4 (HIST1H4D/N=1),
- H4C5 (HIST1H4E/N=17),
- H4C6 (HIST1H4F/N=1),
- H4C9 (HIST1H4I/N=3).

All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors).

The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER.

Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents.

Previous work-up or presence of additional variants are not discussed.

At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones.

There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys).

All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited).

Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11).

For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants.

H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants.

------
[RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala]
Sources: Literature
Skeletal dysplasia v2.190 DVL2 Michael Oldridge gene: DVL2 was added
gene: DVL2 was added to Skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: DVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DVL2 were set to PMID: 35047859
Phenotypes for gene: DVL2 were set to autosomal dominant Robinow sydrome
Penetrance for gene: DVL2 were set to Complete
Mode of pathogenicity for gene: DVL2 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: DVL2 was set to GREEN
Added comment: De novo fs variant in final exon of DVL2 identified in patient with clinical diagnosis of Robinow syndrome. This leads to a 103 residue missense tail extending beyond the WT stop codon. A number of similar fs variants have been identified in DVL1 and DVL3 leading to autosomal dominant Robinow syndrome; these variants also lead to extended missense tails and are therefore thought to act via a very specific gain of function mechanism (LOF variants in these genes do not lead to Robinow). DVL1, 2 and 3 share considerable homology (59-67%) and have overlapping function during development.
Only reported in 1 case but the very specific nature of the mutation explains rareity. Should be tested as Green.
Sources: Expert Review
Ocular coloboma v1.46 RARB Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as biallelic variants also cause disease.
Ocular coloboma v1.46 RARB Ivone Leong Mode of inheritance for gene: RARB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.45 SIX6 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BIALLELIC, autosomal or pseudoautosomal".

Review copied from Structural eye disease panel:
"Aldamesh (2013) reported one family; Yariz (2015) one family; Patel (2018) one family), all three variants homozygous. Gallardo reported a heterozygous variant in a patient with bilateral microphthalmia, inherited from the unaffected father. This variant has now been reclassified on OMIM as VUS. Mode of inheritance should be changed.
Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust), 19 Jun 2019"
Anophthalmia or microphthalmia v1.45 SIX6 Ivone Leong Mode of inheritance for gene: SIX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.44 SIX6 Ivone Leong Phenotypes for gene: SIX6 were changed from Anophthalmia/Microphthalmia; Microphthalmia with cataract 2, 212550 to Optic disc anomalies with retinal and/or macular dystrophy, OMIM:212550
Corneal dystrophy v1.10 TGFBI Ivone Leong reviewed gene: TGFBI: Rating: ; Mode of pathogenicity: None; Publications: 31322463, 30830990, 32952948; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Corneal abnormalities v1.12 TGFBI Ivone Leong Added comment: Comment on publications: New publications added: 31322463, 30830990, 32952948
Corneal abnormalities v1.12 TGFBI Ivone Leong Publications for gene: TGFBI were set to 11146721; 15531312; 16652336; 9780098; 9727509
Corneal abnormalities v1.11 TGFBI Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more severe disease)".
Corneal abnormalities v1.11 TGFBI Ivone Leong Mode of inheritance for gene: TGFBI 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
Familial non syndromic congenital heart disease v1.75 MYH6 Ivone Leong Added comment: Comment on mode of inheritance: MOI change dfrom "BIALLELIC, autosomal or pseudoautosomal" to "Both Monoallelic and Biallelic" as Monoallelic variants also cause disease.
Familial non syndromic congenital heart disease v1.75 MYH6 Ivone Leong Mode of inheritance for gene: MYH6 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.844 MYH6 Ivone Leong reviewed gene: MYH6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.234 QARS Sarah Leigh Mode of inheritance for gene: QARS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.233 QARS Sarah Leigh Mode of inheritance for gene: QARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.233 QARS Sarah Leigh Publications for gene: QARS were set to
Mitochondrial disorders v2.95 GATC Sarah Leigh Phenotypes for gene: GATC were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Combined oxidative phosphorylation deficiency 42, OMIM:618839
Mitochondrial disorders v2.94 GATC Sarah Leigh Mode of inheritance for gene: GATC was changed from to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.232 GATC Sarah Leigh Added comment: Comment on phenotypes: Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Likely inborn error of metabolism v2.232 GATC Sarah Leigh Phenotypes for gene: GATC were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Combined oxidative phosphorylation deficiency 42, OMIM:618839
Likely inborn error of metabolism v2.231 GATC Sarah Leigh Mode of inheritance for gene: GATC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.83 UNC45B Sarah Leigh commented on gene: UNC45B: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Congenital myopathy v2.83 UNC45B Sarah Leigh Deleted their comment
Congenital myopathy v2.83 UNC45B Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: UNC45B.
Congenital myopathy v2.83 UNC45B Sarah Leigh Classified gene: UNC45B as Amber List (moderate evidence)
Congenital myopathy v2.83 UNC45B Sarah Leigh Gene: unc45b has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.82 KY Sarah Leigh Deleted their comment
Congenital myopathy v2.82 KY Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: KY.
Congenital myopathy v2.82 KY Sarah Leigh Classified gene: KY as Amber List (moderate evidence)
Congenital myopathy v2.82 KY Sarah Leigh Added comment: Comment on list classification: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Congenital myopathy v2.82 KY Sarah Leigh Gene: ky has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.81 KY Sarah Leigh Deleted their comment
Congenital myopathy v2.81 GFER Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: GFER.
Congenital myopathy v2.81 GFER Sarah Leigh Classified gene: GFER as Amber List (moderate evidence)
Congenital myopathy v2.81 GFER Sarah Leigh Gene: gfer has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.80 GFER Sarah Leigh reviewed gene: GFER: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.80 GFER Sarah Leigh Deleted their review
Intellectual disability v3.1520 GLS Arina Puzriakova Tag for-review was removed from gene: GLS.
Tag watchlist tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.514 GLS Arina Puzriakova Tag watchlist tag was added to gene: GLS.
Undiagnosed metabolic disorders v1.514 GLS Arina Puzriakova Tag for-review was removed from gene: GLS.
Renal ciliopathies v1.61 DLG5 Eleanor Williams commented on gene: DLG5: Changed the mode of inheritance to be inline with that recommended by the NHS reviewer. Removed the Q3_21_MOI and Q3_21_NHS_review tags.
Renal ciliopathies v1.61 DLG5 Eleanor Williams Tag Q3_21_MOI was removed from gene: DLG5.
Tag Q3_21_NHS_review was removed from gene: DLG5.
Renal ciliopathies v1.61 DLG5 Eleanor Williams Mode of inheritance for gene: DLG5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia, adult onset v2.149 ABCB7 Eleanor Williams Added comment: Comment on mode of inheritance: Changed the mode of inheritance now this gene has been demoted to amber on this panel and removed the Q3_21_MOI tag.
Hereditary ataxia, adult onset v2.149 ABCB7 Eleanor Williams Mode of inheritance for gene: ABCB7 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary ataxia, adult onset v2.148 ABCB7 Eleanor Williams Tag Q3_21_MOI was removed from gene: ABCB7.
Ataxia and cerebellar anomalies - childhood onset v2.289 GLS Eleanor Williams commented on gene: GLS
Ataxia and cerebellar anomalies - childhood onset v2.289 GLS Eleanor Williams Tag for-review was removed from gene: GLS.
Tag watchlist tag was added to gene: GLS.
Multiple monogenic benign skin tumours v1.20 NOTCH3 Eleanor Williams commented on gene: NOTCH3: Removed the Q4_21_expert_review and Q4_21_NHS_review tags from this gene, and added the watchlist tag as it has only enough evidence for Amber at the moment. If more evidence is found to support the gene-disease association then the eligibility criteria for the panel needs to be expanded before promoting the gene to green.
Multiple monogenic benign skin tumours v1.20 NOTCH3 Eleanor Williams Tag Q4_21_expert_review was removed from gene: NOTCH3.
Tag Q4_21_NHS_review was removed from gene: NOTCH3.
Tag watchlist tag was added to gene: NOTCH3.
Early onset or syndromic epilepsy v2.500 FAR1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline); to: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, in 2019, the rating was set to Amber for this allelic requirement (no new related evidence since). However, there is now evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel.
Fetal anomalies v1.844 TUBA8 Arina Puzriakova Classified gene: TUBA8 as Amber List (moderate evidence)
Fetal anomalies v1.844 TUBA8 Arina Puzriakova Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.843 TUBA8 Arina Puzriakova Tag for-review was removed from gene: TUBA8.
Fetal anomalies v1.843 TUBA8 Arina Puzriakova commented on gene: TUBA8
Fetal anomalies v1.843 NEK9 Arina Puzriakova Classified gene: NEK9 as Green List (high evidence)
Fetal anomalies v1.843 NEK9 Arina Puzriakova Gene: nek9 has been classified as Green List (High Evidence).
Fetal anomalies v1.842 NEK9 Arina Puzriakova Tag for-review was removed from gene: NEK9.
Fetal anomalies v1.842 NEK9 Arina Puzriakova commented on gene: NEK9: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Skeletal dysplasia v2.190 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Intellectual disability v3.1520 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Clefting v2.66 ISCA-37423-Gain Arina Puzriakova commented on Region: ISCA-37423-Gain
Intellectual disability v3.1520 ISCA-37423-Loss Arina Puzriakova commented on Region: ISCA-37423-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Loss Arina Puzriakova commented on Region: ISCA-37423-Loss
Intellectual disability v3.1520 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37441-Loss Eleanor Williams commented on Region: ISCA-37441-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Undiagnosed metabolic disorders v1.514 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Malformations of cortical development v2.137 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Mitochondrial disorders v2.93 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37430-Gain Arina Puzriakova commented on Region: ISCA-37430-Gain
Hereditary neuropathy v1.442 ISCA-37436-Gain Arina Puzriakova commented on Region: ISCA-37436-Gain
Intellectual disability v3.1520 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Skeletal dysplasia v2.190 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37434-Loss Arina Puzriakova commented on Region: ISCA-37434-Loss
Intellectual disability v3.1520 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37430-Loss Arina Puzriakova commented on Region: ISCA-37430-Loss
Likely inborn error of metabolism v2.230 ISCA-37440-Loss Eleanor Williams commented on Region: ISCA-37440-Loss
Intellectual disability v3.1520 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Hereditary neuropathy v1.442 ISCA-37436-Loss Eleanor Williams commented on Region: ISCA-37436-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Paediatric motor neuronopathies v1.77 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Congenital myopathy v2.80 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
IUGR and IGF abnormalities v1.51 ISCA-37429-Loss Arina Puzriakova commented on Region: ISCA-37429-Loss
Intellectual disability v3.1520 ISCA-46299-Gain Arina Puzriakova commented on Region: ISCA-46299-Gain
Intellectual disability v3.1520 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Skeletal dysplasia v2.190 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Severe microcephaly v2.294 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Deafness and congenital structural abnormalities v1.19 ISCA-37501-Loss Arina Puzriakova commented on Region: ISCA-37501-Loss
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37478-Loss Eleanor Williams commented on Region: ISCA-37478-Loss
Intellectual disability v3.1520 ISCA-37494-Gain Arina Puzriakova commented on Region: ISCA-37494-Gain
Intellectual disability v3.1520 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Neurodegenerative disorders, adult onset v2.268 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37493-Loss Arina Puzriakova commented on Region: ISCA-37493-Loss
Intellectual disability v3.1520 ISCA-37494-Loss Arina Puzriakova commented on Region: ISCA-37494-Loss
Hereditary ataxia v1.299 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Intellectual disability v3.1520 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Hereditary ataxia, adult onset v2.148 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37478-Gain Eleanor Williams commented on Region: ISCA-37478-Gain
Dystonia, chorea or related movement disorder, adult onset v1.167 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Hereditary ataxia, adult onset v2.148 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Intellectual disability v3.1520 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Neurodegenerative disorders, adult onset v2.268 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Paroxysmal central nervous system disorders v1.41 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Primary immunodeficiency or monogenic inflammatory bowel disease v2.537 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval.
Brain channelopathy v1.78 ISCA-37468-Loss Arina Puzriakova commented on Region: ISCA-37468-Loss
Clefting v2.66 ISCA-37467-Gain Arina Puzriakova commented on Region: ISCA-37467-Gain
Familial non syndromic congenital heart disease v1.74 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
COVID-19 research v1.116 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Neonatal diabetes v2.38 ISCA-37442-Gain Arina Puzriakova commented on Region: ISCA-37442-Gain
Intellectual disability v3.1520 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Clefting v2.66 ISCA-37446-Loss Eleanor Williams commented on Region: ISCA-37446-Loss
Intellectual disability v3.1520 ISCA-37433-Gain Arina Puzriakova commented on Region: ISCA-37433-Gain
Intellectual disability v3.1520 ISCA-37446-Gain Arina Puzriakova commented on Region: ISCA-37446-Gain
Intellectual disability v3.1520 ISCA-37443-Loss Arina Puzriakova commented on Region: ISCA-37443-Loss
Intellectual disability v3.1520 ISCA-37439-Gain Arina Puzriakova commented on Region: ISCA-37439-Gain
Intellectual disability v3.1520 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Clefting v2.66 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Primary immunodeficiency or monogenic inflammatory bowel disease v2.537 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
COVID-19 research v1.116 ISCA-37433-Loss Arina Puzriakova commented on Region: ISCA-37433-Loss
Renal ciliopathies v1.60 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Rare multisystem ciliopathy disorders v1.159 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Intellectual disability v3.1520 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Unexplained young onset end-stage renal disease v1.33 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
CAKUT v1.167 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Monogenic diabetes v2.47 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Unexplained kidney failure in young people v1.105 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Cystic kidney disease v2.36 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Familial diabetes v1.66 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.66 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Neonatal cholestasis v1.24 ISCA-37432-Loss Arina Puzriakova commented on Region: ISCA-37432-Loss
Intellectual disability v3.1520 ISCA-37432-Gain Arina Puzriakova commented on Region: ISCA-37432-Gain
Early onset or syndromic epilepsy v2.500 ISCA-37432-Gain Arina Puzriakova commented on Region: ISCA-37432-Gain
Intellectual disability v3.1520 ISCA-37431-Gain Arina Puzriakova commented on Region: ISCA-37431-Gain
Paediatric or syndromic cardiomyopathy v1.68 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
RASopathies v1.78 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Intellectual disability v3.1520 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Pigmentary skin disorders v1.46 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Neurofibromatosis Type 1 v1.27 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Familial Tumours Syndromes of the central & peripheral Nervous system v1.12 ISCA-37431-Loss Arina Puzriakova commented on Region: ISCA-37431-Loss
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.116 ISCA-37425-Loss Arina Puzriakova commented on Region: ISCA-37425-Loss
Intellectual disability v3.1520 ISCA-37425-Loss Arina Puzriakova commented on Region: ISCA-37425-Loss
Intellectual disability v3.1520 ISCA-37425-Gain Arina Puzriakova commented on Region: ISCA-37425-Gain
Severe microcephaly v2.294 ISCA-37425-Gain Arina Puzriakova commented on Region: ISCA-37425-Gain
Intellectual disability v3.1520 ISCA-37424-Loss Arina Puzriakova commented on Region: ISCA-37424-Loss
Intellectual disability v3.1520 ISCA-37421-Gain Arina Puzriakova commented on Region: ISCA-37421-Gain
Intellectual disability v3.1520 ISCA-37421-Loss Arina Puzriakova commented on Region: ISCA-37421-Loss
Intellectual disability v3.1520 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Paediatric motor neuronopathies v1.77 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Congenital myopathy v2.80 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
IUGR and IGF abnormalities v1.51 ISCA-37420-Loss Arina Puzriakova commented on Region: ISCA-37420-Loss
Intellectual disability v3.1520 ISCA-37418-Gain Arina Puzriakova commented on Region: ISCA-37418-Gain
Intellectual disability v3.1520 ISCA-37418-Loss Arina Puzriakova commented on Region: ISCA-37418-Loss
Skeletal dysplasia v2.190 ISCA-37418-Loss Arina Puzriakova commented on Region: ISCA-37418-Loss
Ichthyosis and erythrokeratoderma v1.72 ISCA-37417-Loss Arina Puzriakova commented on Region: ISCA-37417-Loss
Autosomal recessive congenital ichthyosis v1.14 ISCA-37417-Loss Arina Puzriakova commented on Region: ISCA-37417-Loss
Intellectual disability v3.1520 ISCA-37415-Loss Arina Puzriakova commented on Region: ISCA-37415-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37415-Loss Arina Puzriakova commented on Region: ISCA-37415-Loss
Intellectual disability v3.1520 ISCA-37415-Gain Arina Puzriakova commented on Region: ISCA-37415-Gain
Intellectual disability v3.1520 ISCA-37411-Loss Arina Puzriakova commented on Region: ISCA-37411-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37411-Loss Arina Puzriakova commented on Region: ISCA-37411-Loss
Renal ciliopathies v1.60 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Rare multisystem ciliopathy disorders v1.159 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Intellectual disability v3.1520 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Unexplained young onset end-stage renal disease v1.33 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Unexplained kidney failure in young people v1.105 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Cystic kidney disease v2.36 ISCA-37405-Loss Arina Puzriakova commented on Region: ISCA-37405-Loss
Severe early-onset obesity v2.49 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Paediatric motor neuronopathies v1.77 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Neurodegenerative disorders, adult onset v2.268 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval.
Intellectual disability v3.1520 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Hereditary ataxia, adult onset v2.148 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Hereditary ataxia v1.299 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Congenital hypothyroidism v2.10 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37404-Loss Arina Puzriakova commented on Region: ISCA-37404-Loss
Intellectual disability v3.1520 ISCA-37404-Gain Arina Puzriakova commented on Region: ISCA-37404-Gain
Intellectual disability v3.1520 ISCA-37400-Loss Arina Puzriakova commented on Region: ISCA-37400-Loss
Intellectual disability v3.1520 ISCA-37400-Gain Arina Puzriakova commented on Region: ISCA-37400-Gain
Intellectual disability v3.1520 ISCA-37397-Loss Arina Puzriakova commented on Region: ISCA-37397-Loss
Intellectual disability v3.1520 ISCA-37397-Gain Arina Puzriakova commented on Region: ISCA-37397-Gain
IUGR and IGF abnormalities v1.51 ISCA-37397-Loss Arina Puzriakova commented on Region: ISCA-37397-Loss
Intellectual disability v3.1520 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Paediatric motor neuronopathies v1.77 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Severe microcephaly v2.294 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Congenital myopathy v2.80 ISCA-37408-Loss Ivone Leong commented on Region: ISCA-37408-Loss
Intellectual disability v3.1520 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
Skeletal dysplasia v2.190 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
Severe microcephaly v2.294 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
IUGR and IGF abnormalities v1.51 ISCA-37406-Loss Ivone Leong commented on Region: ISCA-37406-Loss
Intellectual disability v3.1520 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Unexplained young onset end-stage renal disease v1.33 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Differences in sex development v2.59 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss: The required percent of overlap for this region has been changed from 80% to 60% following NHS Genomic Medicine Service approval.
Unexplained kidney failure in young people v1.105 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Sporadic aniridia v2.15 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Childhood solid tumours v2.27 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Adult solid tumours for rare disease v1.27 ISCA-37401-Loss Ivone Leong commented on Region: ISCA-37401-Loss
Intellectual disability v3.1520 ISCA-37396-Loss Ivone Leong commented on Region: ISCA-37396-Loss
Ocular coloboma v1.45 ISCA-37396-Loss Ivone Leong commented on Region: ISCA-37396-Loss
Deafness and congenital structural abnormalities v1.19 ISCA-37396-Loss Ivone Leong commented on Region: ISCA-37396-Loss
Structural eye disease v1.117 ISCA-37396-Loss Ivone Leong commented on Region: ISCA-37396-Loss
Early onset or syndromic epilepsy v2.500 ISCA-46295-Loss Ivone Leong commented on Region: ISCA-46295-Loss
Intellectual disability v3.1520 ISCA-46295-Loss Ivone Leong commented on Region: ISCA-46295-Loss
Intellectual disability v3.1520 ISCA-46290-Gain Ivone Leong commented on Region: ISCA-46290-Gain
Early onset or syndromic epilepsy v2.500 ISCA-46290-Gain Ivone Leong commented on Region: ISCA-46290-Gain
Intellectual disability v3.1520 ISCA-37500-Loss Ivone Leong commented on Region: ISCA-37500-Loss
Intellectual disability v3.1520 ISCA-37486-Loss Ivone Leong commented on Region: ISCA-37486-Loss
Severe early-onset obesity v2.49 ISCA-37486-Loss Ivone Leong commented on Region: ISCA-37486-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval.
Severe early-onset obesity v2.49 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval.
Neurodegenerative disorders, adult onset v2.268 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Paediatric motor neuronopathies v1.77 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Hereditary ataxia v1.299 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Intellectual disability v3.1520 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Congenital hypothyroidism v2.10 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss: The required percent of overlap for this region has been changed from 80% to 60% and the genomic location has been updated inline with ClinGen following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.148 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Early onset or syndromic epilepsy v2.500 ISCA-37478-Loss Ivone Leong commented on Region: ISCA-37478-Loss
Limb disorders v2.75 ISCA-37394-Loss Ivone Leong commented on Region: ISCA-37394-Loss
Skeletal dysplasia v2.190 ISCA-37394-Loss Ivone Leong commented on Region: ISCA-37394-Loss
Intellectual disability v3.1520 ISCA-37394-Loss Ivone Leong commented on Region: ISCA-37394-Loss
Clefting v2.66 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Deafness and congenital structural abnormalities v1.19 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Familial non syndromic congenital heart disease v1.74 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Intellectual disability v3.1520 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Ocular coloboma v1.45 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Structural eye disease v1.117 ISCA-37393-Gain Ivone Leong commented on Region: ISCA-37393-Gain
Intellectual disability v3.1520 ISCA-37390-Loss Ivone Leong commented on Region: ISCA-37390-Loss
Severe microcephaly v2.294 ISCA-37390-Loss Ivone Leong commented on Region: ISCA-37390-Loss
IUGR and IGF abnormalities v1.51 ISCA-37392-Loss Arina Puzriakova commented on Region: ISCA-37392-Loss
Intellectual disability v3.1520 ISCA-37392-Loss Arina Puzriakova commented on Region: ISCA-37392-Loss
Familial non syndromic congenital heart disease v1.74 ISCA-37392-Loss Arina Puzriakova commented on Region: ISCA-37392-Loss
Intellectual disability v3.1520 ISCA-37392-Gain Arina Puzriakova commented on Region: ISCA-37392-Gain
Limb disorders v2.75 ISCA-37394-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37394-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37494-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37494-Loss was changed from None to .
Required Overlap Percentage for ISCA-37494-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37494-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-37494-Gain was changed from None to .
Required Overlap Percentage for ISCA-37494-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37439-Gain Arina Puzriakova GRCh38 position for ISCA-37439-Gain was changed from 154336276-154660745 to 154396223-154555683.
Required Overlap Percentage for ISCA-37439-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37468-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46290-Gain Arina Puzriakova GRCh38 position for ISCA-46290-Gain was changed from 48447780-52444265 to 48447780-52444264.
Required Overlap Percentage for ISCA-46290-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46299-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-46299-Gain was changed from None to .
Required Overlap Percentage for ISCA-46299-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37423-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37423-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37423-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37392-Loss Arina Puzriakova GRCh38 position for ISCA-37392-Loss was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37392-Gain Arina Puzriakova GRCh38 position for ISCA-37392-Gain was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37425-Loss Arina Puzriakova GRCh38 position for ISCA-37425-Loss was changed from 176301975-177586960 to 176301976-177620792.
Required Overlap Percentage for ISCA-37425-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37425-Gain Arina Puzriakova GRCh38 position for ISCA-37425-Gain was changed from 176301975-177586960 to 176301976-177620792.
Required Overlap Percentage for ISCA-37425-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37390-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37390-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37429-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37443-Loss Arina Puzriakova GRCh38 position for ISCA-37443-Loss was changed from 196029183-197617794 to 196029183-197617791.
Required Overlap Percentage for ISCA-37443-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37394-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37394-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37440-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37440-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37408-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37397-Loss Arina Puzriakova GRCh38 position for ISCA-37397-Loss was changed from 21443089-23306926 to 21562828-23306924.
Required Overlap Percentage for ISCA-37397-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37397-Gain Arina Puzriakova GRCh38 position for ISCA-37397-Gain was changed from 21443089-23306926 to 21562828-23306924.
Required Overlap Percentage for ISCA-37397-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37446-Gain Arina Puzriakova GRCh38 position for ISCA-37446-Gain was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37433-Gain Arina Puzriakova GRCh38 position for ISCA-37433-Gain was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37493-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37493-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37421-Loss Arina Puzriakova GRCh38 position for ISCA-37421-Loss was changed from 147105904-147922392 to 147105904-147917509.
Required Overlap Percentage for ISCA-37421-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37421-Gain Arina Puzriakova GRCh38 position for ISCA-37421-Gain was changed from 147105904-147922392 to 147105904-147917509.
Required Overlap Percentage for ISCA-37421-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37434-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37432-Gain Arina Puzriakova GRCh38 position for ISCA-37432-Gain was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37431-Gain Arina Puzriakova GRCh38 position for ISCA-37431-Gain was changed from 30835804-31891648 to 30780079-31937008.
Triplosensitivity Score for ISCA-37431-Gain was changed from 3 to 2.
Required Overlap Percentage for ISCA-37431-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37430-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37430-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37430-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37430-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37418-Loss Arina Puzriakova GRCh38 position for ISCA-37418-Loss was changed from 16853797-20316338 to 16906714-20309889.
Required Overlap Percentage for ISCA-37418-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37418-Gain Arina Puzriakova GRCh38 position for ISCA-37418-Gain was changed from 16853797-20316338 to 16906714-20309889.
Required Overlap Percentage for ISCA-37418-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37406-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37415-Loss Arina Puzriakova GRCh38 position for ISCA-37415-Loss was changed from 15410597-16198411 to 15417854-16198408.
Required Overlap Percentage for ISCA-37415-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37415-Gain Arina Puzriakova GRCh38 position for ISCA-37415-Gain was changed from 15410597-16198411 to 15417854-16198408.
Required Overlap Percentage for ISCA-37415-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37400-Loss Arina Puzriakova GRCh38 position for ISCA-37400-Loss was changed from 29638675-30188534 to 29638676-30188531.
Required Overlap Percentage for ISCA-37400-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37400-Gain Arina Puzriakova GRCh38 position for ISCA-37400-Gain was changed from 29638675-30188534 to 29638676-30188531.
Required Overlap Percentage for ISCA-37400-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37486-Loss Arina Puzriakova GRCh38 position for ISCA-37486-Loss was changed from 28811313-29035181 to 28811314-29035178.
Required Overlap Percentage for ISCA-37486-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37500-Loss Arina Puzriakova GRCh38 position for ISCA-37500-Loss was changed from 82534141-84045981 to 82534140-84045981.
Required Overlap Percentage for ISCA-37500-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37396-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37396-Loss was changed from None to .
Required Overlap Percentage for ISCA-37396-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-46295-Loss Arina Puzriakova GRCh38 position for ISCA-46295-Loss was changed from 31727418-32153205 to 31727418-32153204.
Required Overlap Percentage for ISCA-46295-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37411-Loss Arina Puzriakova GRCh38 position for ISCA-37411-Loss was changed from 30844901-32153207 to 30900686-32153204.
Required Overlap Percentage for ISCA-37411-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37404-Gain Arina Puzriakova GRCh38 position for ISCA-37404-Gain was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Gain was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37441-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37441-Loss was changed from 80 to 60.
Intellectual disability v3.1520 ISCA-37424-Loss Arina Puzriakova GRCh38 position for ISCA-37424-Loss was changed from 79923892-86983483 to 79923087-86979631.
Required Overlap Percentage for ISCA-37424-Loss was changed from 80 to 60.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.116 ISCA-37425-Loss Arina Puzriakova GRCh38 position for ISCA-37425-Loss was changed from 176301975-177586960 to 176301976-177620792.
Triplosensitivity Score for ISCA-37425-Loss was changed from to None.
Required Overlap Percentage for ISCA-37425-Loss was changed from 80 to 60.
Unexplained young onset end-stage renal disease v1.33 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Unexplained young onset end-stage renal disease v1.33 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Unexplained young onset end-stage renal disease v1.33 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Unexplained kidney failure in young people v1.105 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Unexplained kidney failure in young people v1.105 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Unexplained kidney failure in young people v1.105 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Undiagnosed metabolic disorders v1.514 ISCA-37440-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37440-Loss was changed from 80 to 60.
Extreme early-onset hypertension v1.14 TTC21B John Sayer edited their review of gene: TTC21B: Added comment: Careful literature review supports the notion that biallelic, often hypomorph, missense variants in TTC21B are commonly associated with early-onset hypertension and histological features of both FSGS and NPHP. Increased clinical recognition of this mixed glomerular and tubulointerstitial disease with often mild or absent features of a typical ciliopathy as well as inclusion of TTC21B on gene panels for early-onset arterial hypertension might shorten the diagnostic odyssey for patients affected by this rare tubuloglomerular kidney disease.; Changed publications to: 24876116, 26940125, 34957165, 34805047, PMID: 35289079
Childhood solid tumours v2.26 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Structural eye disease v1.116 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Structural eye disease v1.116 ISCA-37396-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37396-Loss was changed from None to .
Required Overlap Percentage for ISCA-37396-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37394-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37394-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37434-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37418-Loss Arina Puzriakova GRCh38 position for ISCA-37418-Loss was changed from 16853797-20316338 to 16906714-20309889.
Required Overlap Percentage for ISCA-37418-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37406-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Skeletal dysplasia v2.190 ISCA-37441-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37441-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37425-Gain Arina Puzriakova GRCh38 position for ISCA-37425-Gain was changed from 176301975-177586960 to 176301976-177620792.
Haploinsufficiency Score for ISCA-37425-Gain was changed from None to .
Required Overlap Percentage for ISCA-37425-Gain was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37390-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37390-Loss was changed from None to .
Required Overlap Percentage for ISCA-37390-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37408-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37408-Loss was changed from None to .
Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Severe microcephaly v2.294 ISCA-37406-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37406-Loss was changed from None to .
Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Severe early-onset obesity v2.49 ISCA-37486-Loss Arina Puzriakova GRCh38 position for ISCA-37486-Loss was changed from 28811313-29035181 to 28811314-29035178.
Triplosensitivity Score for ISCA-37486-Loss was changed from None to .
Required Overlap Percentage for ISCA-37486-Loss was changed from 80 to 60.
Severe early-onset obesity v2.49 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Triplosensitivity Score for ISCA-37478-Loss was changed from None to .
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Severe early-onset obesity v2.49 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Triplosensitivity Score for ISCA-37404-Loss was changed from None to .
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Renal ciliopathies v1.60 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Renal ciliopathies v1.60 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
RASopathies v1.78 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Rare multisystem ciliopathy disorders v1.159 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Rare multisystem ciliopathy disorders v1.159 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.537 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.537 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Pigmentary skin disorders v1.46 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Triplosensitivity Score for ISCA-37431-Loss was changed from None to .
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Paroxysmal central nervous system disorders v1.41 ISCA-37468-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Paediatric motor neuronopathies v1.77 ISCA-37429-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Paediatric motor neuronopathies v1.77 ISCA-37408-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Paediatric motor neuronopathies v1.77 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Paediatric motor neuronopathies v1.77 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Paediatric motor neuronopathies v1.77 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Ocular coloboma v1.45 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Ocular coloboma v1.45 ISCA-37396-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37396-Loss was changed from None to .
Required Overlap Percentage for ISCA-37396-Loss was changed from 80 to 60.
Neurofibromatosis Type 1 v1.27 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Neurodegenerative disorders, adult onset v2.268 ISCA-37468-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37468-Loss was changed from None to .
Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Neurodegenerative disorders, adult onset v2.268 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Neurodegenerative disorders, adult onset v2.268 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Neurodegenerative disorders, adult onset v2.268 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Neonatal cholestasis v1.24 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Monogenic diabetes v2.47 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Mitochondrial disorders v2.93 ISCA-37440-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37440-Loss was changed from 80 to 60.
Likely inborn error of metabolism v2.230 ISCA-37440-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37440-Loss was changed from 80 to 60.
Malformations of cortical development v2.137 ISCA-37430-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37430-Loss was changed from 80 to 60.
IUGR and IGF abnormalities v1.51 ISCA-37392-Loss Arina Puzriakova GRCh38 position for ISCA-37392-Loss was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Loss was changed from 80 to 60.
IUGR and IGF abnormalities v1.51 ISCA-37429-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
IUGR and IGF abnormalities v1.51 ISCA-37397-Loss Arina Puzriakova GRCh38 position for ISCA-37397-Loss was changed from 21443089-23306926 to 21562828-23306924.
Required Overlap Percentage for ISCA-37397-Loss was changed from 80 to 60.
IUGR and IGF abnormalities v1.51 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
IUGR and IGF abnormalities v1.51 ISCA-37406-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37406-Loss was changed from 80 to 60.
Ichthyosis and erythrokeratoderma v1.72 ISCA-37417-Loss Arina Puzriakova GRCh38 position for ISCA-37417-Loss was changed from 6537771-8156914 to 6537771-8156913.
Required Overlap Percentage for ISCA-37417-Loss was changed from 80 to 60.
Hereditary neuropathy v1.442 ISCA-37436-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37436-Loss was changed from 80 to 60.
Hereditary neuropathy v1.442 ISCA-37436-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37436-Gain was changed from 80 to 60.
Hereditary ataxia v1.299 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Hereditary ataxia v1.299 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Hereditary ataxia v1.299 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Hereditary ataxia, adult onset v2.148 ISCA-37468-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37468-Loss was changed from None to .
Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Hereditary ataxia, adult onset v2.148 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Triplosensitivity Score for ISCA-37478-Loss was changed from None to .
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Hereditary ataxia, adult onset v2.148 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Hereditary ataxia, adult onset v2.148 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-46290-Gain Arina Puzriakova GRCh38 position for ISCA-46290-Gain was changed from 48447780-52444265 to 48447780-52444264.
Haploinsufficiency Score for ISCA-46290-Gain was changed from None to .
Required Overlap Percentage for ISCA-46290-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37423-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-37423-Gain was changed from None to .
Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37429-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37429-Loss was changed from None to .
Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37493-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37493-Loss was changed from None to .
Required Overlap Percentage for ISCA-37493-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37434-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37434-Loss was changed from None to .
Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37432-Gain Arina Puzriakova GRCh38 position for ISCA-37432-Gain was changed from 36458167-37854617 to 36458167-37854616.
Haploinsufficiency Score for ISCA-37432-Gain was changed from None to .
Required Overlap Percentage for ISCA-37432-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37430-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37430-Loss was changed from None to .
Required Overlap Percentage for ISCA-37430-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37415-Loss Arina Puzriakova GRCh38 position for ISCA-37415-Loss was changed from 15410597-16198411 to 15417854-16198408.
Triplosensitivity Score for ISCA-37415-Loss was changed from None to .
Required Overlap Percentage for ISCA-37415-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-46295-Loss Arina Puzriakova GRCh38 position for ISCA-46295-Loss was changed from 31727418-32153205 to 31727418-32153204.
Triplosensitivity Score for ISCA-46295-Loss was changed from None to .
Required Overlap Percentage for ISCA-46295-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37411-Loss Arina Puzriakova GRCh38 position for ISCA-37411-Loss was changed from 30844901-32153207 to 30900686-32153204.
Triplosensitivity Score for ISCA-37411-Loss was changed from None to .
Required Overlap Percentage for ISCA-37411-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Triplosensitivity Score for ISCA-37478-Loss was changed from None to .
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Haploinsufficiency Score for ISCA-37478-Gain was changed from None to .
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Early onset or syndromic epilepsy v2.500 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Triplosensitivity Score for ISCA-37404-Loss was changed from None to .
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Familial Tumours Syndromes of the central & peripheral Nervous system v1.12 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37423-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37423-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37392-Loss Arina Puzriakova GRCh38 position for ISCA-37392-Loss was changed from 73330451-74728175 to 73330452-74728172.
Required Overlap Percentage for ISCA-37392-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37434-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37434-Loss was changed from 80 to 60.
Familial non syndromic congenital heart disease v1.74 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Familial diabetes v1.66 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Differences in sex development v2.59 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.66 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Neonatal diabetes v2.38 ISCA-37442-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37442-Gain was changed from 80 to 60.
Deafness and congenital structural abnormalities v1.19 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Deafness and congenital structural abnormalities v1.19 ISCA-37501-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37501-Loss was changed from None to .
Required Overlap Percentage for ISCA-37501-Loss was changed from 80 to 60.
Deafness and congenital structural abnormalities v1.19 ISCA-37396-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37396-Loss was changed from None to .
Required Overlap Percentage for ISCA-37396-Loss was changed from 80 to 60.
Cystic kidney disease v2.36 ISCA-37405-Loss Arina Puzriakova GRCh38 position for ISCA-37405-Loss was changed from 110122329-110205017 to 110104531-110228181.
Haploinsufficiency Score for ISCA-37405-Loss was changed from 3 to 30.
Required Overlap Percentage for ISCA-37405-Loss was changed from 80 to 60.
Cystic kidney disease v2.36 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.67 ISCA-37441-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37441-Loss was changed from 80 to 60.
COVID-19 research v1.116 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
COVID-19 research v1.116 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Congenital myopathy v2.80 ISCA-37429-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37429-Loss was changed from 80 to 60.
Congenital myopathy v2.80 ISCA-37408-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37408-Loss was changed from 80 to 60.
Congenital myopathy v2.80 ISCA-37420-Loss Arina Puzriakova GRCh38 position for ISCA-37420-Loss was changed from 45608879-46087510 to 45627800-46087514.
Required Overlap Percentage for ISCA-37420-Loss was changed from 80 to 60.
Congenital hypothyroidism v2.10 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Congenital hypothyroidism v2.10 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Clefting v2.66 ISCA-37423-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37423-Gain was changed from 80 to 60.
Clefting v2.66 ISCA-37467-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37467-Gain was changed from 80 to 60.
Clefting v2.66 ISCA-37393-Gain Arina Puzriakova Required Overlap Percentage for ISCA-37393-Gain was changed from 80 to 60.
Clefting v2.66 ISCA-37446-Loss Arina Puzriakova GRCh38 position for ISCA-37446-Loss was changed from 18924718-21111384 to 18924718-21111383.
Required Overlap Percentage for ISCA-37446-Loss was changed from 80 to 60.
Clefting v2.66 ISCA-37433-Loss Arina Puzriakova GRCh38 position for ISCA-37433-Loss was changed from 18924718-20299686 to 18924718-20299685.
Required Overlap Percentage for ISCA-37433-Loss was changed from 80 to 60.
Paediatric or syndromic cardiomyopathy v1.68 ISCA-37431-Loss Arina Puzriakova GRCh38 position for ISCA-37431-Loss was changed from 30835804-31891648 to 30780079-31937008.
Required Overlap Percentage for ISCA-37431-Loss was changed from 80 to 60.
CAKUT v1.167 ISCA-37432-Loss Arina Puzriakova GRCh38 position for ISCA-37432-Loss was changed from 36458167-37854617 to 36458167-37854616.
Required Overlap Percentage for ISCA-37432-Loss was changed from 80 to 60.
Brain channelopathy v1.78 ISCA-37468-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37468-Loss was changed from None to .
Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Autosomal recessive congenital ichthyosis v1.14 ISCA-37417-Loss Arina Puzriakova GRCh38 position for ISCA-37417-Loss was changed from 6537771-8156914 to 6537771-8156913.
Required Overlap Percentage for ISCA-37417-Loss was changed from 80 to 60.
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37478-Loss Arina Puzriakova GRCh38 position for ISCA-37478-Loss was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Loss was changed from 80 to 60.
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37478-Gain Arina Puzriakova GRCh38 position for ISCA-37478-Gain was changed from 23513243-28312040 to 23465365-28134728.
Required Overlap Percentage for ISCA-37478-Gain was changed from 80 to 60.
Ataxia and cerebellar anomalies - childhood onset v2.289 ISCA-37404-Loss Arina Puzriakova GRCh38 position for ISCA-37404-Loss was changed from 22782170-28134729 to 22782170-28134728.
Required Overlap Percentage for ISCA-37404-Loss was changed from 80 to 60.
Sporadic aniridia v2.15 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Adult solid tumours for rare disease v1.27 ISCA-37401-Loss Arina Puzriakova Required Overlap Percentage for ISCA-37401-Loss was changed from 80 to 60.
Dystonia, chorea or related movement disorder, adult onset v1.167 ISCA-37468-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37468-Loss was changed from None to .
Required Overlap Percentage for ISCA-37468-Loss was changed from 80 to 60.
Severe microcephaly v2.293 DPP6 Eleanor Williams Tag to_be_confirmed_NHSE tag was added to gene: DPP6.
Monogenic hearing loss v2.237 COL9A3 Eleanor Williams Tag for-review was removed from gene: COL9A3.
Congenital myopathy v2.79 GFER Sarah Leigh changed review comment from: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.; to: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Leukodystrophy, adult onset v1.40 RNASET2 Sarah Leigh commented on gene: RNASET2
Leukodystrophy, adult onset v1.40 RNASET2 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: RNASET2.
Leukodystrophy, adult onset v1.40 POLR1C Sarah Leigh commented on gene: POLR1C
Leukodystrophy, adult onset v1.40 POLR1C Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: POLR1C.
Leukodystrophy, adult onset v1.40 MARS Sarah Leigh commented on gene: MARS
Leukodystrophy, adult onset v1.40 MARS Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: MARS.
Leukodystrophy, adult onset v1.40 COL4A2 Sarah Leigh commented on gene: COL4A2
Leukodystrophy, adult onset v1.40 COL4A2 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: COL4A2.
Leukodystrophy, adult onset v1.40 AARS Sarah Leigh commented on gene: AARS
Leukodystrophy, adult onset v1.40 AARS Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AARS.
Intellectual disability v3.1519 FAR1 Sarah Leigh reviewed gene: FAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25439727, 30561787; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1519 FAR1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: FAR1.
Hydrocephalus v2.127 MYMK Sarah Leigh reviewed gene: MYMK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.127 MYMK Sarah Leigh Deleted their review
Hydrocephalus v2.127 MYMK Sarah Leigh commented on gene: MYMK: As the recommendation is to demote MYMK from Green to Amber on this panel, the to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Hydrocephalus v2.127 MYMK Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: MYMK.
Hydrocephalus v2.127 HYLS1 Sarah Leigh reviewed gene: HYLS1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.127 HYLS1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: HYLS1.
Hydrocephalus v2.127 ERF Sarah Leigh reviewed gene: ERF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.127 ERF Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: ERF.
Holoprosencephaly v2.27 DISP1 Sarah Leigh commented on gene: DISP1: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Holoprosencephaly v2.27 DISP1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: DISP1.
Dystonia, chorea or related movement disorder, childhood onset v1.217 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Dystonia, chorea or related movement disorder, childhood onset v1.217 AFG3L2 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AFG3L2.
Dystonia, chorea or related movement disorder, adult onset v1.166 GBA Sarah Leigh reviewed gene: GBA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Dystonia, chorea or related movement disorder, adult onset v1.166 GBA Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: GBA.
Early onset or syndromic epilepsy v2.499 EEF1A2 Sarah Leigh Mode of pathogenicity for gene: EEF1A2 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
Dystonia, chorea or related movement disorder, adult onset v1.166 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary ataxia, adult onset v2.147 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Neurodegenerative disorders, adult onset v2.267 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary spastic paraplegia, adult onset v1.95 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary spastic paraplegia, childhood onset v2.130 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary spastic paraplegia v1.289 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Structural basal ganglia disorders v1.30 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Hereditary ataxia v1.298 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Brain channelopathy v1.77 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Parkinson Disease and Complex Parkinsonism v1.105 HTT_CAG Arina Puzriakova commented on STR: HTT_CAG
Dystonia, chorea or related movement disorder, childhood onset v1.217 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Dystonia, chorea or related movement disorder, adult onset v1.166 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Hereditary ataxia, adult onset v2.147 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Neurodegenerative disorders, adult onset v2.267 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary spastic paraplegia, adult onset v1.95 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Hereditary spastic paraplegia, childhood onset v2.130 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Hereditary spastic paraplegia v1.289 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Paroxysmal central nervous system disorders v1.40 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Hereditary ataxia v1.298 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Brain channelopathy v1.77 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Parkinson Disease and Complex Parkinsonism v1.105 TBP_CAG Arina Puzriakova commented on STR: TBP_CAG
Hereditary spastic paraplegia, adult onset v1.95 AP4B1 Sarah Leigh commented on gene: AP4B1
Hereditary spastic paraplegia, adult onset v1.95 AP4S1 Sarah Leigh commented on gene: AP4S1
Hereditary spastic paraplegia, adult onset v1.95 AP4E1 Sarah Leigh commented on gene: AP4E1
Hereditary spastic paraplegia, adult onset v1.95 AP4M1 Sarah Leigh commented on gene: AP4M1
Hereditary spastic paraplegia, adult onset v1.95 AP4E1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AP4E1.
Hereditary spastic paraplegia, adult onset v1.95 AP4B1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AP4B1.
Hereditary spastic paraplegia, adult onset v1.95 AP4S1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AP4S1.
Hereditary spastic paraplegia, adult onset v1.95 AP4M1 Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: AP4M1.
Hereditary neuropathy or pain disorder v1.88 SLC12A6 Sarah Leigh commented on gene: SLC12A6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Hereditary neuropathy or pain disorder v1.88 SPTBN4 Sarah Leigh commented on gene: SPTBN4
Hereditary neuropathy or pain disorder v1.88 NEMF Sarah Leigh commented on gene: NEMF
Dystonia, chorea or related movement disorder, adult onset v1.166 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Early onset or syndromic epilepsy v2.498 CPA6 Sarah Leigh commented on gene: CPA6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Hereditary ataxia, adult onset v2.147 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Intellectual disability v3.1519 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Hereditary neuropathy v1.441 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Neurodegenerative disorders, adult onset v2.267 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary spastic paraplegia, adult onset v1.95 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Hereditary spastic paraplegia, childhood onset v2.130 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Hereditary spastic paraplegia v1.289 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Early onset or syndromic epilepsy v2.498 SCN8A Sarah Leigh commented on gene: SCN8A: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Hereditary ataxia v1.298 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Parkinson Disease and Complex Parkinsonism v1.105 PPP2R2B_CAG Arina Puzriakova commented on STR: PPP2R2B_CAG
Possible mitochondrial disorder, nuclear genes v1.69 HPDL Sarah Leigh commented on gene: HPDL: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Mitochondrial disorders v2.92 HPDL Sarah Leigh commented on gene: HPDL: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Rhabdomyolysis and metabolic muscle disorders v1.78 ISCU Sarah Leigh commented on gene: ISCU: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Neurodegenerative disorders, adult onset v2.267 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Hereditary neuropathy v1.441 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG
Hereditary ataxia, adult onset v2.147 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG
Hereditary ataxia v1.298 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG
Ataxia and cerebellar anomalies - childhood onset v2.288 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Amyotrophic lateral sclerosis/motor neuron disease v1.56 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG
Early onset or syndromic epilepsy v2.498 SLC5A6 Sarah Leigh commented on gene: SLC5A6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Rhabdomyolysis and metabolic muscle disorders v1.78 ISCU Sarah Leigh Tag to_be_confirmed_NHSE tag was added to gene: ISCU.
Lysosomal storage disorder v1.78 ARSG Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least five variants reported in at least four unrelated cases, together with supportive functional and animal models.; to: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least five variants reported in at least four unrelated cases, together with supportive functional studies and animal models.
Dystonia, chorea or related movement disorder, adult onset v1.166 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG
Neurodegenerative disorders, adult onset v2.267 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG
Early onset dystonia v1.111 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG
Parkinson Disease and Complex Parkinsonism v1.105 JPH3_CTG Sarah Leigh commented on STR: JPH3_CTG
Skeletal muscle channelopathy v1.39 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Hereditary ataxia, adult onset v2.147 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Mitochondrial disorders v2.92 FXN_GAA Sarah Leigh commented on STR: FXN_GAA: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Intellectual disability v3.1519 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hereditary neuropathy v1.441 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Paroxysmal central nervous system disorders v1.40 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Likely inborn error of metabolism v2.229 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Neurodegenerative disorders, adult onset v2.267 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hereditary spastic paraplegia, adult onset v1.95 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hereditary spastic paraplegia, childhood onset v2.130 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hereditary spastic paraplegia v1.289 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hypertrophic cardiomyopathy v2.38 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Hereditary ataxia v1.298 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Ataxia and cerebellar anomalies - childhood onset v2.288 FXN_GAA Sarah Leigh commented on STR: FXN_GAA
Skeletal Muscle Channelopathies v1.45 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Mitochondrial disorders v2.92 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Paediatric motor neuronopathies v1.76 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Intellectual disability v3.1519 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Gastrointestinal neuromuscular disorders v1.21 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Fetal hydrops v1.50 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Fetal anomalies v1.842 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Dystonia, chorea or related movement disorder, childhood onset v1.217 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Dystonia, chorea or related movement disorder, adult onset v1.166 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Hereditary ataxia, adult onset v2.147 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Intellectual disability v3.1519 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Early onset or syndromic epilepsy v2.498 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Neurodegenerative disorders, adult onset v2.267 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Paroxysmal central nervous system disorders v1.40 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Hereditary ataxia v1.298 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Ataxia and cerebellar anomalies - childhood onset v2.288 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG: STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Brain channelopathy v1.77 CSTB_CCCCGCCCCGCG Sarah Leigh commented on STR: CSTB_CCCCGCCCCGCG
Likely inborn error of metabolism v2.229 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
DDG2P v2.65 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Congenital myopathy v2.79 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Congenital muscular dystrophy v2.27 DMPK_CTG Eleanor Williams commented on STR: DMPK_CTG
Skeletal muscle channelopathy v1.39 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG
Skeletal Muscle Channelopathies v1.45 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG
Fetal anomalies v1.842 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG
Hereditary ataxia, adult onset v2.147 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Intellectual disability v3.1519 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Hereditary neuropathy v1.441 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Distal myopathies v1.45 CNBP_CCTG Eleanor Williams commented on STR: CNBP_CCTG
Hereditary ataxia v1.298 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Primary ovarian insufficiency v1.67 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG
Paroxysmal central nervous system disorders v1.40 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Neurodegenerative disorders, adult onset v2.267 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Hereditary spastic paraplegia, childhood onset v2.130 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Hereditary spastic paraplegia, adult onset v1.95 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Hereditary spastic paraplegia v1.289 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Hereditary ataxia, adult onset v2.147 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Hereditary ataxia v1.298 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Brain channelopathy v1.77 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Dystonia, chorea or related movement disorder, adult onset v1.166 CACNA1A_CAG Eleanor Williams commented on STR: CACNA1A_CAG
Neurodegenerative disorders, adult onset v2.267 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Parkinson Disease and Complex Parkinsonism v1.105 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Intellectual disability v3.1519 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Dystonia, chorea or related movement disorder, childhood onset v1.217 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Amyotrophic lateral sclerosis/motor neuron disease v1.56 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Dystonia, chorea or related movement disorder, adult onset v1.166 C9orf72_GGGGCC Eleanor Williams commented on STR: C9orf72_GGGGCC
Neurodegenerative disorders, adult onset v2.267 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Undiagnosed metabolic disorders v1.513 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Intellectual disability v3.1519 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary spastic paraplegia, childhood onset v2.130 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary spastic paraplegia, adult onset v1.95 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary spastic paraplegia v1.289 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary neuropathy v1.441 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary ataxia, adult onset v2.147 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Hereditary ataxia v1.298 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 ATXN7_CAG Eleanor Williams commented on STR: ATXN7_CAG
Neurodegenerative disorders, adult onset v2.267 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Parkinson Disease and Complex Parkinsonism v1.105 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Intellectual disability v3.1519 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary spastic paraplegia, childhood onset v2.130 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary spastic paraplegia, adult onset v1.95 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary spastic paraplegia v1.289 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary neuropathy v1.441 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary ataxia v1.298 ATXN3 Eleanor Williams Deleted their review
Hereditary ataxia v1.298 ATXN3 Eleanor Williams Deleted their comment
Hereditary ataxia v1.298 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary ataxia, adult onset v2.147 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Hereditary ataxia, adult onset v2.147 ATXN3 Eleanor Williams Deleted their review
Hereditary ataxia, adult onset v2.147 ATXN3 Eleanor Williams Deleted their comment
Hereditary ataxia, adult onset v2.147 ATXN3 Eleanor Williams commented on gene: ATXN3
Hereditary ataxia v1.298 ATXN3 Eleanor Williams commented on gene: ATXN3
Early onset dystonia v1.111 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Dystonia, chorea or related movement disorder, adult onset v1.166 ATXN3_CAG Eleanor Williams commented on STR: ATXN3_CAG
Parkinson Disease and Complex Parkinsonism v1.105 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Neurodegenerative disorders, adult onset v2.267 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Intellectual disability v3.1519 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary spastic paraplegia, childhood onset v2.130 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary spastic paraplegia, adult onset v1.95 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary spastic paraplegia v1.289 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary neuropathy v1.441 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary ataxia, adult onset v2.147 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Hereditary ataxia v1.298 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Early onset dystonia v1.111 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Dystonia, chorea or related movement disorder, childhood onset v1.217 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Amyotrophic lateral sclerosis/motor neuron disease v1.56 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Dystonia, chorea or related movement disorder, adult onset v1.166 ATXN2_CAG Ivone Leong commented on STR: ATXN2_CAG
Thoracic dystrophies v1.18 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Skeletal dysplasia v2.189 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Neurodegenerative disorders, adult onset v2.267 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Intellectual disability v3.1519 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary spastic paraplegia, childhood onset v2.130 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary spastic paraplegia, adult onset v1.95 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary spastic paraplegia v1.289 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary neuropathy v1.441 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary ataxia, adult onset v2.147 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary ataxia v1.298 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Early onset dystonia v1.111 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Ataxia and cerebellar anomalies - childhood onset v2.288 ATXN10_ATTCT Ivone Leong commented on STR: ATXN10_ATTCT
Hereditary ataxia v1.298 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Dystonia, chorea or related movement disorder, adult onset v1.166 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Neurodegenerative disorders, adult onset v2.267 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Parkinson Disease and Complex Parkinsonism v1.105 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Intellectual disability v3.1519 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Hereditary spastic paraplegia, childhood onset v2.130 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Hereditary spastic paraplegia, adult onset v1.95 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Hereditary spastic paraplegia v1.289 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Hereditary neuropathy v1.441 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Hereditary ataxia, adult onset v2.147 ATXN1_CAG Ivone Leong commented on STR: ATXN1_CAG
Paroxysmal central nervous system disorders v1.40 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Neurodegenerative disorders, adult onset v2.267 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Parkinson Disease and Complex Parkinsonism v1.105 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Hereditary ataxia, adult onset v2.147 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Hereditary ataxia v1.298 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Early onset or syndromic epilepsy v2.498 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Brain channelopathy v1.77 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Ataxia and cerebellar anomalies - childhood onset v2.288 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Dystonia, chorea or related movement disorder, adult onset v1.166 ATN1_CAG Ivone Leong commented on STR: ATN1_CAG
Neurodegenerative disorders, adult onset v2.267 AR_CAG Ivone Leong commented on STR: AR_CAG
Paediatric motor neuronopathies v1.76 AR_CAG Ivone Leong commented on STR: AR_CAG
Hereditary neuropathy or pain disorder v1.88 AR_CAG Ivone Leong commented on STR: AR_CAG
Hereditary neuropathy v1.441 AR_CAG Ivone Leong commented on STR: AR_CAG
Distal myopathies v1.45 AR_CAG Ivone Leong commented on STR: AR_CAG
Congenital myopathy v2.79 AR_CAG Ivone Leong commented on STR: AR_CAG
Amyotrophic lateral sclerosis/motor neuron disease v1.56 AR_CAG Ivone Leong commented on STR: AR_CAG
Dilated Cardiomyopathy and conduction defects v1.77 LDB3 Ivone Leong Classified gene: LDB3 as Amber List (moderate evidence)
Dilated Cardiomyopathy and conduction defects v1.77 LDB3 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Amber. This gene is associated with a phenotype in OMIM and Gene2Phenotype (requires clinical review). However, based on the expert reviews there is not enough evidence to support a gene-disease association. Therefore this gene has been given an Amber rating.
Dilated Cardiomyopathy and conduction defects v1.77 LDB3 Ivone Leong Gene: ldb3 has been classified as Amber List (Moderate Evidence).
Dilated Cardiomyopathy and conduction defects v1.76 LDB3 Ivone Leong Added comment: Comment on publications: Added new publications
Dilated Cardiomyopathy and conduction defects v1.76 LDB3 Ivone Leong Publications for gene: LDB3 were set to
Segmental overgrowth disorders - Deep sequencing v2.16 PADI6 Catherine Snow Tag for-review was removed from gene: PADI6.
Segmental overgrowth disorders - Deep sequencing v2.16 SUZ12 Catherine Snow Tag for-review was removed from gene: SUZ12.
Segmental overgrowth disorders - Deep sequencing v2.16 SUZ12 Catherine Snow commented on gene: SUZ12
Segmental overgrowth disorders - Deep sequencing v2.16 PADI6 Catherine Snow commented on gene: PADI6
Segmental overgrowth disorders - Deep sequencing v2.15 SUZ12 Catherine Snow Source Expert Review Green was added to SUZ12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Segmental overgrowth disorders - Deep sequencing v2.15 PADI6 Catherine Snow Source Expert Review Green was added to PADI6.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Pigmentary skin disorders v1.45 ANAPC1 Catherine Snow Tag for-review was removed from gene: ANAPC1.
Pigmentary skin disorders v1.45 ANAPC1 Catherine Snow commented on gene: ANAPC1
Pigmentary skin disorders v1.44 ANAPC1 Catherine Snow Source Expert Review Green was added to ANAPC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Palmoplantar keratodermas v1.12 ST14 Catherine Snow Tag for-review was removed from gene: ST14.
Palmoplantar keratodermas v1.12 ST14 Catherine Snow commented on gene: ST14
Palmoplantar keratodermas v1.11 ST14 Catherine Snow Source Expert Review Red was added to ST14.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Cutaneous photosensitivity with a likely genetic cause v1.10 ANAPC1 Catherine Snow Tag for-review was removed from gene: ANAPC1.
Tag Q4_21_NHS_review was removed from gene: ANAPC1.
Cutaneous photosensitivity with a likely genetic cause v1.10 ANAPC1 Catherine Snow commented on gene: ANAPC1: Submitted on behalf of NHS GMS "Agree. There is an intronic variant which will be outside the targeted region of exomes which has been identified in multiple patients (c.2705-198C-T, NM_022662.3). This gene will also provide difficulties due to pseudogenes - coverage of uniquely mapping reads is ~50% (TWIST exome).""Green - mutations in ANAPC1 cause RTS type 1 (e.g. Ajeawung et al. AJHG 2019)"
Cutaneous photosensitivity with a likely genetic cause v1.10 ANAPC1 Catherine Snow commented on gene: ANAPC1
Cutaneous photosensitivity with a likely genetic cause v1.9 ANAPC1 Catherine Snow Source Expert Review Green was added to ANAPC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v1.37 C3orf52 Catherine Snow Tag for-review was removed from gene: C3orf52.
Ectodermal dysplasia v1.37 ANAPC1 Catherine Snow Tag for-review was removed from gene: ANAPC1.
Tag Q4_21_NHS_review was removed from gene: ANAPC1.
Ectodermal dysplasia v1.37 ST14 Catherine Snow Tag for-review was removed from gene: ST14.
Ectodermal dysplasia v1.37 ST14 Catherine Snow changed review comment from: The rating of this gene has been updated following NHS Genomic Medicine Service approval.Submitted on behalf of NHS GMS "I think we can keep ST14 green for ED because there is skin and hair involvement and some cases may well come as a hair phenotype query"; to: The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Submitted on behalf of NHS GMS."I think we can keep ST14 green for ED because there is skin and hair involvement and some cases may well come as a hair phenotype query"
Ectodermal dysplasia v1.37 PRKD1 Catherine Snow changed review comment from: The rating of this gene has been updated following NHS Genomic Medicine Service approval.Submitted on behalf of NHS GMS "Green - rare form of EB (telangietasia-ED-brachydactyly-cardia anomaly syndrome) (Alter et al. J Med Genet 2021)"; to: The rating of this gene has been updated following NHS Genomic Medicine Service approval.Submitted on behalf of NHS GMS.
"Green - rare form of EB (telangietasia-ED-brachydactyly-cardia anomaly syndrome) (Alter et al. J Med Genet 2021)"
Ectodermal dysplasia v1.37 PRKD1 Catherine Snow Tag for-review was removed from gene: PRKD1.
Ectodermal dysplasia v1.37 C3orf52 Catherine Snow commented on gene: C3orf52
Ectodermal dysplasia v1.37 ANAPC1 Catherine Snow commented on gene: ANAPC1
Ectodermal dysplasia v1.37 ST14 Catherine Snow commented on gene: ST14
Ectodermal dysplasia v1.37 PRKD1 Catherine Snow commented on gene: PRKD1
Ectodermal dysplasia v1.36 C3orf52 Catherine Snow Source Expert Review Green was added to C3orf52.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v1.36 ANAPC1 Catherine Snow Source Expert Review Green was added to ANAPC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v1.36 ST14 Catherine Snow Source Expert Review Green was added to ST14.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ectodermal dysplasia v1.36 PRKD1 Catherine Snow Source Expert Review Green was added to PRKD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CACNA1I Ivone Leong Tag Q4_21_rating was removed from gene: CACNA1I.
Intellectual disability v3.1519 ZNF699 Ivone Leong Tag Q4_21_rating was removed from gene: ZNF699.
Intellectual disability v3.1519 YIPF5 Ivone Leong Tag Q2_21_rating was removed from gene: YIPF5.
Intellectual disability v3.1519 WDR4 Ivone Leong Tag Q2_21_rating was removed from gene: WDR4.
Intellectual disability v3.1519 VPS41 Ivone Leong Tag Q2_21_rating was removed from gene: VPS41.
Intellectual disability v3.1519 VPS11 Ivone Leong Tag Q2_21_rating was removed from gene: VPS11.
Intellectual disability v3.1519 UFSP2 Ivone Leong Tag Q2_21_rating was removed from gene: UFSP2.
Tag Q2_21_expert_review was removed from gene: UFSP2.
Intellectual disability v3.1519 UBE4A Ivone Leong Tag Q2_21_rating was removed from gene: UBE4A.
Intellectual disability v3.1519 TP73 Ivone Leong Tag Q3_21_rating was removed from gene: TP73.
Intellectual disability v3.1519 TNPO2 Ivone Leong Tag Q3_21_rating was removed from gene: TNPO2.
Intellectual disability v3.1519 TMEM222 Ivone Leong Tag Q2_21_rating was removed from gene: TMEM222.
Intellectual disability v3.1519 TCF7L2 Ivone Leong Tag Q4_21_rating was removed from gene: TCF7L2.
Intellectual disability v3.1519 SYNCRIP Ivone Leong Tag Q3_21_rating was removed from gene: SYNCRIP.
Intellectual disability v3.1519 SPTBN1 Ivone Leong Tag Q3_21_rating was removed from gene: SPTBN1.
Intellectual disability v3.1519 SPEN Ivone Leong Tag Q2_21_rating was removed from gene: SPEN.
Intellectual disability v3.1519 SNIP1 Ivone Leong Tag Q4_21_expert_review was removed from gene: SNIP1.
Intellectual disability v3.1519 SMARCA5 Ivone Leong Tag Q2_21_rating was removed from gene: SMARCA5.
Tag Q2_21_NHS_review was removed from gene: SMARCA5.
Intellectual disability v3.1519 SIN3B Ivone Leong Tag Q2_21_rating was removed from gene: SIN3B.
Intellectual disability v3.1519 SIAH1 Ivone Leong Tag Q2_21_rating was removed from gene: SIAH1.
Intellectual disability v3.1519 SCYL1 Ivone Leong Tag Q2_21_rating was removed from gene: SCYL1.
Intellectual disability v3.1519 SATB1 Ivone Leong Tag Q2_21_rating was removed from gene: SATB1.
Intellectual disability v3.1519 RFX7 Ivone Leong Tag Q3_21_rating was removed from gene: RFX7.
Intellectual disability v3.1519 RFX4 Ivone Leong Tag Q3_21_rating was removed from gene: RFX4.
Intellectual disability v3.1519 RFX3 Ivone Leong Tag Q3_21_rating was removed from gene: RFX3.
Intellectual disability v3.1519 PTPN4 Ivone Leong Tag Q3_21_rating was removed from gene: PTPN4.
Intellectual disability v3.1519 PRICKLE2 Ivone Leong Tag Q4_21_rating was removed from gene: PRICKLE2.
Intellectual disability v3.1519 PIGC Ivone Leong Tag Q2_21_rating was removed from gene: PIGC.
Intellectual disability v3.1519 PIDD1 Ivone Leong Tag Q3_21_rating was removed from gene: PIDD1.
Intellectual disability v3.1519 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Intellectual disability v3.1519 PGM2L1 Ivone Leong Tag Q3_21_rating was removed from gene: PGM2L1.
Intellectual disability v3.1519 PCDHGC4 Ivone Leong Tag Q3_21_rating was removed from gene: PCDHGC4.
Intellectual disability v3.1519 OTUD5 Ivone Leong Tag Q2_21_rating was removed from gene: OTUD5.
Intellectual disability v3.1519 NEUROD2 Ivone Leong Tag Q2_21_rating was removed from gene: NEUROD2.
Intellectual disability v3.1519 NCKAP1 Ivone Leong Tag Q2_21_rating was removed from gene: NCKAP1.
Intellectual disability v3.1519 NCDN Ivone Leong Tag Q2_21_rating was removed from gene: NCDN.
Intellectual disability v3.1519 MINPP1 Ivone Leong Tag Q2_21_rating was removed from gene: MINPP1.
Intellectual disability v3.1519 MED27 Ivone Leong Tag Q2_21_rating was removed from gene: MED27.
Intellectual disability v3.1519 MAP1B Ivone Leong Tag Q3_21_rating was removed from gene: MAP1B.
Intellectual disability v3.1519 LINGO4 Ivone Leong Tag Q3_21_rating was removed from gene: LINGO4.
Intellectual disability v3.1519 KCND2 Ivone Leong Tag Q4_21_rating was removed from gene: KCND2.
Intellectual disability v3.1519 KDM3B Ivone Leong Tag Q2_21_rating was removed from gene: KDM3B.
Intellectual disability v3.1519 KCNN2 Ivone Leong Tag Q2_21_rating was removed from gene: KCNN2.
Intellectual disability v3.1519 IMPDH2 Ivone Leong Tag Q3_21_rating was removed from gene: IMPDH2.
Intellectual disability v3.1519 HPDL Ivone Leong Tag Q2_21_rating was removed from gene: HPDL.
Intellectual disability v3.1519 HNMT Ivone Leong Tag Q3_21_rating was removed from gene: HNMT.
Tag Q3_21_NHS_review was removed from gene: HNMT.
Intellectual disability v3.1519 HIST1H4C Ivone Leong Tag Q3_21_rating was removed from gene: HIST1H4C.
Intellectual disability v3.1519 HID1 Ivone Leong Tag Q3_21_rating was removed from gene: HID1.
Intellectual disability v3.1519 GTF2E2 Ivone Leong Tag Q3_21_rating was removed from gene: GTF2E2.
Intellectual disability v3.1519 GNB2 Ivone Leong Tag Q3_21_rating was removed from gene: GNB2.
Intellectual disability v3.1519 GEMIN5 Ivone Leong Tag Q2_21_rating was removed from gene: GEMIN5.
Intellectual disability v3.1519 GABRD Ivone Leong Tag Q4_21_rating was removed from gene: GABRD.
Intellectual disability v3.1519 FARSA Ivone Leong Tag Q4_21_rating was removed from gene: FARSA.
Intellectual disability v3.1519 FBXO31 Ivone Leong Tag Q2_21_rating was removed from gene: FBXO31.
Intellectual disability v3.1519 ERBB4 Ivone Leong Tag Q2_21_rating was removed from gene: ERBB4.
Tag Q2_21_NHS_review was removed from gene: ERBB4.
Intellectual disability v3.1519 EMC10 Ivone Leong Tag Q2_21_rating was removed from gene: EMC10.
Intellectual disability v3.1519 EIF5A Ivone Leong Tag Q2_21_rating was removed from gene: EIF5A.
Intellectual disability v3.1519 DPYSL5 Ivone Leong Tag Q3_21_rating was removed from gene: DPYSL5.
Intellectual disability v3.1519 DPYS Ivone Leong Tag Q2_21_expert_review was removed from gene: DPYS.
Intellectual disability v3.1519 DPM2 Ivone Leong Tag Q2_21_rating was removed from gene: DPM2.
Intellectual disability v3.1519 DDB1 Ivone Leong Tag Q2_21_rating was removed from gene: DDB1.
Intellectual disability v3.1519 CAMK4 Ivone Leong Tag Q3_21_rating was removed from gene: CAMK4.
Intellectual disability v3.1519 CLCN3 Ivone Leong Tag Q3_21_rating was removed from gene: CLCN3.
Intellectual disability v3.1519 CHD5 Ivone Leong Tag Q3_21_rating was removed from gene: CHD5.
Intellectual disability v3.1519 CEP85L Ivone Leong Tag Q3_21_rating was removed from gene: CEP85L.
Intellectual disability v3.1519 CAPN15 Ivone Leong Tag Q2_21_rating was removed from gene: CAPN15.
Intellectual disability v3.1519 CPE Ivone Leong Tag Q3_21_rating was removed from gene: CPE.
Intellectual disability v3.1519 COPB2 Ivone Leong Tag Q3_21_rating was removed from gene: COPB2.
Intellectual disability v3.1519 CTC1 Ivone Leong Tag Q3_21_rating was removed from gene: CTC1.
Intellectual disability v3.1519 CDH15 Ivone Leong Tag watchlist was removed from gene: CDH15.
Intellectual disability v3.1519 CDH15 Ivone Leong Tag Q4_21_rating was removed from gene: CDH15.
Tag watchlist tag was added to gene: CDH15.
Intellectual disability v3.1519 BCAS3 Ivone Leong Tag Q2_21_rating was removed from gene: BCAS3.
Intellectual disability v3.1519 ATP9A Ivone Leong Tag Q4_21_rating was removed from gene: ATP9A.
Intellectual disability v3.1519 ATP1A3 Ivone Leong Tag Q3_21_expert_review was removed from gene: ATP1A3.
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Tag Q4_21_rating was removed from gene: ARFGEF1.
Intellectual disability v3.1519 ARF1 Ivone Leong Tag Q3_21_rating was removed from gene: ARF1.
Intellectual disability v3.1519 AP1G1 Ivone Leong Tag Q3_21_rating was removed from gene: AP1G1.
Intellectual disability v3.1519 ANKRD17 Ivone Leong Tag Q2_21_rating was removed from gene: ANKRD17.
Intellectual disability v3.1519 ANK2 Ivone Leong Tag Q3_21_rating was removed from gene: ANK2.
Intellectual disability v3.1519 AGO1 Ivone Leong Tag Q2_21_expert_review was removed from gene: AGO1.
Intellectual disability v3.1519 ABHD16A Ivone Leong Tag Q4_21_rating was removed from gene: ABHD16A.
Intellectual disability v3.1519 POLR3B Ivone Leong Tag Q2_21_MOI was removed from gene: POLR3B.
Intellectual disability v3.1519 PHF6 Ivone Leong Tag Q4_21_MOI was removed from gene: PHF6.
Intellectual disability v3.1519 MED12 Ivone Leong Tag Q3_21_MOI was removed from gene: MED12.
Tag Q3_21_expert_review was removed from gene: MED12.
Intellectual disability v3.1519 HCCS Ivone Leong Tag Q4_21_MOI was removed from gene: HCCS.
Intellectual disability v3.1519 GRIK2 Ivone Leong Tag Q4_21_MOI was removed from gene: GRIK2.
Intellectual disability v3.1519 CLPB Ivone Leong Tag Q4_21_MOI was removed from gene: CLPB.
Intellectual disability v3.1519 ZNF699 Sarah Leigh commented on gene: ZNF699
Intellectual disability v3.1519 YIPF5 Sarah Leigh commented on gene: YIPF5
Intellectual disability v3.1519 WDR4 Sarah Leigh commented on gene: WDR4
Intellectual disability v3.1519 VPS41 Sarah Leigh commented on gene: VPS41
Intellectual disability v3.1519 VPS11 Sarah Leigh commented on gene: VPS11
Intellectual disability v3.1519 UFSP2 Sarah Leigh commented on gene: UFSP2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 UBE4A Sarah Leigh commented on gene: UBE4A
Intellectual disability v3.1519 TP73 Sarah Leigh commented on gene: TP73
Intellectual disability v3.1519 TNPO2 Sarah Leigh commented on gene: TNPO2
Intellectual disability v3.1519 TMEM222 Sarah Leigh commented on gene: TMEM222: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 TCF7L2 Sarah Leigh commented on gene: TCF7L2
Intellectual disability v3.1519 SYNCRIP Sarah Leigh commented on gene: SYNCRIP
Intellectual disability v3.1519 SPTBN1 Sarah Leigh commented on gene: SPTBN1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SPEN Sarah Leigh commented on gene: SPEN
Intellectual disability v3.1519 SNIP1 Sarah Leigh commented on gene: SNIP1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SMARCA5 Sarah Leigh commented on gene: SMARCA5
Intellectual disability v3.1519 SIN3B Sarah Leigh commented on gene: SIN3B
Intellectual disability v3.1519 SIAH1 Sarah Leigh commented on gene: SIAH1
Intellectual disability v3.1519 SCYL1 Sarah Leigh commented on gene: SCYL1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 SATB1 Sarah Leigh commented on gene: SATB1
Intellectual disability v3.1519 RFX7 Sarah Leigh commented on gene: RFX7
Intellectual disability v3.1519 RFX4 Sarah Leigh commented on gene: RFX4
Intellectual disability v3.1519 RFX3 Sarah Leigh commented on gene: RFX3
Intellectual disability v3.1519 PTPN4 Sarah Leigh commented on gene: PTPN4
Intellectual disability v3.1519 PRICKLE2 Sarah Leigh commented on gene: PRICKLE2
Intellectual disability v3.1519 POLR3B Sarah Leigh commented on gene: POLR3B
Intellectual disability v3.1519 PIGC Sarah Leigh commented on gene: PIGC
Intellectual disability v3.1519 PIDD1 Sarah Leigh commented on gene: PIDD1
Intellectual disability v3.1519 PI4KA Sarah Leigh commented on gene: PI4KA
Intellectual disability v3.1519 PHF6 Sarah Leigh commented on gene: PHF6
Intellectual disability v3.1519 PGM2L1 Sarah Leigh commented on gene: PGM2L1
Intellectual disability v3.1519 PCDHGC4 Sarah Leigh commented on gene: PCDHGC4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 OTUD5 Sarah Leigh commented on gene: OTUD5
Intellectual disability v3.1519 NEUROD2 Sarah Leigh commented on gene: NEUROD2
Intellectual disability v3.1519 NCKAP1 Sarah Leigh commented on gene: NCKAP1
Intellectual disability v3.1519 NCDN Sarah Leigh commented on gene: NCDN
Intellectual disability v3.1519 MINPP1 Sarah Leigh commented on gene: MINPP1
Intellectual disability v3.1519 MED27 Sarah Leigh commented on gene: MED27
Intellectual disability v3.1519 MED12 Sarah Leigh commented on gene: MED12
Intellectual disability v3.1519 MAP1B Sarah Leigh commented on gene: MAP1B
Intellectual disability v3.1519 LINGO4 Sarah Leigh commented on gene: LINGO4
Intellectual disability v3.1519 KDM3B Sarah Leigh commented on gene: KDM3B
Intellectual disability v3.1519 KCNN2 Sarah Leigh commented on gene: KCNN2
Intellectual disability v3.1519 KCND2 Sarah Leigh commented on gene: KCND2
Intellectual disability v3.1519 IMPDH2 Sarah Leigh commented on gene: IMPDH2
Intellectual disability v3.1519 HPDL Sarah Leigh commented on gene: HPDL
Intellectual disability v3.1519 HNMT Sarah Leigh commented on gene: HNMT
Intellectual disability v3.1519 HIST1H4C Sarah Leigh commented on gene: HIST1H4C
Intellectual disability v3.1519 HID1 Sarah Leigh commented on gene: HID1
Intellectual disability v3.1519 HCCS Sarah Leigh commented on gene: HCCS
Intellectual disability v3.1519 GTF2E2 Sarah Leigh commented on gene: GTF2E2
Intellectual disability v3.1519 GRIK2 Sarah Leigh commented on gene: GRIK2
Intellectual disability v3.1519 GNB2 Sarah Leigh commented on gene: GNB2
Intellectual disability v3.1519 GEMIN5 Sarah Leigh commented on gene: GEMIN5
Intellectual disability v3.1519 GABRD Sarah Leigh commented on gene: GABRD
Intellectual disability v3.1519 FBXO31 Sarah Leigh commented on gene: FBXO31
Intellectual disability v3.1519 FARSA Sarah Leigh commented on gene: FARSA
Intellectual disability v3.1519 ERBB4 Sarah Leigh commented on gene: ERBB4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 EMC10 Sarah Leigh commented on gene: EMC10
Intellectual disability v3.1519 EIF5A Sarah Leigh commented on gene: EIF5A
Intellectual disability v3.1519 DPYSL5 Sarah Leigh commented on gene: DPYSL5
Intellectual disability v3.1519 DPYS Sarah Leigh commented on gene: DPYS
Intellectual disability v3.1519 DPM2 Sarah Leigh commented on gene: DPM2
Intellectual disability v3.1519 DDB1 Sarah Leigh commented on gene: DDB1
Intellectual disability v3.1519 CTC1 Sarah Leigh commented on gene: CTC1
Intellectual disability v3.1519 CPE Sarah Leigh commented on gene: CPE
Intellectual disability v3.1519 COPB2 Sarah Leigh commented on gene: COPB2
Intellectual disability v3.1519 CLPB Sarah Leigh commented on gene: CLPB
Intellectual disability v3.1519 CLCN3 Sarah Leigh commented on gene: CLCN3
Intellectual disability v3.1519 CHD5 Sarah Leigh commented on gene: CHD5
Intellectual disability v3.1519 CEP85L Sarah Leigh commented on gene: CEP85L: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 CDH15 Sarah Leigh commented on gene: CDH15
Intellectual disability v3.1519 CAPN15 Sarah Leigh commented on gene: CAPN15
Intellectual disability v3.1519 CAMK4 Sarah Leigh commented on gene: CAMK4
Intellectual disability v3.1519 CACNA1I Sarah Leigh commented on gene: CACNA1I
Intellectual disability v3.1519 BCAS3 Sarah Leigh commented on gene: BCAS3
Intellectual disability v3.1519 ATP9A Sarah Leigh commented on gene: ATP9A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 ATP1A3 Sarah Leigh commented on gene: ATP1A3
Intellectual disability v3.1519 ARFGEF1 Sarah Leigh commented on gene: ARFGEF1
Intellectual disability v3.1519 ARF1 Sarah Leigh commented on gene: ARF1
Intellectual disability v3.1519 AP1G1 Sarah Leigh commented on gene: AP1G1
Intellectual disability v3.1519 ANKRD17 Sarah Leigh commented on gene: ANKRD17
Intellectual disability v3.1519 ANK2 Sarah Leigh commented on gene: ANK2
Intellectual disability v3.1519 AGO1 Sarah Leigh commented on gene: AGO1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1519 ABHD16A Sarah Leigh commented on gene: ABHD16A
Intellectual disability v3.1519 ZNF699 Ivone Leong Source Expert Review Green was added to ZNF699.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 YIPF5 Ivone Leong Source Expert Review Green was added to YIPF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 WDR4 Ivone Leong Source Expert Review Green was added to WDR4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 VPS41 Ivone Leong Source Expert Review Green was added to VPS41.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 VPS11 Ivone Leong Source Expert Review Green was added to VPS11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 UFSP2 Ivone Leong Source Expert Review Green was added to UFSP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 UBE4A Ivone Leong Source Expert Review Green was added to UBE4A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TP73 Ivone Leong Source Expert Review Green was added to TP73.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TNPO2 Ivone Leong Source Expert Review Green was added to TNPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TMEM222 Ivone Leong Source Expert Review Green was added to TMEM222.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 TCF7L2 Ivone Leong Source Expert Review Green was added to TCF7L2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SYNCRIP Ivone Leong Source Expert Review Green was added to SYNCRIP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SPTBN1 Ivone Leong Source Expert Review Green was added to SPTBN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SPEN Ivone Leong Source Expert Review Green was added to SPEN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SNIP1 Ivone Leong Source Expert Review Green was added to SNIP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SMARCA5 Ivone Leong Source Expert Review Green was added to SMARCA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SIN3B Ivone Leong Source Expert Review Green was added to SIN3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SIAH1 Ivone Leong Source Expert Review Green was added to SIAH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SCYL1 Ivone Leong Source Expert Review Green was added to SCYL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 SATB1 Ivone Leong Source Expert Review Green was added to SATB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX7 Ivone Leong Source Expert Review Green was added to RFX7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX4 Ivone Leong Source Expert Review Green was added to RFX4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 RFX3 Ivone Leong Source Expert Review Green was added to RFX3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PTPN4 Ivone Leong Source Expert Review Green was added to PTPN4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PRICKLE2 Ivone Leong Source Expert Review Green was added to PRICKLE2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 POLR3B Ivone Leong Source NHS GMS was added to POLR3B.
Mode of inheritance for gene POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 PIGC Ivone Leong Source Expert Review Green was added to PIGC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PIDD1 Ivone Leong Source Expert Review Green was added to PIDD1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PI4KA Ivone Leong Source Expert Review Green was added to PI4KA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PHF6 Ivone Leong Source NHS GMS was added to PHF6.
Mode of inheritance for gene PHF6 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 PGM2L1 Ivone Leong Source Expert Review Green was added to PGM2L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 PCDHGC4 Ivone Leong Source Expert Review Green was added to PCDHGC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 OTUD5 Ivone Leong Source Expert Review Green was added to OTUD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NEUROD2 Ivone Leong Source Expert Review Green was added to NEUROD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NCKAP1 Ivone Leong Source Expert Review Green was added to NCKAP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 NCDN Ivone Leong Source Expert Review Green was added to NCDN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MINPP1 Ivone Leong Source Expert Review Green was added to MINPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MED27 Ivone Leong Source Expert Review Green was added to MED27.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 MED12 Ivone Leong Source NHS GMS was added to MED12.
Mode of inheritance for gene MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 MAP1B Ivone Leong Source Expert Review Green was added to MAP1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 LINGO4 Ivone Leong Source Expert Review Green was added to LINGO4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KDM3B Ivone Leong Source Expert Review Green was added to KDM3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KCNN2 Ivone Leong Source Expert Review Green was added to KCNN2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 KCND2 Ivone Leong Source Expert Review Green was added to KCND2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 IMPDH2 Ivone Leong Source Expert Review Green was added to IMPDH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HPDL Ivone Leong Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HNMT Ivone Leong Source Expert Review Green was added to HNMT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HIST1H4C Ivone Leong Source Expert Review Green was added to HIST1H4C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HID1 Ivone Leong Source Expert Review Green was added to HID1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 HCCS Ivone Leong Source NHS GMS was added to HCCS.
Mode of inheritance for gene HCCS was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1519 GTF2E2 Ivone Leong Source Expert Review Green was added to GTF2E2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GRIK2 Ivone Leong Source NHS GMS was added to GRIK2.
Mode of inheritance for gene GRIK2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1519 GNB2 Ivone Leong Source Expert Review Green was added to GNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GEMIN5 Ivone Leong Source Expert Review Green was added to GEMIN5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 GABRD Ivone Leong Source Expert Review Green was added to GABRD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 FBXO31 Ivone Leong Source Expert Review Green was added to FBXO31.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 FARSA Ivone Leong Source Expert Review Green was added to FARSA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ERBB4 Ivone Leong Source Expert Review Green was added to ERBB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 EMC10 Ivone Leong Source Expert Review Green was added to EMC10.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 EIF5A Ivone Leong Source Expert Review Green was added to EIF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPYSL5 Ivone Leong Source Expert Review Green was added to DPYSL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPYS Ivone Leong Source Expert Review Green was added to DPYS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DPM2 Ivone Leong Source Expert Review Green was added to DPM2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 DDB1 Ivone Leong Source Expert Review Green was added to DDB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CTC1 Ivone Leong Source Expert Review Amber was added to CTC1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1519 CPE Ivone Leong Source Expert Review Green was added to CPE.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 COPB2 Ivone Leong Source Expert Review Green was added to COPB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CLPB Ivone Leong Source NHS GMS was added to CLPB.
Mode of inheritance for gene CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1519 CLCN3 Ivone Leong Source Expert Review Green was added to CLCN3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CHD5 Ivone Leong Source Expert Review Green was added to CHD5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CEP85L Ivone Leong Source Expert Review Green was added to CEP85L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CDH15 Ivone Leong Source Expert Review Red was added to CDH15.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1519 CAPN15 Ivone Leong Source Expert Review Green was added to CAPN15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CAMK4 Ivone Leong Source Expert Review Green was added to CAMK4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 CACNA1I Ivone Leong Source Expert Review Green was added to CACNA1I.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 BCAS3 Ivone Leong Source Expert Review Green was added to BCAS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ATP9A Ivone Leong Source Expert Review Green was added to ATP9A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ATP1A3 Ivone Leong Source Expert Review Green was added to ATP1A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARFGEF1 Ivone Leong Source Expert Review Green was added to ARFGEF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ARF1 Ivone Leong Source Expert Review Green was added to ARF1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AP1G1 Ivone Leong Source Expert Review Green was added to AP1G1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ANKRD17 Ivone Leong Source Expert Review Green was added to ANKRD17.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 ANK2 Ivone Leong Source Expert Review Green was added to ANK2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AGO1 Ivone Leong Source Expert Review Green was added to AGO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1519 AFG3L2 Ivone Leong Source NHS GMS was added to AFG3L2.
Intellectual disability v3.1519 ABHD16A Ivone Leong Source Expert Review Green was added to ABHD16A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Lysosomal storage disorder v1.78 VPS16 Ivone Leong Tag Q2_21_rating was removed from gene: VPS16.
Tag Q2_21_MOI was removed from gene: VPS16.
Lysosomal storage disorder v1.78 VPS16 Sarah Leigh commented on gene: VPS16
Lysosomal storage disorder v1.77 VPS16 Ivone Leong Source Expert Review Green was added to VPS16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Familial Chylomicronaemia Syndrome v1.21 APOB Ivone Leong Tag Q3_21_NHS_review was removed from gene: APOB.
Tag Q3_21_expert_review was removed from gene: APOB.
Familial Chylomicronaemia Syndrome v1.21 APOB Sarah Leigh commented on gene: APOB: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Familial Chylomicronaemia Syndrome v1.20 APOB Ivone Leong Source Expert Review Red was added to APOB.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Likely inborn error of metabolism v2.229 TARS2 Ivone Leong Tag Q4_21_rating was removed from gene: TARS2.
Likely inborn error of metabolism v2.229 POMK Ivone Leong Tag Q2_21_rating was removed from gene: POMK.
Likely inborn error of metabolism v2.229 NDUFC2 Ivone Leong Tag Q2_21_rating was removed from gene: NDUFC2.
Likely inborn error of metabolism v2.229 NDUFA12 Ivone Leong Tag Q2_21_rating was removed from gene: NDUFA12.
Likely inborn error of metabolism v2.229 GALNT2 Ivone Leong Tag Q2_21_rating was removed from gene: GALNT2.
Likely inborn error of metabolism v2.229 EOGT Ivone Leong Tag Q2_21_rating was removed from gene: EOGT.
Likely inborn error of metabolism v2.229 EHBP1L1 Ivone Leong Tag Q4_21_rating was removed from gene: EHBP1L1.
Likely inborn error of metabolism v2.229 CSGALNACT1 Ivone Leong Tag Q2_21_rating was removed from gene: CSGALNACT1.
Likely inborn error of metabolism v2.229 B4GALNT1 Ivone Leong Tag Q2_21_rating was removed from gene: B4GALNT1.
Likely inborn error of metabolism v2.229 FAR1 Ivone Leong Tag Q2_21_rating was removed from gene: FAR1.
Likely inborn error of metabolism v2.229 CLPB Ivone Leong Tag Q4_21_MOI was removed from gene: CLPB.
Likely inborn error of metabolism v2.229 NAXD Ivone Leong Tag Q2_21_rating was removed from gene: NAXD.
Likely inborn error of metabolism v2.229 NAXD Sarah Leigh commented on gene: NAXD
Likely inborn error of metabolism v2.229 TARS2 Sarah Leigh commented on gene: TARS2: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 POMK Sarah Leigh commented on gene: POMK: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 NDUFC2 Sarah Leigh commented on gene: NDUFC2: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 NDUFA12 Sarah Leigh commented on gene: NDUFA12: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 GALNT2 Sarah Leigh commented on gene: GALNT2: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 FAR1 Sarah Leigh commented on gene: FAR1
Likely inborn error of metabolism v2.229 EOGT Sarah Leigh commented on gene: EOGT: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 EHBP1L1 Sarah Leigh commented on gene: EHBP1L1: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 CSGALNACT1 Sarah Leigh commented on gene: CSGALNACT1
Likely inborn error of metabolism v2.229 CLPB Sarah Leigh commented on gene: CLPB
Likely inborn error of metabolism v2.229 B4GALNT1 Sarah Leigh commented on gene: B4GALNT1: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Likely inborn error of metabolism v2.229 NAXD Ivone Leong Source Expert Review Green was added to NAXD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 TARS2 Ivone Leong Source Expert Review Green was added to TARS2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 POMK Ivone Leong Source Expert Review Green was added to POMK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 NDUFC2 Ivone Leong Source Expert Review Green was added to NDUFC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 NDUFA12 Ivone Leong Source Expert Review Green was added to NDUFA12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 GALNT2 Ivone Leong Source Expert Review Green was added to GALNT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 FAR1 Ivone Leong Source Expert Review Red was added to FAR1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Likely inborn error of metabolism v2.229 EOGT Ivone Leong Source Expert Review Green was added to EOGT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 EHBP1L1 Ivone Leong Source Expert Review Green was added to EHBP1L1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 CSGALNACT1 Ivone Leong Source Expert Review Green was added to CSGALNACT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Likely inborn error of metabolism v2.229 CLPB Ivone Leong Source NHS GMS was added to CLPB.
Mode of inheritance for gene CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.229 B4GALNT1 Ivone Leong Source Expert Review Green was added to B4GALNT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.224 FIG4 Ivone Leong Tag Q2_21_rating was removed from gene: FIG4.
White matter disorders and cerebral calcification - childhood onset v1.224 FIG4 Sarah Leigh commented on gene: FIG4
White matter disorders and cerebral calcification - childhood onset v1.224 FIG4 Ivone Leong Source Expert Review Green was added to FIG4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.127 B4GAT1 Ivone Leong Tag Q3_21_rating was removed from gene: B4GAT1.
Hydrocephalus v2.127 EEF2 Ivone Leong Tag Q2_21_rating was removed from gene: EEF2.
Hydrocephalus v2.127 KIDINS220 Ivone Leong Tag deletions was removed from gene: KIDINS220.
Hydrocephalus v2.127 KIDINS220 Ivone Leong Tag Q2_21_rating was removed from gene: KIDINS220.
Tag deletions tag was added to gene: KIDINS220.
Hydrocephalus v2.127 MPDZ Ivone Leong Tag Q2_21_rating was removed from gene: MPDZ.
Hydrocephalus v2.127 SMARCC1 Ivone Leong Tag Q2_21_rating was removed from gene: SMARCC1.
Hydrocephalus v2.127 TBC1D32 Ivone Leong Tag Q4_21_rating was removed from gene: TBC1D32.
Hydrocephalus v2.127 TCIRG1 Ivone Leong Tag Q4_21_rating was removed from gene: TCIRG1.
Hydrocephalus v2.127 TNFRSF11A Ivone Leong Tag Q4_21_rating was removed from gene: TNFRSF11A.
Hydrocephalus v2.127 TRIM71 Ivone Leong Tag Q2_21_rating was removed from gene: TRIM71.
Hydrocephalus v2.127 TRIM71 Sarah Leigh commented on gene: TRIM71
Hydrocephalus v2.127 TNFRSF11A Sarah Leigh commented on gene: TNFRSF11A
Hydrocephalus v2.127 TCIRG1 Sarah Leigh commented on gene: TCIRG1
Hydrocephalus v2.127 TBC1D32 Sarah Leigh commented on gene: TBC1D32
Hydrocephalus v2.127 SMARCC1 Sarah Leigh commented on gene: SMARCC1
Hydrocephalus v2.127 MPDZ Sarah Leigh commented on gene: MPDZ
Hydrocephalus v2.127 KIDINS220 Sarah Leigh commented on gene: KIDINS220
Hydrocephalus v2.127 EEF2 Sarah Leigh commented on gene: EEF2
Hydrocephalus v2.127 B4GAT1 Sarah Leigh commented on gene: B4GAT1
Hydrocephalus v2.126 TRIM71 Ivone Leong Source Expert Review Green was added to TRIM71.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 TNFRSF11A Ivone Leong Source Expert Review Green was added to TNFRSF11A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 TCIRG1 Ivone Leong Source Expert Review Green was added to TCIRG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 TBC1D32 Ivone Leong Source Expert Review Green was added to TBC1D32.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 SMARCC1 Ivone Leong Source Expert Review Green was added to SMARCC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 MPDZ Ivone Leong Source Expert Review Green was added to MPDZ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 KIDINS220 Ivone Leong Source Expert Review Green was added to KIDINS220.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 EEF2 Ivone Leong Source Expert Review Green was added to EEF2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hydrocephalus v2.126 B4GAT1 Ivone Leong Source Expert Review Green was added to B4GAT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Holoprosencephaly v2.27 KMT2D Ivone Leong Tag Q3_21_rating was removed from gene: KMT2D.
Holoprosencephaly v2.27 RAD21 Ivone Leong Tag Q3_21_rating was removed from gene: RAD21.
Holoprosencephaly v2.27 RAD21 Sarah Leigh commented on gene: RAD21
Holoprosencephaly v2.27 KMT2D Sarah Leigh commented on gene: KMT2D
Holoprosencephaly v2.26 RAD21 Ivone Leong Source Expert Review Green was added to RAD21.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Holoprosencephaly v2.26 KMT2D Ivone Leong Source Expert Review Green was added to KMT2D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.130 SLC25A15 Ivone Leong Tag Q3_21_rating was removed from gene: SLC25A15.
Hereditary spastic paraplegia, childhood onset v2.130 RNASEH2B Ivone Leong Tag Q4_21_rating was removed from gene: RNASEH2B.
Hereditary spastic paraplegia, childhood onset v2.130 MAPK8IP3 Ivone Leong Tag Q4_21_rating was removed from gene: MAPK8IP3.
Hereditary spastic paraplegia, childhood onset v2.130 IFIH1 Ivone Leong Tag Q4_21_rating was removed from gene: IFIH1.
Hereditary spastic paraplegia, childhood onset v2.130 HPDL Ivone Leong Tag Q2_21_rating was removed from gene: HPDL.
Tag Q2_21_NHS_review was removed from gene: HPDL.
Hereditary spastic paraplegia, childhood onset v2.130 HIKESHI Ivone Leong Tag Q2_21_rating was removed from gene: HIKESHI.
Hereditary spastic paraplegia, childhood onset v2.130 GPT2 Ivone Leong Tag Q4_21_rating was removed from gene: GPT2.
Hereditary spastic paraplegia, childhood onset v2.130 GLRX5 Ivone Leong Tag Q2_21_rating was removed from gene: GLRX5.
Hereditary spastic paraplegia, childhood onset v2.130 GJA1 Ivone Leong Tag Q3_21_rating was removed from gene: GJA1.
Hereditary spastic paraplegia, childhood onset v2.130 GALC Ivone Leong Tag Q3_21_rating was removed from gene: GALC.
Hereditary spastic paraplegia, childhood onset v2.130 FAR1 Ivone Leong Tag Q2_21_rating was removed from gene: FAR1.
Hereditary spastic paraplegia, childhood onset v2.130 ELOVL1 Ivone Leong Tag Q4_21_rating was removed from gene: ELOVL1.
Hereditary spastic paraplegia, childhood onset v2.130 BCAS3 Ivone Leong Tag Q2_21_rating was removed from gene: BCAS3.
Hereditary spastic paraplegia, childhood onset v2.130 ARL6IP1 Ivone Leong Tag Q2_21_rating was removed from gene: ARL6IP1.
Hereditary spastic paraplegia, childhood onset v2.130 ALDH3A2 Ivone Leong Tag Q3_21_rating was removed from gene: ALDH3A2.
Hereditary spastic paraplegia, childhood onset v2.130 AFG3L2 Ivone Leong Tag Q2_21_MOI was removed from gene: AFG3L2.
Hereditary spastic paraplegia, childhood onset v2.130 SLC25A15 Sarah Leigh commented on gene: SLC25A15
Hereditary spastic paraplegia, childhood onset v2.130 RNASEH2B Sarah Leigh commented on gene: RNASEH2B
Hereditary spastic paraplegia, childhood onset v2.130 MAPK8IP3 Sarah Leigh commented on gene: MAPK8IP3
Hereditary spastic paraplegia, childhood onset v2.130 IFIH1 Sarah Leigh commented on gene: IFIH1
Hereditary spastic paraplegia, childhood onset v2.130 HPDL Sarah Leigh commented on gene: HPDL: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Hereditary spastic paraplegia, childhood onset v2.130 HPDL Sarah Leigh commented on gene: HPDL: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Hereditary spastic paraplegia, childhood onset v2.130 HPDL Sarah Leigh commented on gene: HPDL
Hereditary spastic paraplegia, childhood onset v2.130 HIKESHI Sarah Leigh commented on gene: HIKESHI
Hereditary spastic paraplegia, childhood onset v2.130 GPT2 Sarah Leigh commented on gene: GPT2
Hereditary spastic paraplegia, childhood onset v2.130 GLRX5 Sarah Leigh commented on gene: GLRX5
Hereditary spastic paraplegia, childhood onset v2.130 GJA1 Sarah Leigh commented on gene: GJA1
Hereditary spastic paraplegia, childhood onset v2.130 GALC Sarah Leigh commented on gene: GALC
Hereditary spastic paraplegia, childhood onset v2.130 FAR1 Sarah Leigh commented on gene: FAR1
Hereditary spastic paraplegia, childhood onset v2.130 ELOVL1 Sarah Leigh commented on gene: ELOVL1
Hereditary spastic paraplegia, childhood onset v2.130 BCAS3 Sarah Leigh commented on gene: BCAS3
Hereditary spastic paraplegia, childhood onset v2.130 ARL6IP1 Sarah Leigh commented on gene: ARL6IP1
Hereditary spastic paraplegia, childhood onset v2.130 ALDH3A2 Sarah Leigh commented on gene: ALDH3A2
Hereditary spastic paraplegia, childhood onset v2.130 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary spastic paraplegia, childhood onset v2.129 SLC25A15 Ivone Leong Source Expert Review Green was added to SLC25A15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 RNASEH2B Ivone Leong Source Expert Review Green was added to RNASEH2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 MAPK8IP3 Ivone Leong Source Expert Review Green was added to MAPK8IP3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 IFIH1 Ivone Leong Source Expert Review Green was added to IFIH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 HPDL Ivone Leong Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 HIKESHI Ivone Leong Source Expert Review Green was added to HIKESHI.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 GPT2 Ivone Leong Source Expert Review Green was added to GPT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 GLRX5 Ivone Leong Source Expert Review Green was added to GLRX5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 GJA1 Ivone Leong Source Expert Review Green was added to GJA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 GALC Ivone Leong Source Expert Review Green was added to GALC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 FAR1 Ivone Leong Source Expert Review Green was added to FAR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 ELOVL1 Ivone Leong Source Expert Review Green was added to ELOVL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 BCAS3 Ivone Leong Source Expert Review Green was added to BCAS3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 ARL6IP1 Ivone Leong Source Expert Review Green was added to ARL6IP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 ALDH3A2 Ivone Leong Source Expert Review Green was added to ALDH3A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.129 AFG3L2 Ivone Leong Mode of inheritance for gene AFG3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.95 WDR45B Ivone Leong Tag Q3_21_phenotype was removed from gene: WDR45B.
Hereditary spastic paraplegia, adult onset v1.95 UCHL1 Ivone Leong Tag Q2_21_expert_review was removed from gene: UCHL1.
Hereditary spastic paraplegia, adult onset v1.95 TFG Ivone Leong Tag Q3_21_phenotype was removed from gene: TFG.
Hereditary spastic paraplegia, adult onset v1.95 SPART Ivone Leong Tag Q3_21_phenotype was removed from gene: SPART.
Hereditary spastic paraplegia, adult onset v1.95 SLC1A4 Ivone Leong Tag Q2_21_phenotype was removed from gene: SLC1A4.
Hereditary spastic paraplegia, adult onset v1.95 SLC16A2 Ivone Leong Tag Q3_21_phenotype was removed from gene: SLC16A2.
Hereditary spastic paraplegia, adult onset v1.95 SERAC1 Ivone Leong Tag Q3_21_phenotype was removed from gene: SERAC1.
Hereditary spastic paraplegia, adult onset v1.95 REEP2 Ivone Leong Tag Q3_21_phenotype was removed from gene: REEP2.
Hereditary spastic paraplegia, adult onset v1.95 NT5C2 Ivone Leong Tag Q3_21_phenotype was removed from gene: NT5C2.
Hereditary spastic paraplegia, adult onset v1.95 NKX6-2 Ivone Leong Tag Q3_21_phenotype was removed from gene: NKX6-2.
Hereditary spastic paraplegia, adult onset v1.95 L1CAM Ivone Leong Tag Q3_21_phenotype was removed from gene: L1CAM.
Hereditary spastic paraplegia, adult onset v1.95 KIDINS220 Ivone Leong Tag Q3_21_phenotype was removed from gene: KIDINS220.
Hereditary spastic paraplegia, adult onset v1.95 KDM5C Ivone Leong Tag Q3_21_expert_review was removed from gene: KDM5C.
Tag Q3_21_phenotype was removed from gene: KDM5C.
Hereditary spastic paraplegia, adult onset v1.95 HACE1 Ivone Leong Tag Q3_21_phenotype was removed from gene: HACE1.
Hereditary spastic paraplegia, adult onset v1.95 SLC25A15 Ivone Leong Tag Q3_21_rating was removed from gene: SLC25A15.
Hereditary spastic paraplegia, adult onset v1.95 GJA1 Ivone Leong Tag Q3_21_rating was removed from gene: GJA1.
Hereditary spastic paraplegia, adult onset v1.95 GBE1 Ivone Leong Tag Q3_21_rating was removed from gene: GBE1.
Hereditary spastic paraplegia, adult onset v1.95 GALC Ivone Leong Tag Q3_21_rating was removed from gene: GALC.
Hereditary spastic paraplegia, adult onset v1.95 FBXO7 Ivone Leong Tag Q3_21_rating was removed from gene: FBXO7.
Hereditary spastic paraplegia, adult onset v1.95 FARS2 Ivone Leong Tag Q3_21_phenotype was removed from gene: FARS2.
Hereditary spastic paraplegia, adult onset v1.95 ERLIN1 Ivone Leong Tag Q3_21_phenotype was removed from gene: ERLIN1.
Hereditary spastic paraplegia, adult onset v1.95 ENTPD1 Ivone Leong Tag Q3_21_phenotype was removed from gene: ENTPD1.
Hereditary spastic paraplegia, adult onset v1.95 CYP2U1 Ivone Leong Tag Q2_21_expert_review was removed from gene: CYP2U1.
Hereditary spastic paraplegia, adult onset v1.95 CPT1C Ivone Leong Tag Q4_21_rating was removed from gene: CPT1C.
Hereditary spastic paraplegia, adult onset v1.95 C12orf65 Ivone Leong Tag Q3_21_expert_review was removed from gene: C12orf65.
Tag Q3_21_phenotype was removed from gene: C12orf65.
Hereditary spastic paraplegia, adult onset v1.95 ARG1 Ivone Leong Tag Q3_21_phenotype was removed from gene: ARG1.
Hereditary spastic paraplegia, adult onset v1.95 ALS2 Ivone Leong Tag Q3_21_expert_review was removed from gene: ALS2.
Tag Q3_21_phenotype was removed from gene: ALS2.
Hereditary spastic paraplegia, adult onset v1.95 AIMP1 Ivone Leong Tag Q3_21_phenotype was removed from gene: AIMP1.
Hereditary spastic paraplegia, adult onset v1.95 AFG3L2 Ivone Leong Tag Q2_21_phenotype was removed from gene: AFG3L2.
Tag Q2_21_MOI was removed from gene: AFG3L2.
Hereditary spastic paraplegia, adult onset v1.95 WDR45B Sarah Leigh commented on gene: WDR45B
Hereditary spastic paraplegia, adult onset v1.95 UCHL1 Sarah Leigh commented on gene: UCHL1
Hereditary spastic paraplegia, adult onset v1.95 TFG Sarah Leigh commented on gene: TFG
Hereditary spastic paraplegia, adult onset v1.95 SPART Sarah Leigh commented on gene: SPART
Hereditary spastic paraplegia, adult onset v1.95 SLC25A15 Sarah Leigh commented on gene: SLC25A15
Hereditary spastic paraplegia, adult onset v1.95 SLC1A4 Sarah Leigh commented on gene: SLC1A4
Hereditary spastic paraplegia, adult onset v1.95 SLC16A2 Sarah Leigh commented on gene: SLC16A2
Hereditary spastic paraplegia, adult onset v1.95 SERAC1 Sarah Leigh commented on gene: SERAC1
Hereditary spastic paraplegia, adult onset v1.95 REEP2 Sarah Leigh commented on gene: REEP2
Hereditary spastic paraplegia, adult onset v1.95 NT5C2 Sarah Leigh commented on gene: NT5C2
Hereditary spastic paraplegia, adult onset v1.95 NKX6-2 Sarah Leigh commented on gene: NKX6-2
Hereditary spastic paraplegia, adult onset v1.95 L1CAM Sarah Leigh commented on gene: L1CAM
Hereditary spastic paraplegia, adult onset v1.95 KIDINS220 Sarah Leigh commented on gene: KIDINS220
Hereditary spastic paraplegia, adult onset v1.95 KDM5C Sarah Leigh commented on gene: KDM5C
Hereditary spastic paraplegia, adult onset v1.95 HACE1 Sarah Leigh commented on gene: HACE1
Hereditary spastic paraplegia, adult onset v1.95 GJA1 Sarah Leigh commented on gene: GJA1
Hereditary spastic paraplegia, adult onset v1.95 GBE1 Sarah Leigh commented on gene: GBE1
Hereditary spastic paraplegia, adult onset v1.95 GALC Sarah Leigh commented on gene: GALC
Hereditary spastic paraplegia, adult onset v1.95 FBXO7 Sarah Leigh commented on gene: FBXO7
Hereditary spastic paraplegia, adult onset v1.95 FARS2 Sarah Leigh commented on gene: FARS2
Hereditary spastic paraplegia, adult onset v1.95 ERLIN1 Sarah Leigh commented on gene: ERLIN1
Hereditary spastic paraplegia, adult onset v1.95 ENTPD1 Sarah Leigh commented on gene: ENTPD1
Hereditary spastic paraplegia, adult onset v1.95 CYP2U1 Sarah Leigh commented on gene: CYP2U1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary spastic paraplegia, adult onset v1.95 CPT1C Sarah Leigh commented on gene: CPT1C
Hereditary spastic paraplegia, adult onset v1.95 C12orf65 Sarah Leigh commented on gene: C12orf65
Hereditary spastic paraplegia, adult onset v1.95 ARG1 Sarah Leigh commented on gene: ARG1
Hereditary spastic paraplegia, adult onset v1.95 ALS2 Sarah Leigh commented on gene: ALS2
Hereditary spastic paraplegia, adult onset v1.95 AIMP1 Sarah Leigh commented on gene: AIMP1
Hereditary spastic paraplegia, adult onset v1.95 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary spastic paraplegia, adult onset v1.94 WDR45B Ivone Leong Source Expert Review Amber was added to WDR45B.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 UCHL1 Ivone Leong Source Expert Review Amber was added to UCHL1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 TFG Ivone Leong Source Expert Review Amber was added to TFG.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 SPART Ivone Leong Source Expert Review Amber was added to SPART.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 SLC25A15 Ivone Leong Source Expert Review Green was added to SLC25A15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 SLC1A4 Ivone Leong Source Expert Review Amber was added to SLC1A4.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 SLC16A2 Ivone Leong Source Expert Review Amber was added to SLC16A2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 SERAC1 Ivone Leong Source Expert Review Amber was added to SERAC1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 REEP2 Ivone Leong Source Expert Review Amber was added to REEP2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 NT5C2 Ivone Leong Source Expert Review Amber was added to NT5C2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 NKX6-2 Ivone Leong Source Expert Review Amber was added to NKX6-2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 L1CAM Ivone Leong Source Expert Review Amber was added to L1CAM.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 KIDINS220 Ivone Leong Source Expert Review Amber was added to KIDINS220.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 KDM5C Ivone Leong Source Expert Review Amber was added to KDM5C.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 HACE1 Ivone Leong Source Expert Review Amber was added to HACE1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 GJA1 Ivone Leong Source Expert Review Green was added to GJA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 GBE1 Ivone Leong Source Expert Review Green was added to GBE1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 GALC Ivone Leong Source Expert Review Green was added to GALC.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 FBXO7 Ivone Leong Source Expert Review Green was added to FBXO7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 FARS2 Ivone Leong Source Expert Review Amber was added to FARS2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 ERLIN1 Ivone Leong Source Expert Review Amber was added to ERLIN1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 ENTPD1 Ivone Leong Source Expert Review Amber was added to ENTPD1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 CYP2U1 Ivone Leong Source Expert Review Amber was added to CYP2U1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 CPT1C Ivone Leong Source Expert Review Green was added to CPT1C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.94 C12orf65 Ivone Leong Source Expert Review Amber was added to C12orf65.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 ARG1 Ivone Leong Source Expert Review Amber was added to ARG1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 ALS2 Ivone Leong Source Expert Review Amber was added to ALS2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 AIMP1 Ivone Leong Source Expert Review Amber was added to AIMP1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary spastic paraplegia, adult onset v1.94 AFG3L2 Ivone Leong Source Expert Review Amber was added to AFG3L2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.88 VWA1 Ivone Leong Tag Q3_21_rating was removed from gene: VWA1.
Tag Q3_21_NHS_review was removed from gene: VWA1.
Hereditary neuropathy or pain disorder v1.88 POLR3B Ivone Leong Tag Q2_21_rating was removed from gene: POLR3B.
Hereditary neuropathy or pain disorder v1.88 PIGB Ivone Leong Tag Q3_21_rating was removed from gene: PIGB.
Hereditary neuropathy or pain disorder v1.88 HEXB Ivone Leong Tag Q4_21_rating was removed from gene: HEXB.
Hereditary neuropathy or pain disorder v1.88 HEXA Ivone Leong Tag Q4_21_rating was removed from gene: HEXA.
Hereditary neuropathy or pain disorder v1.88 MME Ivone Leong Tag Q4_21_expert_review was removed from gene: MME.
Tag Q4_21_MOI was removed from gene: MME.
Tag Q4_21_NHS_review was removed from gene: MME.
Hereditary neuropathy or pain disorder v1.88 GSN Ivone Leong Tag Q3_21_rating was removed from gene: GSN.
Hereditary neuropathy or pain disorder v1.88 C1orf194 Ivone Leong Tag Q3_21_rating was removed from gene: C1orf194.
Tag Q3_21_NHS_review was removed from gene: C1orf194.
Hereditary neuropathy or pain disorder v1.88 VWA1 Sarah Leigh commented on gene: VWA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v1.88 POLR3B Sarah Leigh commented on gene: POLR3B
Hereditary neuropathy or pain disorder v1.88 PIGB Sarah Leigh commented on gene: PIGB
Hereditary neuropathy or pain disorder v1.88 MME Sarah Leigh commented on gene: MME
Hereditary neuropathy or pain disorder v1.88 HEXB Sarah Leigh commented on gene: HEXB
Hereditary neuropathy or pain disorder v1.88 HEXA Sarah Leigh commented on gene: HEXA
Hereditary neuropathy or pain disorder v1.88 GSN Sarah Leigh commented on gene: GSN
Hereditary neuropathy or pain disorder v1.88 C1orf194 Sarah Leigh commented on gene: C1orf194: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v1.87 VWA1 Ivone Leong Source Expert Review Green was added to VWA1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 POLR3B Ivone Leong Source Expert Review Green was added to POLR3B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 PIGB Ivone Leong Source Expert Review Green was added to PIGB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 MME Ivone Leong Mode of inheritance for gene MME was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.87 HEXB Ivone Leong Source Expert Review Green was added to HEXB.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 HEXA Ivone Leong Source Expert Review Green was added to HEXA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 GSN Ivone Leong Source Expert Review Green was added to GSN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.87 C1orf194 Ivone Leong Source Expert Review Green was added to C1orf194.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.217 VPS41 Sarah Leigh commented on gene: VPS41: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 VPS16 Sarah Leigh commented on gene: VPS16: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 UBTF Sarah Leigh commented on gene: UBTF: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 TARS2 Sarah Leigh commented on gene: TARS2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 SLC16A2 Sarah Leigh commented on gene: SLC16A2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 SCN1A Sarah Leigh commented on gene: SCN1A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 MED27 Sarah Leigh commented on gene: MED27: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 IRF2BPL Sarah Leigh commented on gene: IRF2BPL: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 IMPDH2 Sarah Leigh commented on gene: IMPDH2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 HPRT1 Sarah Leigh commented on gene: HPRT1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 GRIN1 Sarah Leigh commented on gene: GRIN1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 GNB1 Sarah Leigh commented on gene: GNB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 GLRB Sarah Leigh commented on gene: GLRB: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 FUCA1 Sarah Leigh commented on gene: FUCA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 FOXG1 Sarah Leigh commented on gene: FOXG1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 FITM2 Sarah Leigh commented on gene: FITM2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 DHDDS Sarah Leigh commented on gene: DHDDS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 CSTB Sarah Leigh commented on gene: CSTB: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 CLPB Sarah Leigh commented on gene: CLPB: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 CAMK4 Sarah Leigh commented on gene: CAMK4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 C9orf72 Sarah Leigh commented on gene: C9orf72: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dystonia, chorea or related movement disorder, childhood onset v1.217 ALDH18A1 Sarah Leigh commented on gene: ALDH18A1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Dilated Cardiomyopathy and conduction defects v1.75 LDB3 Matthew Edwards reviewed gene: LDB3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 4662268, PMID: 14660611, PMID: 16427346; Phenotypes: Cardiomyopathy, dilated, 1C, with or without LVNC (OMIM #601493); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.498 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Genetic epilepsy syndromes. Sources: Literature
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 Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concern highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Intellectual disability v3.1518 CPSF3 Konstantinos Varvagiannis gene: CPSF3 was added
gene: CPSF3 was added to Intellectual disability. Sources: Literature
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 Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Microcephaly; Seizures
Penetrance for gene: CPSF3 were set to Complete
Review for gene: CPSF3 was set to AMBER
Added comment: Arnadottir (2022 - PMID: 35121750) describe the phenotype associated with biallelic CPSF3 pathogenic variants.

Based on WGS of 56,969 Icelanders and imputing the genotype of another 153,054 chip-genotyped Icelanders, the authors identified missense variants with a deficit of homozygous carriers to what would be expected based on AF. (For variants with MAF>0.4%, for which >=3 hmz carriers would be expected by H-W equilibrium, no identified hmz carriers within this cohort/dataset). A total of 114 such missense variants was identified.

5 of these SNVs, among which a CPSF3 one (NM_016207.3:c.1403G>A / p.Gly468Glu), were however observed in a series of 764 individuals investigated with clinical WGS at the National University Hospital.

The CPSF3 variant with a MAF of 0.41% (3 hmz expected but none observed in the population set) was found in homozygosity in 2 closely related individuals, both investigated for FTT, severe DD, ID, microcephaly, seizures but remaining unresolved following WGS with no other candidate variants.

Using genealogical information from the db of deCODE genetics, the authors identified 3 couples from the 153k genotyped Icelanders where both partners were htz carriers for this SNV. These 3 couples had 10 offspring, 4 of whom deceased but with the same phenotypic features as above (hypotonia 4/4, ID 4/4, seizures 3/4, microcephaly 2/4). Paraffin embedded samples of 2 of these children and WG & Sanger sequencing confirmed hmz for Gly468Glu in 2 sibs, without other candidate variants. Samples of the 2 other individuals were N/A.

Through GeneMatcher 2 additional first-cousin patients from Mexico were identified, being hmz for another CPSF3 variant (c.1061T>C/p.Ile354Thr) and having overlapping phenotype of abnormal muscle tone, ID, seizures and microcephaly. There were no other variants in WES analysis.

mRNA studies in WBCs from Gly468Glu htz carriers did not reveal reduced levels and W.Blot of lymphocytes from a hmz individual confirmed expression, overall suggesting that the variant does not affect the protein levels but presumably the function.

CPSF3 encodes cleavage and polyadenylation specificity factor 3, a 684 aa protein, subunit of the cleavage and polyadenylation specificity factor compex. As discussed, cleavage and polyadenylation of the 3' of pre-mRNAs is necessary before transport out of the nucleus with CPSF playing a crucial role in the process of cleavage.

CPSF3 ko mice exhibit embryonic lethality, while in yeast mutations in key residues of the CPSF3 homolog are lethal.

In gnomAD, CPSF3 has a pLI of 0, z-score of 3.61 with no homozygotes for pLoF variants in 141k individuals (or ~57k WGS Icelanders).

The 2 missense variants concerned highly conserved residues (GERP ~5.8). Both are hypothesized to affect the ability of the protein to bind other factors involved in pre-mRNA cleavage.

Overall the authors speculate that not only complete loss of CPSF3 would result in drastic phenotypic effects - as in the murine model - but also variants altering its enzymatic function.

There is currently no CPSF3-related phenotype in OMIM, G2P, SysID, The gene is included with green rating in the ID, epilepsy and microcephaly panels in PanelApp Australia.

Consider inclusion probably with amber rating (Highly consistent phenotype, biological function, evidence from animal models. 2 identified variants, authors state that follow-up functional studies are needed). Also consider inclusion in other possibly relevant panels.
Sources: Literature
Intellectual disability v3.1518 NRCAM Konstantinos Varvagiannis gene: NRCAM was added
gene: NRCAM was added to Intellectual disability. Sources: Literature
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 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
Penetrance for gene: NRCAM were set to Complete
Review for gene: NRCAM was set to GREEN
Added comment: Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM.

Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8.

Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic.

All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype.

NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD.

Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain.

Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins.

There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon.

The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness).

Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating.

Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied).
Sources: Literature
Early onset or syndromic epilepsy v2.498 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Intellectual disability v3.1518 TIAM1 Konstantinos Varvagiannis gene: TIAM1 was added
gene: TIAM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TIAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIAM1 were set to 35240055; 33328293
Phenotypes for gene: TIAM1 were set to Delayed speech and language development; Global developmental delay; Intellectual disability; Seizures; Behavioral abnormality; Abnormality of the endocrine system; Hypothyroidism; Abnormality of nervous system morphology
Penetrance for gene: TIAM1 were set to Complete
Review for gene: TIAM1 was set to AMBER
Added comment: Lu et al (2022 - PMID: 35240055) describe 5 individuals (from 4 families) with biallelic TIAM1 missense variants.

The phenotype overall corresponded to a neurodevelopmental disorder with DD (5/5), ID (4/4 individuals of relevant age - 3 families), speech delay (5/5), seizures (5/5 - onset: 2m-13y) and behavioral abnormalities (2/2, sibs with autism and ADHD). Several subjects had endocrine symptoms, namely hypothyroidism (N=3 - 2 families), Addison's disease (1) or hypomagnesemia (1). Non-consistent abnormalities were reported in (3/3) subjects who had a brain MRI.

Previous investigations were mentioned for 3 individuals (incl. 2 sibs) and included normal CMA and/or metabolic workup.

Singleton or trio exome sequencing (in one family) revealed biallelic missense TIAM1 variants.

6 different missense variants were reported, all ultra-rare or not present in gnomAD (also o/e:0.2, pLI:0.96), with CADD scores in favor of deleterious effect (NM_001353694.2): c.67C>T/p.Arg23Cys*, c.2584C>T/p.Leu862Phe*, c.983G>T/p.Gly328Val*, c.4640C>A/p.Ala1547Glu, c.1144G>C/p.Gly382Arg, c.4016C>T/p.Ala1339Val.

TIAM1 encodes a RAC1-specific guanine exchange factor (GEF), regulating RAC1 signaling pathways that in turn affect cell shape, migration, adhesion, growth, survival, and polarity, and influence actin cytoskeletal organization, endocytosis, and membrane trafficking. RAC1 signaling plays important role in control of neuronal morphogenesis and neurite outgrowth (based on the summary by Entrez and authors).

TIAM1 is highly expressed in human brain (GTEx).

The authors provide evidence that sif, the Drosophila ortholog, is expressed primarily in neurons of the fly CNS (but not in glia). Using different sif LoF mutant flies they demonstrate that loss of sif impairs viability. Surviving flies exhibited climbing defects and seizure-like behaviors, both significantly rescued upon UAS-sif expression. Neuronal specific sif knockdown resulted in similar phenotypes to ubiquitous knockdown, while glial knockdown did not result in climbing defects.

The semi-lethal phenotype could be fully rescued by expression of the fly sif cDNA, but only partially by human TIAM1 cDNA reference. Upon expression, 3 patient-variants (R23C, L862F, G328V) had variable rescue abilities similar to or lower (R23C) than TIAM1 Ref. TIAM1 Ref and variants could not rescue the neurological phenotypes though. Higher/ectopic expression of sif or TIAM1 Ref was toxic, which was also observed to a lesser extent for variants.

Overall, the evidence provided suggests that the 3 variants tested induce partial LoF.

In a recent study cited (PMID: 33328293), Tiam1 KO mice had simplified dendritic arbors, reduced spine density and diminished excitatory transmission in dentate gyrus. The authors comment that this mouse model presented only subtle behavioral abnormalities which they speculate may be secondary to GEF redundancy (eg. Tiam2).

There is no TIAM1-associated phenotype in OMIM/G2P/SysID. TIAM1 is included in PanelApp Australia in the ID and epilepsy panels with green rating.

Consider inclusion in the current panel with amber rating [As authors discuss: some phenotypic features differed in their small cohort and the contribution of other recessive conditions in 2 consanguineous families cannot be excluded. Also: in fig S1 only status of parents but not of affected/unaffected sibs is specified with the exception of Fam1].
Sources: Literature
Intellectual disability v3.1518 THUMPD1 Konstantinos Varvagiannis reviewed gene: THUMPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30237576, 35196516; Phenotypes: Global developmental delay, Intellectual disability, Microcephaly, Hearing abnormality, Abnormality of the eye, Febrile seizures, Behavioral abnormality, Abnormality of brain morphology, Abnormality of the face; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v2.498 GABRD Ivone Leong Tag Q4_21_rating was removed from gene: GABRD.
Tag Q4_21_NHS_review was removed from gene: GABRD.
Early onset or syndromic epilepsy v2.498 HPDL Ivone Leong Tag Q2_21_rating was removed from gene: HPDL.
Early onset or syndromic epilepsy v2.498 UFSP2 Ivone Leong Tag Q2_21_rating was removed from gene: UFSP2.
Tag Q2_21_expert_review was removed from gene: UFSP2.
Tag Q2_21_NHS_review was removed from gene: UFSP2.
Early onset or syndromic epilepsy v2.498 UFSP2 Sarah Leigh commented on gene: UFSP2: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Early onset or syndromic epilepsy v2.498 HPDL Sarah Leigh commented on gene: HPDL
Early onset or syndromic epilepsy v2.498 GABRD Sarah Leigh commented on gene: GABRD: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Early onset or syndromic epilepsy v2.498 UFSP2 Ivone Leong Source Expert Review Green was added to UFSP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.498 HPDL Ivone Leong Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.498 GABRD Ivone Leong Source Expert Review Green was added to GABRD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Ataxia and cerebellar anomalies - childhood onset v2.288 VPS41 Ivone Leong Tag Q2_21_rating was removed from gene: VPS41.
Tag Q2_21_NHS_review was removed from gene: VPS41.
Ataxia and cerebellar anomalies - childhood onset v2.288 VPS41 Sarah Leigh commented on gene: VPS41
Ataxia and cerebellar anomalies - childhood onset v2.287 VPS41 Ivone Leong Source Expert Review Green was added to VPS41.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.154 EBP Ivone Leong Tag Q2_21_expert_review was removed from gene: EBP.
Arthrogryposis v3.154 ERBB3 Ivone Leong Tag Q2_21_rating was removed from gene: ERBB3.
Arthrogryposis v3.154 ERGIC1 Ivone Leong Tag Q3_21_rating was removed from gene: ERGIC1.
Arthrogryposis v3.154 FLNA Ivone Leong Tag Q3_21_rating was removed from gene: FLNA.
Arthrogryposis v3.154 KIDINS220 Ivone Leong Tag Q2_21_rating was removed from gene: KIDINS220.
Arthrogryposis v3.154 MED12 Ivone Leong Tag Q3_21_rating was removed from gene: MED12.
Arthrogryposis v3.154 MYLPF Ivone Leong Tag Q2_21_expert_review was removed from gene: MYLPF.
Arthrogryposis v3.154 SLC29A3 Ivone Leong Tag Q4_21_rating was removed from gene: SLC29A3.
Tag Q4_21_NHS_review was removed from gene: SLC29A3.
Arthrogryposis v3.154 SLC6A9 Ivone Leong Tag Q4_21_rating was removed from gene: SLC6A9.
Tag Q4_21_NHS_review was removed from gene: SLC6A9.
Arthrogryposis v3.154 SYNE1 Ivone Leong Tag Q2_21_rating was removed from gene: SYNE1.
Arthrogryposis v3.154 MYL1 Ivone Leong Tag Q2_21_rating was removed from gene: MYL1.
Arthrogryposis v3.154 FBN2 Ivone Leong Tag Q2_21_MOI was removed from gene: FBN2.
Arthrogryposis v3.154 SYNE1 Sarah Leigh commented on gene: SYNE1
Arthrogryposis v3.154 SLC6A9 Sarah Leigh commented on gene: SLC6A9
Arthrogryposis v3.154 SLC29A3 Sarah Leigh commented on gene: SLC29A3
Arthrogryposis v3.154 MYLPF Sarah Leigh commented on gene: MYLPF
Arthrogryposis v3.154 MYL1 Sarah Leigh commented on gene: MYL1
Arthrogryposis v3.154 MED12 Sarah Leigh commented on gene: MED12
Arthrogryposis v3.154 KIDINS220 Sarah Leigh commented on gene: KIDINS220
Arthrogryposis v3.154 FLNA Sarah Leigh commented on gene: FLNA
Arthrogryposis v3.154 FBN2 Sarah Leigh commented on gene: FBN2: The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.
Arthrogryposis v3.154 ERGIC1 Sarah Leigh commented on gene: ERGIC1
Arthrogryposis v3.154 ERBB3 Sarah Leigh commented on gene: ERBB3: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Arthrogryposis v3.154 EBP Sarah Leigh commented on gene: EBP
Arthrogryposis v3.153 SYNE1 Ivone Leong Source Expert Review Green was added to SYNE1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 SLC6A9 Ivone Leong Source Expert Review Green was added to SLC6A9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 SLC29A3 Ivone Leong Source Expert Review Green was added to SLC29A3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 MYL1 Ivone Leong Source Expert Review Red was added to MYL1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Arthrogryposis v3.153 MED12 Ivone Leong Source Expert Review Green was added to MED12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 KIDINS220 Ivone Leong Source Expert Review Green was added to KIDINS220.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 FLNA Ivone Leong Source Expert Review Green was added to FLNA.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 FBN2 Ivone Leong Source NHS GMS was added to FBN2.
Mode of inheritance for gene FBN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.153 ERGIC1 Ivone Leong Source Expert Review Green was added to ERGIC1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 ERBB3 Ivone Leong Source Expert Review Green was added to ERBB3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Arthrogryposis v3.153 EBP Ivone Leong Source Expert Review Green was added to EBP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, adult onset v1.166 PPP2R5D Ivone Leong Tag Q2_21_phenotype was removed from gene: PPP2R5D.
Dystonia, chorea or related movement disorder, adult onset v1.166 VPS16 Ivone Leong Tag Q2_21_rating was removed from gene: VPS16.
Tag Q2_21_NHS_review was removed from gene: VPS16.
Dystonia, chorea or related movement disorder, adult onset v1.166 VPS41 Ivone Leong Tag Q2_21_expert_review was removed from gene: VPS41.
Tag Q2_21_NHS_review was removed from gene: VPS41.
Dystonia, chorea or related movement disorder, adult onset v1.166 VPS41 Sarah Leigh commented on gene: VPS41
Dystonia, chorea or related movement disorder, adult onset v1.166 VPS16 Sarah Leigh commented on gene: VPS16
Dystonia, chorea or related movement disorder, adult onset v1.166 PPP2R5D Sarah Leigh commented on gene: PPP2R5D: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Dystonia, chorea or related movement disorder, adult onset v1.165 VPS16 Ivone Leong Source Expert Review Green was added to VPS16.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Dystonia, chorea or related movement disorder, adult onset v1.165 PPP2R5D Ivone Leong Source Expert Review Green was added to PPP2R5D.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Cystic kidney disease v2.35 DZIP1L Yu Leng Phua Deleted their comment
Cystic kidney disease v2.35 DZIP1L Yu Leng Phua edited their review of gene: DZIP1L: Added comment: Four children from three consanguineous families presenting with polycystic kidney disease;
Variants: c.193 T > C; p.(Cys65Arg), and c.216C > G; p.(Cys72Trp);
Functional analyses of the c.216C > G; p.(Cys72Trp) variant indicated mislocalization of mutant DZIP1L;
NOTE: Lack of liver phenotype in these patients; Changed phenotypes to: # 617610 POLYCYSTIC KIDNEY DISEASE 5, PKD5
Cystic kidney disease v2.35 DZIP1L Yu Leng Phua reviewed gene: DZIP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 35211789; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1518 HEATR3 Konstantinos Varvagiannis gene: HEATR3 was added
gene: HEATR3 was added to Intellectual disability. Sources: Literature
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
Review for gene: HEATR3 was set to AMBER
Added comment: O'Donohue et al (2022 - PMID: 35213692) describe the clinical features of 6 individuals (from 4 unrelated families) with biallelic pathogenic HEATR3 variants.

These included bone marrow failure (anemia/anemia and thrombocytopenia at presentation), short stature/growth retardation (4/6), facial features (5/6 - in some: straight eyebrows, d-s palpebral fissures, synophrys) and skeletal findings incl. disproportionately short fingers/thumb anomaly. ID was reported in 4/6 individuals from 3 families (all: mild ID | 2/6 without ID). The phenotype corresponded overall to a variant form Diamond-Blackfan anemia (DBA, disorder caused by variants in genes encoding for ribosomal proteins) with additional features.

The 1st family (2 affected sibs and parents) underwent WES, not diagnostic for DBA. Analysis suggested variants in HEATR3 (prioritized due to its potential role in ribosome biogenesis) and 4 additional genes as candidates. Collaboration in the European DBA consortium and national DBA consortia led to identification of additional families.

HEATR3 encodes Heat-repeat-containing protein 3 or symportin, a protein that co-imports uL5 (encoded by RPL11) and uL18 (RPL5) in the nucleus where they assemble with 5S rRNA to form 5S RNP. The 5S RNP complex incorporates with maturing large ribosomal subunits to form the central protuberance. When 5S RNP is not incorporated, it accumulates and associates with Hdm2 ubiquitin ligase, the later normally targeting p53 proteasomal degradation.

The following missense and splice variants were identified (NM_182922):
- c.1751G>Α/p.(Gly584Glu) hmz
- c.1337G>A/p.(Cys446Tyr) hmz
- c.399+1G>T in trans with c.719C>T/p.(Pro240Leu)
- c.400T>C/p.(Cys134Arg) hmz

Variants were confirmed with Sanger sequencing. They were dispersed across HEATR3 without clustering although they affect residues either in the ARM (38-320) or HEAT (415-675) repeat domains, at positions evolutionary conserved, with in silico predictions in favor of a deleterious effect. With the exception of Cys134Arg (AF:4.11x10-6/no hmz), all were absent from gnomAD.

Studies in yeast suggested that deletions in symportin gene (syo1) lead to a mild growth defect and accumulation of 40S subunits. Similarly, two yeast strains engineered to test for the effect of the p.Gly584Glu (yeast p.Gly522Glu/Ala) exhibited growth defect and ribosomal subunit imbalance, both restored by wt Syo1.

HA-tagged HEATR3 in HeLa cells suggested that the co-translational capture mechanism to chaperone uL18 (RPL5) is conserved in human cells but was not observed upon expression of the p.Cys446Tyr variant.

While HEATR3 transcription was not affected in LCLs from individuals hmz for Gly584Glu or Cys446Tyr, protein levels were barely detectable, suggesting destabilization of the protein.

While uL18 accumulates in cytoplasm and nucleus with expected enrichment in nucleolus, upon siRNA knockdown of HEATR3 in HeLa cells this enrichment was lost. Studies in fibroblasts (Gly584Glu) demonstrated reduced uL18 nuclear staining. Overall, HEATR3 was suggested to be important for nuclear import of uL18 (though not for uL5).

LCL studies demonstrated pre-rRNA processing defects in patient cells with accumulation of 32S and 12S pre-rRNAs, the former being reminiscent of accumulations observed in individuals with RPL5- and RPL11-related DBA. Expression of wt HEATR3 restored processing defects.

LCLs from affected individuals revealed loss of free 60S subunits (as in yeast) with expression of wt cDNA restoring Nl levels.

Western blots of LCLs demonstrated that the levels of uL5, uL18 and p53 were not affected (the latter also observed in RPL5-related DBA)

Studies of bone marrow smears from 2 affected individuals allowed to conclude in a strong defect in erythroid cell proliferation.

Currently, there is no HEATR3-associated phenotype in OMIM, PanelApp Australia, G2P or the SysID database.

Consider inclusion in the ID panel with amber (mild ID in >3 individuals/families/variants although not universal feature) or green rating. Also consider inclusion in other possibly relevant panels eg. for cytopenias/congenital anemias, short stature, etc.
Sources: Literature
Neurodegenerative disorders, adult onset v2.267 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as Green List (high evidence)
Neurodegenerative disorders, adult onset v2.267 HTT_CAG Arina Puzriakova Str: htt_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.105 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.105 HTT_CAG Arina Puzriakova Str: htt_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.289 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.289 HTT_CAG Arina Puzriakova Str: htt_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.298 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as Green List (high evidence)
Hereditary ataxia v1.298 HTT_CAG Arina Puzriakova Str: htt_cag has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 HTT_CAG Arina Puzriakova Classified STR: HTT_CAG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.76 HTT_CAG Arina Puzriakova Str: htt_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.104 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.104 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.288 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.288 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.297 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Hereditary ataxia v1.297 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.75 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.75 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Brain channelopathy v1.77 TBP_CAG Arina Puzriakova Classified STR: TBP_CAG as Green List (high evidence)
Brain channelopathy v1.77 TBP_CAG Arina Puzriakova Str: tbp_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.103 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.103 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.287 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.287 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.296 PPP2R2B_CAG Arina Puzriakova Classified STR: PPP2R2B_CAG as Green List (high evidence)
Hereditary ataxia v1.296 PPP2R2B_CAG Arina Puzriakova Str: ppp2r2b_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.295 NOP56_GGCCTG Arina Puzriakova Classified STR: NOP56_GGCCTG as Green List (high evidence)
Hereditary ataxia v1.295 NOP56_GGCCTG Arina Puzriakova Str: nop56_ggcctg has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.74 NOP56_GGCCTG Arina Puzriakova Classified STR: NOP56_GGCCTG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.74 NOP56_GGCCTG Arina Puzriakova Str: nop56_ggcctg has been classified as Green List (High Evidence).
Amyotrophic lateral sclerosis/motor neuron disease v1.56 NOP56_GGCCTG Arina Puzriakova Classified STR: NOP56_GGCCTG as Green List (high evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.56 NOP56_GGCCTG Arina Puzriakova Str: nop56_ggcctg has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.102 JPH3_CTG Arina Puzriakova Classified STR: JPH3_CTG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.102 JPH3_CTG Arina Puzriakova Str: jph3_ctg has been classified as Green List (High Evidence).
Early onset dystonia v1.111 JPH3_CTG Arina Puzriakova Classified STR: JPH3_CTG as Green List (high evidence)
Early onset dystonia v1.111 JPH3_CTG Arina Puzriakova Str: jph3_ctg has been classified as Green List (High Evidence).
Intellectual disability v3.1518 FMR1_CGG Arina Puzriakova Classified STR: FMR1_CGG as Green List (high evidence)
Intellectual disability v3.1518 FMR1_CGG Arina Puzriakova Str: fmr1_cgg has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.73 JPH3_CTG Arina Puzriakova Classified STR: JPH3_CTG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.73 JPH3_CTG Arina Puzriakova Str: jph3_ctg has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.286 FXN_GAA Arina Puzriakova Classified STR: FXN_GAA as Green List (high evidence)
Hereditary spastic paraplegia v1.286 FXN_GAA Arina Puzriakova Str: fxn_gaa has been classified as Green List (High Evidence).
Hereditary neuropathy v1.441 FXN_GAA Arina Puzriakova Classified STR: FXN_GAA as Green List (high evidence)
Hereditary neuropathy v1.441 FXN_GAA Arina Puzriakova Str: fxn_gaa has been classified as Green List (High Evidence).
Hereditary ataxia v1.294 FXN_GAA Arina Puzriakova Classified STR: FXN_GAA as Green List (high evidence)
Hereditary ataxia v1.294 FXN_GAA Arina Puzriakova Str: fxn_gaa has been classified as Green List (High Evidence).
Intellectual disability v3.1518 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Intellectual disability v3.1518 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Mitochondrial disorders v2.92 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Mitochondrial disorders v2.92 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.45 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Skeletal Muscle Channelopathies v1.45 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Congenital myopathy v2.79 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Congenital myopathy v2.79 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Congenital muscular dystrophy v2.27 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Green List (high evidence)
Congenital muscular dystrophy v2.27 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Green List (High Evidence).
Hereditary ataxia v1.293 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Hereditary ataxia v1.293 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.497 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Early onset or syndromic epilepsy v2.497 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Brain channelopathy v1.76 CSTB_CCCCGCCCCGCG Arina Puzriakova Classified STR: CSTB_CCCCGCCCCGCG as Green List (high evidence)
Brain channelopathy v1.76 CSTB_CCCCGCCCCGCG Arina Puzriakova Str: cstb_ccccgccccgcg has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.285 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.285 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.292 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Green List (high evidence)
Hereditary ataxia v1.292 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Green List (High Evidence).
Brain channelopathy v1.75 CACNA1A_CAG Arina Puzriakova Classified STR: CACNA1A_CAG as Green List (high evidence)
Brain channelopathy v1.75 CACNA1A_CAG Arina Puzriakova Str: cacna1a_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.101 C9orf72_GGGGCC Arina Puzriakova Classified STR: C9orf72_GGGGCC as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.101 C9orf72_GGGGCC Arina Puzriakova Str: c9orf72_ggggcc has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.72 C9orf72_GGGGCC Arina Puzriakova Classified STR: C9orf72_GGGGCC as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.72 C9orf72_GGGGCC Arina Puzriakova Str: c9orf72_ggggcc has been classified as Green List (High Evidence).
Amyotrophic lateral sclerosis/motor neuron disease v1.55 C9orf72_GGGGCC Arina Puzriakova Classified STR: C9orf72_GGGGCC as Green List (high evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.55 C9orf72_GGGGCC Arina Puzriakova Str: c9orf72_ggggcc has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.284 ATXN7_CAG Arina Puzriakova Classified STR: ATXN7_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.284 ATXN7_CAG Arina Puzriakova Str: atxn7_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.291 ATXN7_CAG Arina Puzriakova Classified STR: ATXN7_CAG as Green List (high evidence)
Hereditary ataxia v1.291 ATXN7_CAG Arina Puzriakova Str: atxn7_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.100 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.100 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.283 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.283 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Green List (High Evidence).
Hereditary neuropathy v1.440 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Green List (high evidence)
Hereditary neuropathy v1.440 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.290 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Green List (high evidence)
Hereditary ataxia v1.290 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Green List (High Evidence).
Early onset dystonia v1.110 ATXN3_CAG Arina Puzriakova Classified STR: ATXN3_CAG as Green List (high evidence)
Early onset dystonia v1.110 ATXN3_CAG Arina Puzriakova Str: atxn3_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.99 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.99 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.282 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.282 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Hereditary neuropathy v1.439 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Hereditary neuropathy v1.439 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.289 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Hereditary ataxia v1.289 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Early onset dystonia v1.109 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Early onset dystonia v1.109 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.71 ATXN2_CAG Arina Puzriakova Classified STR: ATXN2_CAG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.71 ATXN2_CAG Arina Puzriakova Str: atxn2_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.281 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Green List (high evidence)
Hereditary spastic paraplegia v1.281 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Green List (High Evidence).
Hereditary neuropathy v1.438 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Green List (high evidence)
Hereditary neuropathy v1.438 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Green List (High Evidence).
Hereditary ataxia v1.288 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Green List (high evidence)
Hereditary ataxia v1.288 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.70 ATXN10_ATTCT Arina Puzriakova Classified STR: ATXN10_ATTCT as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.70 ATXN10_ATTCT Arina Puzriakova Str: atxn10_attct has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.98 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.98 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.280 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Green List (high evidence)
Hereditary spastic paraplegia v1.280 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Green List (High Evidence).
Hereditary neuropathy v1.437 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Green List (high evidence)
Hereditary neuropathy v1.437 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.287 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Green List (high evidence)
Hereditary ataxia v1.287 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.69 ATXN1_CAG Arina Puzriakova Classified STR: ATXN1_CAG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.69 ATXN1_CAG Arina Puzriakova Str: atxn1_cag has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.97 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.97 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Hereditary ataxia v1.286 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Hereditary ataxia v1.286 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Early onset or syndromic epilepsy v2.496 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.68 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.68 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Brain channelopathy v1.74 ATN1_CAG Arina Puzriakova Classified STR: ATN1_CAG as Green List (high evidence)
Brain channelopathy v1.74 ATN1_CAG Arina Puzriakova Str: atn1_cag has been classified as Green List (High Evidence).
Distal myopathies v1.45 AR_CAG Arina Puzriakova Classified STR: AR_CAG as Green List (high evidence)
Distal myopathies v1.45 AR_CAG Arina Puzriakova Str: ar_cag has been classified as Green List (High Evidence).
Congenital myopathy v2.78 AR_CAG Arina Puzriakova Classified STR: AR_CAG as Green List (high evidence)
Congenital myopathy v2.78 AR_CAG Arina Puzriakova Str: ar_cag has been classified as Green List (High Evidence).
Amyotrophic lateral sclerosis/motor neuron disease v1.54 AR_CAG Arina Puzriakova Classified STR: AR_CAG as Green List (high evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.54 AR_CAG Arina Puzriakova Str: ar_cag has been classified as Green List (High Evidence).
Neurodegenerative disorders, adult onset v2.264 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source Expert Review Removed was added to STR: HTT_CAG.
Rating Changed from Green List (high evidence) to No List (delete)
Structural basal ganglia disorders v1.28 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Parkinson Disease and Complex Parkinsonism v1.94 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary spastic paraplegia, childhood onset v2.126 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Hereditary spastic paraplegia, adult onset v1.91 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Hereditary spastic paraplegia v1.277 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Hereditary ataxia v1.283 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Brain channelopathy v1.71 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.284 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Source NHS GMS was added to STR: HTT_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 HTT_CAG Arina Puzriakova Normal Number of Repeats for HTT_CAG was changed from 40 to 36.
Paroxysmal central nervous system disorders v1.38 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Neurodegenerative disorders, adult onset v2.264 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Parkinson Disease and Complex Parkinsonism v1.94 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary spastic paraplegia, childhood onset v2.126 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Hereditary spastic paraplegia v1.277 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia v1.283 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.213 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Brain channelopathy v1.71 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 TBP_CAG Arina Puzriakova Source NHS GMS was added to STR: TBP_CAG.
Neurodegenerative disorders, adult onset v2.264 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Parkinson Disease and Complex Parkinsonism v1.94 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Hereditary spastic paraplegia, adult onset v1.91 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Hereditary spastic paraplegia v1.277 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Hereditary ataxia, adult onset v2.145 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Hereditary ataxia v1.283 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Source NHS GMS was added to STR: PPP2R2B_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 PPP2R2B_CAG Arina Puzriakova Normal Number of Repeats for PPP2R2B_CAG was changed from 32 to 33.
Pathogenic Number of Repeats for PPP2R2B_CAG was changed from 51 to 43.
Hereditary neuropathy v1.434 NOP56_GGCCTG Arina Puzriakova Source NHS GMS was added to STR: NOP56_GGCCTG.
Hereditary ataxia v1.283 NOP56_GGCCTG Arina Puzriakova Source NHS GMS was added to STR: NOP56_GGCCTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 NOP56_GGCCTG Arina Puzriakova Source NHS GMS was added to STR: NOP56_GGCCTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 NOP56_GGCCTG Arina Puzriakova Source NHS GMS was added to STR: NOP56_GGCCTG.
Amyotrophic lateral sclerosis/motor neuron disease v1.51 NOP56_GGCCTG Arina Puzriakova Source NHS GMS was added to STR: NOP56_GGCCTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Neurodegenerative disorders, adult onset v2.264 JPH3_CTG Arina Puzriakova Pathogenic Number of Repeats for JPH3_CTG was changed from 41 to 40.
Parkinson Disease and Complex Parkinsonism v1.94 JPH3_CTG Arina Puzriakova Pathogenic Number of Repeats for JPH3_CTG was changed from 41 to 40.
Source NHS GMS was added to STR: JPH3_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dystonia v1.106 JPH3_CTG Arina Puzriakova Pathogenic Number of Repeats for JPH3_CTG was changed from 41 to 40.
Source NHS GMS was added to STR: JPH3_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 JPH3_CTG Arina Puzriakova Pathogenic Number of Repeats for JPH3_CTG was changed from 41 to 40.
Source NHS GMS was added to STR: JPH3_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, adult onset v1.162 JPH3_CTG Arina Puzriakova Pathogenic Number of Repeats for JPH3_CTG was changed from 41 to 40.
Neurodegenerative disorders, adult onset v2.264 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Mitochondrial disorders v2.89 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Intellectual disability v3.1515 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Hypertrophic cardiomyopathy v2.36 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Hereditary spastic paraplegia, childhood onset v2.126 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Hereditary spastic paraplegia v1.277 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia v1.283 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Likely inborn error of metabolism v2.226 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Dystonia, chorea or related movement disorder, childhood onset v1.213 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Ataxia and cerebellar anomalies - childhood onset v2.284 FXN_GAA Arina Puzriakova Source NHS GMS was added to STR: FXN_GAA.
Primary ovarian insufficiency v1.65 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Intellectual disability v3.1515 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Hereditary ataxia, adult onset v2.145 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Hereditary ataxia v1.283 FMR1_CGG Arina Puzriakova Source NHS GMS was added to STR: FMR1_CGG.
Skeletal muscle channelopathy v1.37 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Paroxysmal central nervous system disorders v1.38 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Skeletal Muscle Channelopathies v1.42 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Mitochondrial disorders v2.89 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Paediatric motor neuronopathies v1.74 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Intellectual disability v3.1515 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Gastrointestinal neuromuscular disorders v1.19 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source Expert Review Red was added to STR: DMPK_CTG.
Source NHS GMS was added to STR: DMPK_CTG.
Fetal hydrops v1.48 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source Expert Review Red was added to STR: DMPK_CTG.
Source NHS GMS was added to STR: DMPK_CTG.
Fetal anomalies v1.840 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Likely inborn error of metabolism v2.226 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
DDG2P v2.63 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Congenital myopathy v2.75 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Congenital muscular dystrophy v2.24 DMPK_CTG Arina Puzriakova Normal Number of Repeats for DMPK_CTG was changed from 38 to 35.
Source NHS GMS was added to STR: DMPK_CTG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Paroxysmal central nervous system disorders v1.38 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Neurodegenerative disorders, adult onset v2.264 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Intellectual disability v3.1515 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Hereditary ataxia, adult onset v2.145 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Hereditary ataxia v1.283 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v2.493 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.213 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Brain channelopathy v1.71 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Source NHS GMS was added to STR: CSTB_CCCCGCCCCGCG.
Dystonia, chorea or related movement disorder, adult onset v1.162 CSTB_CCCCGCCCCGCG Arina Puzriakova Normal Number of Repeats for CSTB_CCCCGCCCCGCG was changed from 30 to 18.
Skeletal muscle channelopathy v1.37 CNBP_CCTG Arina Puzriakova Normal Number of Repeats for CNBP_CCTG was changed from 26 to 27.
Source NHS GMS was added to STR: CNBP_CCTG.
Skeletal Muscle Channelopathies v1.42 CNBP_CCTG Arina Puzriakova Normal Number of Repeats for CNBP_CCTG was changed from 26 to 27.
Source Expert Review Red was added to STR: CNBP_CCTG.
Source NHS GMS was added to STR: CNBP_CCTG.
Fetal anomalies v1.840 CNBP_CCTG Arina Puzriakova Normal Number of Repeats for CNBP_CCTG was changed from 26 to 27.
Source NHS GMS was added to STR: CNBP_CCTG.
Distal myopathies v1.42 CNBP_CCTG Arina Puzriakova Normal Number of Repeats for CNBP_CCTG was changed from 26 to 27.
Source Expert Review Red was added to STR: CNBP_CCTG.
Source NHS GMS was added to STR: CNBP_CCTG.
Paroxysmal central nervous system disorders v1.38 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Neurodegenerative disorders, adult onset v2.264 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Hereditary spastic paraplegia, adult onset v1.91 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Hereditary spastic paraplegia v1.277 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Hereditary ataxia v1.283 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Brain channelopathy v1.71 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Source NHS GMS was added to STR: CACNA1A_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 CACNA1A_CAG Arina Puzriakova Normal Number of Repeats for CACNA1A_CAG was changed from 18 to 19.
Neurodegenerative disorders, adult onset v2.264 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Parkinson Disease and Complex Parkinsonism v1.94 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Source NHS GMS was added to STR: C9orf72_GGGGCC.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Source NHS GMS was added to STR: C9orf72_GGGGCC.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Source NHS GMS was added to STR: C9orf72_GGGGCC.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.213 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Amyotrophic lateral sclerosis/motor neuron disease v1.51 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Source NHS GMS was added to STR: C9orf72_GGGGCC.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, adult onset v1.162 C9orf72_GGGGCC Arina Puzriakova Normal Number of Repeats for C9orf72_GGGGCC was changed from 30 to 24.
Pathogenic Number of Repeats for C9orf72_GGGGCC was changed from 30 to 200.
Neurodegenerative disorders, adult onset v2.264 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Undiagnosed metabolic disorders v1.511 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Intellectual disability v3.1515 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Hereditary spastic paraplegia, adult onset v1.91 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Hereditary spastic paraplegia v1.277 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Hereditary ataxia, adult onset v2.145 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Hereditary ataxia v1.283 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 ATXN7_CAG Arina Puzriakova Normal Number of Repeats for ATXN7_CAG was changed from 34 to 28.
Pathogenic Number of Repeats for ATXN7_CAG was changed from 36 to 37.
Source NHS GMS was added to STR: ATXN7_CAG.
Neurodegenerative disorders, adult onset v2.264 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Parkinson Disease and Complex Parkinsonism v1.94 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Hereditary spastic paraplegia, adult onset v1.91 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Hereditary spastic paraplegia v1.277 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Hereditary ataxia v1.283 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dystonia v1.106 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN3_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 ATXN3_CAG Arina Puzriakova Normal Number of Repeats for ATXN3_CAG was changed from 44 to 45.
Neurodegenerative disorders, adult onset v2.264 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Parkinson Disease and Complex Parkinsonism v1.94 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Hereditary spastic paraplegia, adult onset v1.91 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Hereditary spastic paraplegia v1.277 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Hereditary ataxia v1.283 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dystonia v1.106 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Dystonia, chorea or related movement disorder, childhood onset v1.213 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Ataxia and cerebellar anomalies - childhood onset v2.284 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Amyotrophic lateral sclerosis/motor neuron disease v1.51 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Source NHS GMS was added to STR: ATXN2_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 ATXN2_CAG Arina Puzriakova Normal Number of Repeats for ATXN2_CAG was changed from 31 to 32.
Pathogenic Number of Repeats for ATXN2_CAG was changed from 33 to 35.
Thoracic dystrophies v1.16 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Skeletal dysplasia v2.187 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Neurodegenerative disorders, adult onset v2.264 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Intellectual disability v3.1515 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Hereditary spastic paraplegia, childhood onset v2.126 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Hereditary spastic paraplegia, adult onset v1.91 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Hereditary spastic paraplegia v1.277 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Hereditary ataxia v1.283 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dystonia v1.106 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 ATXN10_ATTCT Arina Puzriakova Normal Number of Repeats for ATXN10_ATTCT was changed from 32 to 33.
Source NHS GMS was added to STR: ATXN10_ATTCT.
Neurodegenerative disorders, adult onset v2.264 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Parkinson Disease and Complex Parkinsonism v1.94 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Intellectual disability v3.1515 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Hereditary spastic paraplegia, childhood onset v2.126 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Hereditary spastic paraplegia, adult onset v1.91 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Hereditary spastic paraplegia v1.277 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary neuropathy v1.434 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Hereditary ataxia v1.283 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Source NHS GMS was added to STR: ATXN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 ATXN1_CAG Arina Puzriakova Normal Number of Repeats for ATXN1_CAG was changed from 35 to 36.
Pathogenic Number of Repeats for ATXN1_CAG was changed from 44 to 45.
Paroxysmal central nervous system disorders v1.38 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Neurodegenerative disorders, adult onset v2.264 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Parkinson Disease and Complex Parkinsonism v1.94 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.145 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Hereditary ataxia v1.283 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset or syndromic epilepsy v2.493 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.65 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Brain channelopathy v1.71 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Ataxia and cerebellar anomalies - childhood onset v2.284 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Source NHS GMS was added to STR: ATN1_CAG.
Dystonia, chorea or related movement disorder, adult onset v1.162 ATN1_CAG Arina Puzriakova Normal Number of Repeats for ATN1_CAG was changed from 35 to 36.
Neurodegenerative disorders, adult onset v2.264 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Paediatric motor neuronopathies v1.74 AR_CAG Arina Puzriakova GRCh37 position for AR_CAG was changed from - to 66765160-66765225.
Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Hereditary neuropathy or pain disorder v1.84 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Hereditary neuropathy v1.434 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Distal myopathies v1.42 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Congenital myopathy v2.75 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.51 AR_CAG Arina Puzriakova Normal Number of Repeats for AR_CAG was changed from 34 to 35.
Source NHS GMS was added to STR: AR_CAG.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Neurodegenerative disorders, adult onset v2.263 SORL1 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: SORL1.
Neurodegenerative disorders, adult onset v2.263 FIG4 Eleanor Williams Tag Q3_21_NHS_review was removed from gene: FIG4.
Tag Q4_21_expert_review was removed from gene: FIG4.
Neurodegenerative disorders, adult onset v2.263 ERBB4 Eleanor Williams Tag Q2_21_rating was removed from gene: ERBB4.
Neurodegenerative disorders, adult onset v2.263 FIG4 Sarah Leigh commented on gene: FIG4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Neurodegenerative disorders, adult onset v2.263 ERBB4 Sarah Leigh commented on gene: ERBB4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Neurodegenerative disorders, adult onset v2.262 FIG4 Eleanor Williams Source Expert Review Red was added to FIG4.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Neurodegenerative disorders, adult onset v2.262 ERBB4 Eleanor Williams Source Expert Review Green was added to ERBB4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v1.839 ISCA-46302-Gain Arina Puzriakova Tag for-review was removed from Region: ISCA-46302-Gain.
Differences in sex development v2.58 ISCA-46302-Gain Arina Puzriakova Tag for-review was removed from Region: ISCA-46302-Gain.
Differences in sex development v2.58 ISCA-46302-Gain Arina Puzriakova Classified Region: ISCA-46302-Gain as Green List (high evidence)
Differences in sex development v2.58 ISCA-46302-Gain Arina Puzriakova Region: isca-46302-gain has been classified as Green List (High Evidence).
Differences in sex development v2.57 ISCA-46302-Gain Arina Puzriakova commented on Region: ISCA-46302-Gain
Fetal anomalies v1.839 ISCA-46302-Gain Arina Puzriakova commented on Region: ISCA-46302-Gain
Fetal anomalies v1.839 ISCA-46302-Gain Arina Puzriakova Haploinsufficiency Score for ISCA-46302-Gain was changed from None to .
Source Expert Review Green was added to Region: ISCA-46302-Gain.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.96 NADSYN1 Arina Puzriakova Tag for-review was removed from gene: NADSYN1.
Paediatric disorders - additional genes v1.96 MYOCD Arina Puzriakova Tag for-review was removed from gene: MYOCD.
Paediatric disorders - additional genes v1.96 LRIG2 Arina Puzriakova Tag for-review was removed from gene: LRIG2.
Paediatric disorders - additional genes v1.96 ITGA8 Arina Puzriakova Tag for-review was removed from gene: ITGA8.
Paediatric disorders - additional genes v1.96 GREB1L Arina Puzriakova Tag for-review was removed from gene: GREB1L.
Paediatric disorders - additional genes v1.96 GATA3 Arina Puzriakova Tag for-review was removed from gene: GATA3.
Paediatric disorders - additional genes v1.96 CHRNA3 Arina Puzriakova Tag for-review was removed from gene: CHRNA3.
Paediatric disorders - additional genes v1.96 ANOS1 Arina Puzriakova Tag for-review was removed from gene: ANOS1.
Paediatric disorders - additional genes v1.96 AGT Arina Puzriakova Tag for-review was removed from gene: AGT.
Paediatric disorders - additional genes v1.96 AGTR1 Arina Puzriakova Tag for-review was removed from gene: AGTR1.
Paediatric disorders - additional genes v1.96 ACE Arina Puzriakova Tag for-review was removed from gene: ACE.
Paediatric disorders - additional genes v1.96 ACTG2 Arina Puzriakova Tag for-review was removed from gene: ACTG2.
Paediatric disorders - additional genes v1.96 TBX18 Arina Puzriakova Tag for-review was removed from gene: TBX18.
Paediatric disorders - additional genes v1.96 REN Arina Puzriakova Tag for-review was removed from gene: REN.
Paediatric disorders - additional genes v1.96 TSPYL1 Arina Puzriakova Tag for-review was removed from gene: TSPYL1.
Paediatric disorders - additional genes v1.96 STN1 Arina Puzriakova Tag for-review was removed from gene: STN1.
Paediatric disorders - additional genes v1.96 PIGQ Arina Puzriakova Tag for-review was removed from gene: PIGQ.
Paediatric disorders - additional genes v1.96 CDH2 Arina Puzriakova Tag for-review was removed from gene: CDH2.
Paediatric disorders - additional genes v1.96 RINT1 Arina Puzriakova Tag for-review was removed from gene: RINT1.
Paediatric disorders - additional genes v1.96 HYAL2 Arina Puzriakova Tag for-review was removed from gene: HYAL2.
Paediatric disorders - additional genes v1.96 NADSYN1 Sarah Leigh commented on gene: NADSYN1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Paediatric disorders - additional genes v1.96 MYOCD Sarah Leigh commented on gene: MYOCD: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Paediatric disorders - additional genes v1.96 LRIG2 Sarah Leigh commented on gene: LRIG2
Paediatric disorders - additional genes v1.96 ITGA8 Sarah Leigh commented on gene: ITGA8
Paediatric disorders - additional genes v1.96 GREB1L Sarah Leigh commented on gene: GREB1L
Paediatric disorders - additional genes v1.96 GATA3 Sarah Leigh commented on gene: GATA3
Paediatric disorders - additional genes v1.96 CHRNA3 Sarah Leigh commented on gene: CHRNA3
Paediatric disorders - additional genes v1.96 ANOS1 Sarah Leigh commented on gene: ANOS1
Paediatric disorders - additional genes v1.96 AGTR1 Sarah Leigh commented on gene: AGTR1
Paediatric disorders - additional genes v1.96 AGT Sarah Leigh commented on gene: AGT
Paediatric disorders - additional genes v1.96 ACE Sarah Leigh commented on gene: ACE
Paediatric disorders - additional genes v1.96 ACTG2 Sarah Leigh commented on gene: ACTG2
Paediatric disorders - additional genes v1.96 TBX18 Sarah Leigh commented on gene: TBX18
Paediatric disorders - additional genes v1.96 REN Sarah Leigh commented on gene: REN
Paediatric disorders - additional genes v1.96 TSPYL1 Sarah Leigh commented on gene: TSPYL1
Paediatric disorders - additional genes v1.96 STN1 Sarah Leigh commented on gene: STN1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Paediatric disorders - additional genes v1.96 PIGQ Sarah Leigh commented on gene: PIGQ: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Paediatric disorders - additional genes v1.96 CDH2 Sarah Leigh commented on gene: CDH2
Paediatric disorders - additional genes v1.96 RINT1 Sarah Leigh commented on gene: RINT1
Paediatric disorders - additional genes v1.96 HYAL2 Sarah Leigh commented on gene: HYAL2
Paediatric disorders - additional genes v1.95 NADSYN1 Arina Puzriakova Source Expert Review Green was added to NADSYN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 MYOCD Arina Puzriakova Source Expert Review Green was added to MYOCD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 LRIG2 Arina Puzriakova Source Expert Review Green was added to LRIG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 ITGA8 Arina Puzriakova Source Expert Review Green was added to ITGA8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 GREB1L Arina Puzriakova Source Expert Review Green was added to GREB1L.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 GATA3 Arina Puzriakova Source Expert Review Green was added to GATA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 CHRNA3 Arina Puzriakova Source Expert Review Green was added to CHRNA3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 ANOS1 Arina Puzriakova Source Expert Review Green was added to ANOS1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 AGTR1 Arina Puzriakova Source Expert Review Green was added to AGTR1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 AGT Arina Puzriakova Source Expert Review Green was added to AGT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 ACE Arina Puzriakova Source Expert Review Green was added to ACE.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 ACTG2 Arina Puzriakova Source Expert Review Green was added to ACTG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 TBX18 Arina Puzriakova Source Expert Review Green was added to TBX18.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 REN Arina Puzriakova Source Expert Review Green was added to REN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 TSPYL1 Arina Puzriakova Source Expert Review Green was added to TSPYL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 STN1 Arina Puzriakova Source Expert Review Green was added to STN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 PIGQ Arina Puzriakova Source Expert Review Green was added to PIGQ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 CDH2 Arina Puzriakova Source Expert Review Green was added to CDH2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 RINT1 Arina Puzriakova Source Expert Review Green was added to RINT1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Paediatric disorders - additional genes v1.95 HYAL2 Arina Puzriakova Source Expert Review Green was added to HYAL2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.293 CEP63 Eleanor Williams Tag Q2_21_expert_review was removed from gene: CEP63.
Severe microcephaly v2.293 YIPF5 Eleanor Williams Tag Q2_21_rating was removed from gene: YIPF5.
Severe microcephaly v2.293 WDR4 Eleanor Williams Tag Q2_21_rating was removed from gene: WDR4.
Severe microcephaly v2.293 WDR37 Eleanor Williams Tag Q2_21_rating was removed from gene: WDR37.
Severe microcephaly v2.293 WDR11 Eleanor Williams Tag Q4_21_rating was removed from gene: WDR11.
Severe microcephaly v2.293 VRK1 Eleanor Williams Tag Q3_21_rating was removed from gene: VRK1.
Severe microcephaly v2.293 UNC80 Eleanor Williams Tag Q2_21_rating was removed from gene: UNC80.
Severe microcephaly v2.293 UGP2 Eleanor Williams Tag Q2_21_rating was removed from gene: UGP2.
Severe microcephaly v2.293 TSEN54 Eleanor Williams Tag Q2_21_rating was removed from gene: TSEN54.
Severe microcephaly v2.293 TSEN15 Eleanor Williams Tag Q2_21_rating was removed from gene: TSEN15.
Severe microcephaly v2.293 TRIO Eleanor Williams Tag Q2_21_rating was removed from gene: TRIO.
Severe microcephaly v2.293 TRAPPC9 Eleanor Williams Tag Q2_21_rating was removed from gene: TRAPPC9.
Severe microcephaly v2.293 TRAPPC6B Eleanor Williams Tag Q2_21_rating was removed from gene: TRAPPC6B.
Severe microcephaly v2.293 TP53RK Eleanor Williams Tag Q2_21_rating was removed from gene: TP53RK.
Severe microcephaly v2.293 TNPO2 Eleanor Williams Tag Q3_21_rating was removed from gene: TNPO2.
Severe microcephaly v2.293 SMARCA5 Eleanor Williams Tag Q2_21_rating was removed from gene: SMARCA5.
Severe microcephaly v2.293 SLC1A4 Eleanor Williams Tag Q2_21_rating was removed from gene: SLC1A4.
Severe microcephaly v2.293 RAD51 Eleanor Williams Tag Q4_21_rating was removed from gene: RAD51.
Severe microcephaly v2.293 RAD50 Eleanor Williams Tag Q2_21_rating was removed from gene: RAD50.
Severe microcephaly v2.293 PUS7 Eleanor Williams Tag Q2_21_rating was removed from gene: PUS7.
Severe microcephaly v2.293 PUF60 Eleanor Williams Tag Q2_21_rating was removed from gene: PUF60.
Severe microcephaly v2.293 PTPN23 Eleanor Williams Tag Q2_21_rating was removed from gene: PTPN23.
Severe microcephaly v2.293 POGZ Eleanor Williams Tag Q2_21_rating was removed from gene: POGZ.
Severe microcephaly v2.293 PCDH12 Eleanor Williams Tag Q3_21_rating was removed from gene: PCDH12.
Severe microcephaly v2.293 OSGEP Eleanor Williams Tag Q3_21_rating was removed from gene: OSGEP.
Severe microcephaly v2.293 NUP107 Eleanor Williams Tag Q3_21_rating was removed from gene: NUP107.
Severe microcephaly v2.293 MINPP1 Eleanor Williams Tag Q2_21_rating was removed from gene: MINPP1.
Severe microcephaly v2.293 LAGE3 Eleanor Williams Tag Q3_21_rating was removed from gene: LAGE3.
Severe microcephaly v2.293 HPDL Eleanor Williams Tag Q2_21_rating was removed from gene: HPDL.
Severe microcephaly v2.293 HIST1H4C Eleanor Williams Tag Q3_21_rating was removed from gene: HIST1H4C.
Severe microcephaly v2.293 GTF2E2 Eleanor Williams Tag Q3_21_rating was removed from gene: GTF2E2.
Severe microcephaly v2.293 GPT2 Eleanor Williams Tag Q4_21_rating was removed from gene: GPT2.
Severe microcephaly v2.293 FOXG1 Eleanor Williams Tag Q2_21_rating was removed from gene: FOXG1.
Severe microcephaly v2.293 EIF5A Eleanor Williams Tag Q2_21_rating was removed from gene: EIF5A.
Severe microcephaly v2.293 EIF2S3 Eleanor Williams Tag Q3_21_rating was removed from gene: EIF2S3.
Severe microcephaly v2.293 DYNC1I2 Eleanor Williams Tag Q4_21_rating was removed from gene: DYNC1I2.
Severe microcephaly v2.293 DPM1 Eleanor Williams Tag Q2_21_rating was removed from gene: DPM1.
Severe microcephaly v2.293 DNA2 Eleanor Williams Tag Q2_21_rating was removed from gene: DNA2.
Severe microcephaly v2.293 CTU2 Eleanor Williams Tag Q2_21_rating was removed from gene: CTU2.
Severe microcephaly v2.293 CTCF Eleanor Williams Tag Q2_21_rating was removed from gene: CTCF.
Severe microcephaly v2.293 CSNK2A1 Eleanor Williams Tag Q2_21_rating was removed from gene: CSNK2A1.
Severe microcephaly v2.293 CHAMP1 Eleanor Williams Tag Q2_21_rating was removed from gene: CHAMP1.
Severe microcephaly v2.293 CEP63 Eleanor Williams Phenotypes for gene: CEP63 were changed from MCPH; primary microcephaly; ?Seckel syndrome 6, 614728; Microcephaly to MCPH; primary microcephaly; ?Seckel syndrome 6, OMIM:614728; Microcephaly
Severe microcephaly v2.292 CEP57 Eleanor Williams Tag Q2_21_rating was removed from gene: CEP57.
Severe microcephaly v2.292 CAMK2B Eleanor Williams Tag Q2_21_rating was removed from gene: CAMK2B.
Severe microcephaly v2.292 BUB1B Eleanor Williams Tag Q2_21_rating was removed from gene: BUB1B.
Severe microcephaly v2.292 BPTF Eleanor Williams Tag Q2_21_rating was removed from gene: BPTF.
Severe microcephaly v2.292 AARS Eleanor Williams Tag Q2_21_rating was removed from gene: AARS.
Severe microcephaly v2.292 YIPF5 Sarah Leigh commented on gene: YIPF5
Severe microcephaly v2.292 WDR4 Sarah Leigh commented on gene: WDR4
Severe microcephaly v2.292 WDR37 Sarah Leigh commented on gene: WDR37
Severe microcephaly v2.292 WDR11 Sarah Leigh commented on gene: WDR11
Severe microcephaly v2.292 VRK1 Sarah Leigh commented on gene: VRK1
Severe microcephaly v2.292 UNC80 Sarah Leigh commented on gene: UNC80
Severe microcephaly v2.292 UGP2 Sarah Leigh commented on gene: UGP2
Severe microcephaly v2.292 TSEN54 Sarah Leigh commented on gene: TSEN54
Severe microcephaly v2.292 TSEN15 Sarah Leigh commented on gene: TSEN15
Severe microcephaly v2.292 TRIO Sarah Leigh commented on gene: TRIO
Severe microcephaly v2.292 TRAPPC9 Sarah Leigh commented on gene: TRAPPC9
Severe microcephaly v2.292 TRAPPC6B Sarah Leigh commented on gene: TRAPPC6B
Severe microcephaly v2.292 TP53RK Sarah Leigh commented on gene: TP53RK
Severe microcephaly v2.292 TNPO2 Sarah Leigh commented on gene: TNPO2
Severe microcephaly v2.292 SMARCA5 Sarah Leigh commented on gene: SMARCA5
Severe microcephaly v2.292 SLC1A4 Sarah Leigh commented on gene: SLC1A4
Severe microcephaly v2.292 RAD51 Sarah Leigh commented on gene: RAD51
Severe microcephaly v2.292 RAD50 Sarah Leigh commented on gene: RAD50
Severe microcephaly v2.292 PUS7 Sarah Leigh commented on gene: PUS7
Severe microcephaly v2.292 PUF60 Sarah Leigh commented on gene: PUF60
Severe microcephaly v2.292 PTPN23 Sarah Leigh commented on gene: PTPN23
Severe microcephaly v2.292 POGZ Sarah Leigh commented on gene: POGZ
Severe microcephaly v2.292 PCDH12 Sarah Leigh commented on gene: PCDH12
Severe microcephaly v2.292 OSGEP Sarah Leigh commented on gene: OSGEP
Severe microcephaly v2.292 NUP107 Sarah Leigh commented on gene: NUP107
Severe microcephaly v2.292 MINPP1 Sarah Leigh commented on gene: MINPP1
Severe microcephaly v2.292 LAGE3 Sarah Leigh commented on gene: LAGE3
Severe microcephaly v2.292 HPDL Sarah Leigh commented on gene: HPDL
Severe microcephaly v2.292 HIST1H4C Sarah Leigh commented on gene: HIST1H4C
Severe microcephaly v2.292 GTF2E2 Sarah Leigh commented on gene: GTF2E2
Severe microcephaly v2.292 GPT2 Sarah Leigh commented on gene: GPT2
Severe microcephaly v2.292 FOXG1 Sarah Leigh commented on gene: FOXG1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.292 EIF5A Sarah Leigh commented on gene: EIF5A
Severe microcephaly v2.292 EIF2S3 Sarah Leigh commented on gene: EIF2S3
Severe microcephaly v2.292 DYNC1I2 Sarah Leigh commented on gene: DYNC1I2
Severe microcephaly v2.292 DPM1 Sarah Leigh commented on gene: DPM1
Severe microcephaly v2.292 DNA2 Sarah Leigh commented on gene: DNA2
Severe microcephaly v2.292 CTU2 Sarah Leigh commented on gene: CTU2
Severe microcephaly v2.292 CTCF Sarah Leigh commented on gene: CTCF
Severe microcephaly v2.292 CSNK2A1 Sarah Leigh commented on gene: CSNK2A1
Severe microcephaly v2.292 CHAMP1 Sarah Leigh commented on gene: CHAMP1
Severe microcephaly v2.292 CEP63 Sarah Leigh commented on gene: CEP63
Severe microcephaly v2.292 CEP57 Sarah Leigh commented on gene: CEP57
Severe microcephaly v2.292 CAMK2B Sarah Leigh commented on gene: CAMK2B
Severe microcephaly v2.292 BUB1B Sarah Leigh commented on gene: BUB1B
Severe microcephaly v2.292 BPTF Sarah Leigh commented on gene: BPTF
Severe microcephaly v2.292 AARS Sarah Leigh commented on gene: AARS
Severe microcephaly v2.291 YIPF5 Eleanor Williams Source Expert Review Green was added to YIPF5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR4 Eleanor Williams Source Expert Review Green was added to WDR4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR37 Eleanor Williams Source Expert Review Green was added to WDR37.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 WDR11 Eleanor Williams Source Expert Review Green was added to WDR11.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 VRK1 Eleanor Williams Source Expert Review Green was added to VRK1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 UNC80 Eleanor Williams Source Expert Review Green was added to UNC80.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 UGP2 Eleanor Williams Source Expert Review Green was added to UGP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TSEN54 Eleanor Williams Source Expert Review Green was added to TSEN54.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TSEN15 Eleanor Williams Source Expert Review Green was added to TSEN15.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRIO Eleanor Williams Source Expert Review Green was added to TRIO.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRAPPC9 Eleanor Williams Source Expert Review Green was added to TRAPPC9.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TRAPPC6B Eleanor Williams Source Expert Review Green was added to TRAPPC6B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TP53RK Eleanor Williams Source Expert Review Green was added to TP53RK.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 TNPO2 Eleanor Williams Source Expert Review Green was added to TNPO2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 SMARCA5 Eleanor Williams Source Expert Review Green was added to SMARCA5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 SLC1A4 Eleanor Williams Source Expert Review Green was added to SLC1A4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 RAD51 Eleanor Williams Source Expert Review Green was added to RAD51.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 RAD50 Eleanor Williams Source Expert Review Green was added to RAD50.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PUS7 Eleanor Williams Source Expert Review Green was added to PUS7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PUF60 Eleanor Williams Source Expert Review Green was added to PUF60.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PTPN23 Eleanor Williams Source Expert Review Green was added to PTPN23.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 POGZ Eleanor Williams Source Expert Review Green was added to POGZ.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 PCDH12 Eleanor Williams Source Expert Review Green was added to PCDH12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 OSGEP Eleanor Williams Source Expert Review Green was added to OSGEP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 NUP107 Eleanor Williams Source Expert Review Green was added to NUP107.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 MINPP1 Eleanor Williams Source Expert Review Green was added to MINPP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 LAGE3 Eleanor Williams Source Expert Review Green was added to LAGE3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 HPDL Eleanor Williams Source Expert Review Green was added to HPDL.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 HIST1H4C Eleanor Williams Source Expert Review Green was added to HIST1H4C.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 GTF2E2 Eleanor Williams Source Expert Review Green was added to GTF2E2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 GPT2 Eleanor Williams Source Expert Review Green was added to GPT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 FOXG1 Eleanor Williams Source Expert Review Green was added to FOXG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 EIF5A Eleanor Williams Source Expert Review Green was added to EIF5A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 EIF2S3 Eleanor Williams Source Expert Review Green was added to EIF2S3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DYNC1I2 Eleanor Williams Source Expert Review Green was added to DYNC1I2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DPM1 Eleanor Williams Source Expert Review Green was added to DPM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 DNA2 Eleanor Williams Source Expert Review Green was added to DNA2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CTU2 Eleanor Williams Source Expert Review Green was added to CTU2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CTCF Eleanor Williams Source Expert Review Green was added to CTCF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CSNK2A1 Eleanor Williams Source Expert Review Green was added to CSNK2A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CHAMP1 Eleanor Williams Source Expert Review Green was added to CHAMP1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CEP63 Eleanor Williams Source Expert Review Red was added to CEP63.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Severe microcephaly v2.291 CEP57 Eleanor Williams Source Expert Review Green was added to CEP57.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 CAMK2B Eleanor Williams Source Expert Review Green was added to CAMK2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 BUB1B Eleanor Williams Source Expert Review Green was added to BUB1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 BPTF Eleanor Williams Source Expert Review Green was added to BPTF.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.291 AARS Eleanor Williams Source Expert Review Green was added to AARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.290 METTL5 Eleanor Williams Phenotypes for gene: METTL5 were changed from Intellectual developmental disorder, autosomal recessive 72, 618665 to Intellectual developmental disorder, autosomal recessive 72, OMIM:618665
Severe microcephaly v2.289 METTL5 Eleanor Williams Tag for-review was removed from gene: METTL5.
Severe microcephaly v2.289 AP4S1 Eleanor Williams Publications for gene: AP4S1 were set to 21620353; 25552650; 27444738
Severe microcephaly v2.288 AP4S1 Eleanor Williams Tag for-review was removed from gene: AP4S1.
Severe microcephaly v2.288 AP4M1 Eleanor Williams Tag for-review was removed from gene: AP4M1.
Tag missense tag was added to gene: AP4M1.
Severe microcephaly v2.288 AP4B1 Eleanor Williams Tag for-review was removed from gene: AP4B1.
Severe microcephaly v2.288 UBE3A Eleanor Williams Phenotypes for gene: UBE3A were changed from Angelman syndrome 105830 to Angelman syndrome, OMIM:105830
Severe microcephaly v2.287 UBE3A Eleanor Williams Tag for-review was removed from gene: UBE3A.
Severe microcephaly v2.287 ZNF526 Eleanor Williams Tag for-review was removed from gene: ZNF526.
Severe microcephaly v2.287 SMG8 Eleanor Williams Tag for-review was removed from gene: SMG8.
Intellectual disability v3.1514 EXT2 Arina Puzriakova Tag for-review was removed from gene: EXT2.
Intellectual disability v3.1514 CTNND1 Arina Puzriakova Tag for-review was removed from gene: CTNND1.
Intellectual disability v3.1514 SLC12A6 Arina Puzriakova commented on gene: SLC12A6
Intellectual disability v3.1514 SLC12A6 Arina Puzriakova Tag for-review was removed from gene: SLC12A6.
Intellectual disability v3.1514 SCN8A Arina Puzriakova Tag for-review was removed from gene: SCN8A.
Intellectual disability v3.1514 CDK19 Arina Puzriakova Tag for-review was removed from gene: CDK19.
Intellectual disability v3.1514 ABCA2 Arina Puzriakova Tag for-review was removed from gene: ABCA2.
Intellectual disability v3.1514 PIGH Arina Puzriakova Tag for-review was removed from gene: PIGH.
Intellectual disability v3.1514 METTL5 Arina Puzriakova Tag for-review was removed from gene: METTL5.
Intellectual disability v3.1514 LMBRD2 Arina Puzriakova Tag for-review was removed from gene: LMBRD2.
Intellectual disability v3.1514 LIAS Arina Puzriakova Tag for-review was removed from gene: LIAS.
Intellectual disability v3.1514 CSNK1G1 Arina Puzriakova Tag for-review was removed from gene: CSNK1G1.
Intellectual disability v3.1514 ALG14 Arina Puzriakova Tag for-review was removed from gene: ALG14.
Intellectual disability v3.1514 AGO2 Arina Puzriakova Tag for-review was removed from gene: AGO2.
Intellectual disability v3.1514 PNPT1 Arina Puzriakova Tag for-review was removed from gene: PNPT1.
Intellectual disability v3.1514 SCO1 Arina Puzriakova Tag for-review was removed from gene: SCO1.
Intellectual disability v3.1514 FA2H Arina Puzriakova Tag for-review was removed from gene: FA2H.
Intellectual disability v3.1514 COX6B1 Arina Puzriakova Tag for-review was removed from gene: COX6B1.
Intellectual disability v3.1514 MPI Arina Puzriakova Tag for-review was removed from gene: MPI.
Intellectual disability v3.1514 VAMP1 Arina Puzriakova Tag watchlist was removed from gene: VAMP1.
Tag for-review was removed from gene: VAMP1.
Intellectual disability v3.1514 TRIM32 Arina Puzriakova Tag for-review was removed from gene: TRIM32.
Intellectual disability v3.1514 MGP Arina Puzriakova Tag for-review was removed from gene: MGP.
Intellectual disability v3.1514 LGI4 Arina Puzriakova Tag for-review was removed from gene: LGI4.
Intellectual disability v3.1514 HYLS1 Arina Puzriakova Tag for-review was removed from gene: HYLS1.
Intellectual disability v3.1514 HADH Arina Puzriakova Tag for-review was removed from gene: HADH.
Intellectual disability v3.1514 FLVCR1 Arina Puzriakova Tag for-review was removed from gene: FLVCR1.
Intellectual disability v3.1514 ATL1 Arina Puzriakova Tag for-review was removed from gene: ATL1.
Intellectual disability v3.1514 ANKH Arina Puzriakova Tag for-review was removed from gene: ANKH.
Intellectual disability v3.1514 AFG3L2 Arina Puzriakova Mode of inheritance for gene: AFG3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1513 AFG3L2 Arina Puzriakova Tag for-review was removed from gene: AFG3L2.
Tag Q2_21_MOI was removed from gene: AFG3L2.
Intellectual disability v3.1513 KCNC3 Arina Puzriakova Tag for-review was removed from gene: KCNC3.
Intellectual disability v3.1513 ALKBH8 Arina Puzriakova Tag for-review was removed from gene: ALKBH8.
Intellectual disability v3.1513 SOX3 Arina Puzriakova Tag for-review was removed from gene: SOX3.
Intellectual disability v3.1513 PRKD1 Arina Puzriakova Tag for-review was removed from gene: PRKD1.
Intellectual disability v3.1513 GPSM2 Arina Puzriakova Tag for-review was removed from gene: GPSM2.
Intellectual disability v3.1513 DDOST Arina Puzriakova Tag for-review was removed from gene: DDOST.
Intellectual disability v3.1513 CYP2U1 Arina Puzriakova Tag for-review was removed from gene: CYP2U1.
Intellectual disability v3.1513 AGPS Arina Puzriakova Tag for-review was removed from gene: AGPS.
Intellectual disability v3.1513 TMEM106B Arina Puzriakova Tag for-review was removed from gene: TMEM106B.
Intellectual disability v3.1513 NEMF Arina Puzriakova Tag for-review was removed from gene: NEMF.
Intellectual disability v3.1513 MPP5 Arina Puzriakova Tag for-review was removed from gene: MPP5.
Intellectual disability v3.1513 MAPK1 Arina Puzriakova Tag for-review was removed from gene: MAPK1.
Intellectual disability v3.1513 LMNB1 Arina Puzriakova Tag for-review was removed from gene: LMNB1.
Intellectual disability v3.1513 KIF21B Arina Puzriakova Tag for-review was removed from gene: KIF21B.
Intellectual disability v3.1513 JARID2 Arina Puzriakova Tag for-review was removed from gene: JARID2.
Intellectual disability v3.1513 FAM50A Arina Puzriakova Tag for-review was removed from gene: FAM50A.
Intellectual disability v3.1513 CEP120 Arina Puzriakova Tag for-review was removed from gene: CEP120.
Intellectual disability v3.1513 ZNF526 Arina Puzriakova Tag for-review was removed from gene: ZNF526.
Intellectual disability v3.1513 TFE3 Arina Puzriakova Tag for-review was removed from gene: TFE3.
Intellectual disability v3.1513 PIGQ Arina Puzriakova Tag for-review was removed from gene: PIGQ.
Intellectual disability v3.1513 KAT5 Arina Puzriakova Tag for-review was removed from gene: KAT5.
Intellectual disability v3.1513 ZNF335 Arina Puzriakova Tag for-review was removed from gene: ZNF335.
Intellectual disability v3.1513 ZIC1 Arina Puzriakova Tag for-review was removed from gene: ZIC1.
Intellectual disability v3.1513 SETD1A Arina Puzriakova Tag for-review was removed from gene: SETD1A.
Intellectual disability v3.1513 PET100 Arina Puzriakova Tag for-review was removed from gene: PET100.
Intellectual disability v3.1513 NUDT2 Arina Puzriakova Tag for-review was removed from gene: NUDT2.
Intellectual disability v3.1513 MFSD2A Arina Puzriakova Tag for-review was removed from gene: MFSD2A.
Severe microcephaly v2.287 NARS Eleanor Williams Tag for-review was removed from gene: NARS.
Intellectual disability v3.1513 MAPRE2 Arina Puzriakova Tag for-review was removed from gene: MAPRE2.
Severe microcephaly v2.287 MORC2 Eleanor Williams Tag for-review was removed from gene: MORC2.
Severe microcephaly v2.287 LMNB2 Eleanor Williams Tag for-review was removed from gene: LMNB2.
Intellectual disability v3.1513 CDH2 Arina Puzriakova Tag for-review was removed from gene: CDH2.
Severe microcephaly v2.287 LMNB1 Eleanor Williams Tag for-review was removed from gene: LMNB1.
Intellectual disability v3.1513 SMG8 Arina Puzriakova Tag for-review was removed from gene: SMG8.
Intellectual disability v3.1513 LSS Arina Puzriakova Tag watchlist was removed from gene: LSS.
Tag for-review was removed from gene: LSS.
Intellectual disability v3.1513 KCNMA1 Arina Puzriakova Tag for-review was removed from gene: KCNMA1.
Intellectual disability v3.1513 H3F3B Arina Puzriakova Tag for-review was removed from gene: H3F3B.
Intellectual disability v3.1513 H3F3A Arina Puzriakova Tag for-review was removed from gene: H3F3A.
Intellectual disability v3.1513 KDM4B Arina Puzriakova Tag for-review was removed from gene: KDM4B.
Intellectual disability v3.1513 BICRA Arina Puzriakova Tag for-review was removed from gene: BICRA.
Intellectual disability v3.1513 ZFHX4 Arina Puzriakova Tag for-review was removed from gene: ZFHX4.
Intellectual disability v3.1513 SHMT2 Arina Puzriakova Tag for-review was removed from gene: SHMT2.
Intellectual disability v3.1513 NARS Arina Puzriakova Tag for-review was removed from gene: NARS.
Intellectual disability v3.1513 MORC2 Arina Puzriakova Tag for-review was removed from gene: MORC2.
Intellectual disability v3.1513 LARS Arina Puzriakova Tag for-review was removed from gene: LARS.
Intellectual disability v3.1513 POLR1C Arina Puzriakova Tag for-review was removed from gene: POLR1C.
Intellectual disability v3.1513 NUS1 Arina Puzriakova Tag for-review was removed from gene: NUS1.
Intellectual disability v3.1513 NUS1 Arina Puzriakova Phenotypes for gene: NUS1 were changed from #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082
Early onset or syndromic epilepsy v2.492 NUS1 Arina Puzriakova Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa OMIM:617082; Mental retardation, autosomal dominant 55, with seizures OMIM:617831; Abnormality of extrapyramidal motor function to Mental retardation, autosomal dominant 55, with seizures, OMIM:617831; Congenital disorder of glycosylation, type 1aa, OMIM:617082
Intellectual disability v3.1512 NUS1 Arina Puzriakova Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1511 PUM1 Arina Puzriakova Tag for-review was removed from gene: PUM1.
Intellectual disability v3.1511 RALGAPA1 Arina Puzriakova Tag for-review was removed from gene: RALGAPA1.
Intellectual disability v3.1511 RARS Arina Puzriakova Tag for-review was removed from gene: RARS.
Intellectual disability v3.1511 CEP55 Arina Puzriakova Tag for-review was removed from gene: CEP55.
Intellectual disability v3.1511 CTU2 Arina Puzriakova Tag for-review was removed from gene: CTU2.
Intellectual disability v3.1511 TRAPPC4 Arina Puzriakova Tag for-review was removed from gene: TRAPPC4.
Intellectual disability v3.1511 UGP2 Arina Puzriakova Tag for-review was removed from gene: UGP2.
Intellectual disability v3.1511 CXorf56 Arina Puzriakova Tag for-review was removed from gene: CXorf56.
Intellectual disability v3.1511 KAT8 Arina Puzriakova Tag for-review was removed from gene: KAT8.
Intellectual disability v3.1511 SLC5A6 Arina Puzriakova Tag for-review was removed from gene: SLC5A6.
Intellectual disability v3.1511 SNX27 Arina Puzriakova Tag for-review was removed from gene: SNX27.
Intellectual disability v3.1511 WNT1 Arina Puzriakova Tag for-review was removed from gene: WNT1.
Intellectual disability v3.1511 YIF1B Arina Puzriakova Tag for-review was removed from gene: YIF1B.
Intellectual disability v3.1511 VARS2 Arina Puzriakova Tag for-review was removed from gene: VARS2.
Intellectual disability v3.1511 UGDH Arina Puzriakova Tag for-review was removed from gene: UGDH.
Intellectual disability v3.1511 TTC5 Arina Puzriakova Tag for-review was removed from gene: TTC5.
Intellectual disability v3.1511 TRNT1 Arina Puzriakova Tag for-review was removed from gene: TRNT1.
Intellectual disability v3.1511 TNRC6B Arina Puzriakova Tag for-review was removed from gene: TNRC6B.
Intellectual disability v3.1511 TET3 Arina Puzriakova Tag for-review was removed from gene: TET3.
Intellectual disability v3.1511 TENM3 Arina Puzriakova Tag for-review was removed from gene: TENM3.
Intellectual disability v3.1511 TASP1 Arina Puzriakova Tag for-review was removed from gene: TASP1.
Intellectual disability v3.1511 SUZ12 Arina Puzriakova Tag for-review was removed from gene: SUZ12.
Intellectual disability v3.1511 SUPT16H Arina Puzriakova Tag for-review was removed from gene: SUPT16H.
Intellectual disability v3.1511 SPTBN4 Arina Puzriakova Tag for-review was removed from gene: SPTBN4.
Intellectual disability v3.1511 SPOP Arina Puzriakova Tag for-review was removed from gene: SPOP.
Intellectual disability v3.1511 SOX6 Arina Puzriakova Tag for-review was removed from gene: SOX6.
Intellectual disability v3.1511 SLC1A1 Arina Puzriakova Tag for-review was removed from gene: SLC1A1.
Intellectual disability v3.1511 SLC12A2 Arina Puzriakova Tag for-review was removed from gene: SLC12A2.
Intellectual disability v3.1511 SFXN4 Arina Puzriakova Tag for-review was removed from gene: SFXN4.
Intellectual disability v3.1511 SBF1 Arina Puzriakova Tag for-review was removed from gene: SBF1.
Intellectual disability v3.1511 SARS2 Arina Puzriakova Tag for-review was removed from gene: SARS2.
Intellectual disability v3.1511 RSRC1 Arina Puzriakova Tag for-review was removed from gene: RSRC1.
Intellectual disability v3.1511 PPP1R12A Arina Puzriakova Tag for-review was removed from gene: PPP1R12A.
Intellectual disability v3.1511 PIGS Arina Puzriakova Tag for-review was removed from gene: PIGS.
Intellectual disability v3.1511 PIGK Arina Puzriakova Tag for-review was removed from gene: PIGK.
Intellectual disability v3.1511 PIBF1 Arina Puzriakova Tag for-review was removed from gene: PIBF1.
Intellectual disability v3.1511 PDHB Arina Puzriakova Tag for-review was removed from gene: PDHB.
Intellectual disability v3.1511 OXR1 Arina Puzriakova Tag for-review was removed from gene: OXR1.
Intellectual disability v3.1511 NRROS Arina Puzriakova Tag for-review was removed from gene: NRROS.
Intellectual disability v3.1511 NOVA2 Arina Puzriakova Tag for-review was removed from gene: NOVA2.
Intellectual disability v3.1511 NDUFA2 Arina Puzriakova Tag for-review was removed from gene: NDUFA2.
Intellectual disability v3.1511 MTHFS Arina Puzriakova Tag for-review was removed from gene: MTHFS.
Intellectual disability v3.1511 MN1 Arina Puzriakova Tag for-review was removed from gene: MN1.
Intellectual disability v3.1511 LYRM7 Arina Puzriakova Tag for-review was removed from gene: LYRM7.
Intellectual disability v3.1511 LIPT1 Arina Puzriakova Tag for-review was removed from gene: LIPT1.
Intellectual disability v3.1511 KLF7 Arina Puzriakova Tag for-review was removed from gene: KLF7.
Intellectual disability v3.1511 KCNN3 Arina Puzriakova Tag for-review was removed from gene: KCNN3.
Intellectual disability v3.1511 HNRNPH1 Arina Puzriakova Tag for-review was removed from gene: HNRNPH1.
Intellectual disability v3.1511 GPC4 Arina Puzriakova Tag for-review was removed from gene: GPC4.
Intellectual disability v3.1511 GALNT2 Arina Puzriakova Tag for-review was removed from gene: GALNT2.
Intellectual disability v3.1511 EIF2AK2 Arina Puzriakova Tag for-review was removed from gene: EIF2AK2.
Intellectual disability v3.1511 EARS2 Arina Puzriakova Tag for-review was removed from gene: EARS2.
Intellectual disability v3.1511 DNM1L Arina Puzriakova Tag for-review was removed from gene: DNM1L.
Intellectual disability v3.1511 DHX37 Arina Puzriakova Tag for-review was removed from gene: DHX37.
Intellectual disability v3.1511 CNTNAP1 Arina Puzriakova Tag for-review was removed from gene: CNTNAP1.
Intellectual disability v3.1511 B9D2 Arina Puzriakova Tag for-review was removed from gene: B9D2.
Intellectual disability v3.1511 ATAD1 Arina Puzriakova Tag for-review was removed from gene: ATAD1.
Intellectual disability v3.1511 ADD3 Arina Puzriakova Tag for-review was removed from gene: ADD3.
Intellectual disability v3.1511 ADARB1 Arina Puzriakova Tag for-review was removed from gene: ADARB1.
Intellectual disability v3.1511 DLL1 Arina Puzriakova Tag for-review was removed from gene: DLL1.
Severe microcephaly v2.287 DNMT3A Eleanor Williams Tag for-review was removed from gene: DNMT3A.
Severe microcephaly v2.287 ZNF335 Eleanor Williams Phenotypes for gene: ZNF335 were changed from Microcephaly 10, primary, autosomal recessive, 615095 to Microcephaly 10, primary, autosomal recessive, OMIM:615095
Severe microcephaly v2.286 ZNF335 Eleanor Williams Tag for-review was removed from gene: ZNF335.
Severe microcephaly v2.286 ATP1A2 Eleanor Williams Tag for-review was removed from gene: ATP1A2.
Severe microcephaly v2.286 KIF14 Eleanor Williams Tag for-review was removed from gene: KIF14.
Severe microcephaly v2.286 AP4E1 Eleanor Williams Tag for-review was removed from gene: AP4E1.
Severe microcephaly v2.286 SVBP Eleanor Williams Tag for-review was removed from gene: SVBP.
Severe microcephaly v2.286 CEP55 Eleanor Williams Tag for-review was removed from gene: CEP55.
Severe microcephaly v2.286 TMX2 Eleanor Williams Tag for-review was removed from gene: TMX2.
Severe microcephaly v2.286 TUBGCP2 Eleanor Williams Phenotypes for gene: TUBGCP2 were changed from Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737 to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737
Severe microcephaly v2.285 TUBGCP2 Eleanor Williams Tag for-review was removed from gene: TUBGCP2.
Severe microcephaly v2.285 TTC5 Eleanor Williams Tag for-review was removed from gene: TTC5.
Severe microcephaly v2.285 NUP188 Eleanor Williams Phenotypes for gene: NUP188 were changed from Sandestig-Stefanova syndrome, 618804 to Sandestig-Stefanova syndrome, OMIM:618804
Severe microcephaly v2.284 NUP188 Eleanor Williams Tag for-review was removed from gene: NUP188.
Severe microcephaly v2.284 NCAPD2 Eleanor Williams Phenotypes for gene: NCAPD2 were changed from Microcephaly 21, primary, autosomal recessive, 617983 to Microcephaly 21, primary, autosomal recessive, OMIM:617983
Severe microcephaly v2.283 NCAPD2 Eleanor Williams Tag for-review was removed from gene: NCAPD2.
Severe microcephaly v2.283 ADARB1 Eleanor Williams Phenotypes for gene: ADARB1 were changed from Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862 to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, OMIM:618862
Severe microcephaly v2.282 ADARB1 Eleanor Williams Tag for-review was removed from gene: ADARB1.
Severe microcephaly v2.282 PPIL1 Eleanor Williams Tag for-review was removed from gene: PPIL1.
Severe microcephaly v2.282 FBRSL1 Eleanor Williams Tag for-review was removed from gene: FBRSL1.
Severe microcephaly v2.282 ANKLE2 Eleanor Williams Tag for-review was removed from gene: ANKLE2.
Severe microcephaly v2.282 COASY Eleanor Williams Tag watchlist was removed from gene: COASY.
Tag for-review was removed from gene: COASY.
Severe microcephaly v2.282 TRAPPC12 Eleanor Williams Tag for-review was removed from gene: TRAPPC12.
Severe microcephaly v2.282 METTL5 Sarah Leigh commented on gene: METTL5
Severe microcephaly v2.282 AP4S1 Sarah Leigh commented on gene: AP4S1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these.
Severe microcephaly v2.282 AP4S1 Sarah Leigh commented on gene: AP4S1
Severe microcephaly v2.282 AP4M1 Sarah Leigh commented on gene: AP4M1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these.
Severe microcephaly v2.282 AP4M1 Sarah Leigh commented on gene: AP4M1
Severe microcephaly v2.282 AP4B1 Sarah Leigh commented on gene: AP4B1: Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these
Severe microcephaly v2.282 AP4B1 Sarah Leigh commented on gene: AP4B1
Severe microcephaly v2.282 UBE3A Sarah Leigh commented on gene: UBE3A: Comment from NHS Genomic Medicine Service: Primary presentation is ID/DD: green on ID & other panels - not clear if severe microephaly exists in absence of these other features? Microcephaly isn't listed as a key feature in Genereviews for females, ands is only present in some males (with severe epilepsy).
Severe microcephaly v2.282 UBE3A Sarah Leigh commented on gene: UBE3A: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Severe microcephaly v2.282 ZNF526 Sarah Leigh commented on gene: ZNF526
Severe microcephaly v2.282 SMG8 Sarah Leigh commented on gene: SMG8
Severe microcephaly v2.282 NARS Sarah Leigh commented on gene: NARS
Severe microcephaly v2.282 MORC2 Sarah Leigh commented on gene: MORC2
Severe microcephaly v2.282 LMNB2 Sarah Leigh commented on gene: LMNB2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 LMNB1 Sarah Leigh commented on gene: LMNB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 DNMT3A Sarah Leigh commented on gene: DNMT3A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 ZNF335 Sarah Leigh commented on gene: ZNF335
Severe microcephaly v2.282 ATP1A2 Sarah Leigh commented on gene: ATP1A2
Severe microcephaly v2.282 KIF14 Sarah Leigh commented on gene: KIF14
Severe microcephaly v2.282 AP4E1 Sarah Leigh commented on gene: AP4E1
Severe microcephaly v2.282 SVBP Sarah Leigh commented on gene: SVBP
Severe microcephaly v2.282 CEP55 Sarah Leigh commented on gene: CEP55
Severe microcephaly v2.282 TMX2 Sarah Leigh commented on gene: TMX2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 TUBGCP2 Sarah Leigh commented on gene: TUBGCP2
Severe microcephaly v2.282 TTC5 Sarah Leigh commented on gene: TTC5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 NUP188 Sarah Leigh commented on gene: NUP188
Severe microcephaly v2.282 NCAPD2 Sarah Leigh commented on gene: NCAPD2
Severe microcephaly v2.282 ADARB1 Sarah Leigh commented on gene: ADARB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 PPIL1 Sarah Leigh commented on gene: PPIL1
Severe microcephaly v2.282 FBRSL1 Sarah Leigh commented on gene: FBRSL1
Severe microcephaly v2.282 ANKLE2 Sarah Leigh commented on gene: ANKLE2
Severe microcephaly v2.282 COASY Sarah Leigh commented on gene: COASY: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Severe microcephaly v2.282 TRAPPC12 Sarah Leigh commented on gene: TRAPPC12
Severe microcephaly v2.281 METTL5 Eleanor Williams Source Expert Review Green was added to METTL5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ZNF526 Eleanor Williams Source Expert Review Green was added to ZNF526.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 SMG8 Eleanor Williams Source Expert Review Green was added to SMG8.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NARS Eleanor Williams Source Expert Review Green was added to NARS.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 MORC2 Eleanor Williams Source Expert Review Green was added to MORC2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 LMNB2 Eleanor Williams Source Expert Review Green was added to LMNB2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 LMNB1 Eleanor Williams Source Expert Review Green was added to LMNB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 DNMT3A Eleanor Williams Source Expert Review Green was added to DNMT3A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ZNF335 Eleanor Williams Source Expert Review Green was added to ZNF335.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ATP1A2 Eleanor Williams Source Expert Review Green was added to ATP1A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 KIF14 Eleanor Williams Source Expert Review Green was added to KIF14.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 AP4E1 Eleanor Williams Source Expert Review Green was added to AP4E1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 SVBP Eleanor Williams Source Expert Review Green was added to SVBP.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 CEP55 Eleanor Williams Source Expert Review Green was added to CEP55.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TMX2 Eleanor Williams Source Expert Review Green was added to TMX2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TUBGCP2 Eleanor Williams Source Expert Review Green was added to TUBGCP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TTC5 Eleanor Williams Source Expert Review Green was added to TTC5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NUP188 Eleanor Williams Source Expert Review Green was added to NUP188.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 NCAPD2 Eleanor Williams Source Expert Review Green was added to NCAPD2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ADARB1 Eleanor Williams Source Expert Review Green was added to ADARB1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 PPIL1 Eleanor Williams Source Expert Review Green was added to PPIL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 FBRSL1 Eleanor Williams Source Expert Review Green was added to FBRSL1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 ANKLE2 Eleanor Williams Source Expert Review Green was added to ANKLE2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 COASY Eleanor Williams Source Expert Review Green was added to COASY.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Severe microcephaly v2.281 TRAPPC12 Eleanor Williams Source Expert Review Green was added to TRAPPC12.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary ataxia, adult onset v2.144 ADGRG1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: ADGRG1.
Hereditary ataxia, adult onset v2.144 AP1S2 Eleanor Williams Tag Q2_21_phenotype was removed from gene: AP1S2.
Hereditary ataxia, adult onset v2.144 XRCC1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: XRCC1.
Hereditary ataxia, adult onset v2.144 VPS41 Eleanor Williams Tag Q2_21_expert_review was removed from gene: VPS41.
Tag Q2_21_NHS_review was removed from gene: VPS41.
Hereditary ataxia, adult onset v2.144 UCHL1 Eleanor Williams Tag Q2_21_expert_review was removed from gene: UCHL1.
Hereditary ataxia, adult onset v2.144 TSEN15 Eleanor Williams Tag Q2_21_rating was removed from gene: TSEN15.
Hereditary ataxia, adult onset v2.144 TBC1D23 Eleanor Williams Tag Q2_21_phenotype was removed from gene: TBC1D23.
Hereditary ataxia, adult onset v2.144 SLC9A1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: SLC9A1.
Hereditary ataxia, adult onset v2.144 SCYL1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: SCYL1.
Hereditary ataxia, adult onset v2.144 RORA Eleanor Williams Tag Q2_21_phenotype was removed from gene: RORA.
Hereditary ataxia, adult onset v2.144 PRICKLE1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: PRICKLE1.
Hereditary ataxia, adult onset v2.144 MAPK8IP3 Eleanor Williams Tag Q4_21_rating was removed from gene: MAPK8IP3.
Hereditary ataxia, adult onset v2.144 ERCC4 Eleanor Williams Tag Q2_21_rating was removed from gene: ERCC4.
Hereditary ataxia, adult onset v2.144 EBF3 Eleanor Williams Tag Q2_21_phenotype was removed from gene: EBF3.
Hereditary ataxia, adult onset v2.144 CLP1 Eleanor Williams Tag Q2_21_phenotype was removed from gene: CLP1.
Hereditary ataxia, adult onset v2.144 CHMP1A Eleanor Williams Tag Q2_21_phenotype was removed from gene: CHMP1A.
Hereditary ataxia, adult onset v2.144 B4GAT1 Eleanor Williams Tag Q3_21_rating was removed from gene: B4GAT1.
Hereditary ataxia, adult onset v2.144 AUH Eleanor Williams Tag Q2_21_rating was removed from gene: AUH.
Hereditary ataxia, adult onset v2.144 ATP8A2 Eleanor Williams Tag Q2_21_phenotype was removed from gene: ATP8A2.
Tag Q2_21_expert_review was removed from gene: ATP8A2.
Hereditary ataxia, adult onset v2.144 AMPD2 Eleanor Williams Tag Q2_21_phenotype was removed from gene: AMPD2.
Hereditary ataxia, adult onset v2.144 ADPRHL2 Eleanor Williams Tag Q2_21_expert_review was removed from gene: ADPRHL2.
Hereditary ataxia, adult onset v2.144 ABCB7 Eleanor Williams Tag Q2_21_phenotype was removed from gene: ABCB7.
Hereditary ataxia, adult onset v2.144 XRCC1 Sarah Leigh commented on gene: XRCC1
Hereditary ataxia, adult onset v2.144 VPS41 Sarah Leigh commented on gene: VPS41
Hereditary ataxia, adult onset v2.144 UCHL1 Sarah Leigh commented on gene: UCHL1
Hereditary ataxia, adult onset v2.144 TSEN15 Sarah Leigh commented on gene: TSEN15
Hereditary ataxia, adult onset v2.144 TBC1D23 Sarah Leigh commented on gene: TBC1D23: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 SLC9A1 Sarah Leigh commented on gene: SLC9A1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 SCYL1 Sarah Leigh commented on gene: SCYL1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 RORA Sarah Leigh commented on gene: RORA: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 PRICKLE1 Sarah Leigh commented on gene: PRICKLE1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 MAPK8IP3 Sarah Leigh commented on gene: MAPK8IP3
Hereditary ataxia, adult onset v2.144 ERCC4 Sarah Leigh commented on gene: ERCC4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 EBF3 Sarah Leigh commented on gene: EBF3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 CLP1 Sarah Leigh commented on gene: CLP1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 CHMP1A Sarah Leigh commented on gene: CHMP1A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 B4GAT1 Sarah Leigh commented on gene: B4GAT1
Hereditary ataxia, adult onset v2.144 AUH Sarah Leigh commented on gene: AUH
Hereditary ataxia, adult onset v2.144 ATP8A2 Sarah Leigh commented on gene: ATP8A2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 AP1S2 Sarah Leigh commented on gene: AP1S2
Hereditary ataxia, adult onset v2.144 AMPD2 Sarah Leigh commented on gene: AMPD2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 ADPRHL2 Sarah Leigh commented on gene: ADPRHL2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 ADGRG1 Sarah Leigh commented on gene: ADGRG1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.144 ABCB7 Sarah Leigh commented on gene: ABCB7: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary ataxia, adult onset v2.143 UCHL1 Eleanor Williams Source Expert Review Amber was added to UCHL1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 TSEN15 Eleanor Williams Source Expert Review Red was added to TSEN15.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.143 TBC1D23 Eleanor Williams Source Expert Review Amber was added to TBC1D23.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 SLC9A1 Eleanor Williams Source Expert Review Amber was added to SLC9A1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 SCYL1 Eleanor Williams Source Expert Review Amber was added to SCYL1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 RORA Eleanor Williams Source Expert Review Amber was added to RORA.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 PRICKLE1 Eleanor Williams Source Expert Review Amber was added to PRICKLE1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 MAPK8IP3 Eleanor Williams Source Expert Review Red was added to MAPK8IP3.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.143 ERCC4 Eleanor Williams Source Expert Review Green was added to ERCC4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary ataxia, adult onset v2.143 EBF3 Eleanor Williams Source Expert Review Amber was added to EBF3.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 CLP1 Eleanor Williams Source Expert Review Amber was added to CLP1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 CHMP1A Eleanor Williams Source Expert Review Amber was added to CHMP1A.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 B4GAT1 Eleanor Williams Source Expert Review Red was added to B4GAT1.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Hereditary ataxia, adult onset v2.143 AUH Eleanor Williams Source Expert Review Green was added to AUH.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary ataxia, adult onset v2.143 ATP8A2 Eleanor Williams Source Expert Review Amber was added to ATP8A2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 AP1S2 Eleanor Williams Source Expert Review Amber was added to AP1S2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 AMPD2 Eleanor Williams Source Expert Review Amber was added to AMPD2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 ADPRHL2 Eleanor Williams Source Expert Review Amber was added to ADPRHL2.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 ADGRG1 Eleanor Williams Source Expert Review Amber was added to ADGRG1.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary ataxia, adult onset v2.143 ABCB7 Eleanor Williams Source Expert Review Amber was added to ABCB7.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Intellectual disability v3.1511 RNF113A Arina Puzriakova Tag for-review was removed from gene: RNF113A.
Intellectual disability v3.1511 GAD1 Arina Puzriakova Tag for-review was removed from gene: GAD1.
Intellectual disability v3.1511 ALG9 Arina Puzriakova Tag for-review was removed from gene: ALG9.
Intellectual disability v3.1511 STT3A Arina Puzriakova Tag for-review was removed from gene: STT3A.
Intellectual disability v3.1511 NEDD4L Arina Puzriakova Tag for-review was removed from gene: NEDD4L.
Intellectual disability v3.1511 MADD Arina Puzriakova Mode of inheritance for gene: MADD was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1510 MADD Arina Puzriakova Tag for-review was removed from gene: MADD.
Intellectual disability v3.1510 KDM6B Arina Puzriakova Tag for-review was removed from gene: KDM6B.
Intellectual disability v3.1510 HERC2 Arina Puzriakova Tag for-review was removed from gene: HERC2.
Intellectual disability v3.1510 AHCY Arina Puzriakova Tag for-review was removed from gene: AHCY.
Intellectual disability v3.1510 PIGP Arina Puzriakova Tag for-review was removed from gene: PIGP.
Intellectual disability v3.1510 RNF13 Arina Puzriakova Tag watchlist was removed from gene: RNF13.
Tag for-review was removed from gene: RNF13.
Intellectual disability v3.1510 PTRHD1 Arina Puzriakova Tag for-review was removed from gene: PTRHD1.
Intellectual disability v3.1510 XYLT1 Arina Puzriakova Tag for-review was removed from gene: XYLT1.
Intellectual disability v3.1510 WDFY3 Arina Puzriakova Tag for-review was removed from gene: WDFY3.
Intellectual disability v3.1510 USP7 Arina Puzriakova Tag for-review was removed from gene: USP7.
Intellectual disability v3.1510 TRPM3 Arina Puzriakova Tag watchlist was removed from gene: TRPM3.
Tag for-review was removed from gene: TRPM3.
Intellectual disability v3.1510 NR4A2 Arina Puzriakova Tag watchlist was removed from gene: NR4A2.
Tag for-review was removed from gene: NR4A2.
Intellectual disability v3.1510 CEP104 Arina Puzriakova Tag for-review was removed from gene: CEP104.
Intellectual disability v3.1510 C2CD3 Arina Puzriakova Tag for-review was removed from gene: C2CD3.
Intellectual disability v3.1510 ATP1A2 Arina Puzriakova Tag for-review was removed from gene: ATP1A2.
Intellectual disability v3.1510 ABAT Arina Puzriakova Tag for-review was removed from gene: ABAT.
Intellectual disability v3.1510 TCTN3 Arina Puzriakova Tag for-review was removed from gene: TCTN3.
Intellectual disability v3.1510 TOR1A Arina Puzriakova Tag for-review was removed from gene: TOR1A.
Intellectual disability v3.1510 TANC2 Arina Puzriakova Tag for-review was removed from gene: TANC2.
Intellectual disability v3.1510 ADAM22 Arina Puzriakova Tag for-review was removed from gene: ADAM22.
Intellectual disability v3.1510 UBR7 Arina Puzriakova Tag for-review was removed from gene: UBR7.
Intellectual disability v3.1510 VPS4A Arina Puzriakova Tag for-review was removed from gene: VPS4A.
Intellectual disability v3.1510 RNU7-1 Arina Puzriakova Tag for-review was removed from gene: RNU7-1.
Intellectual disability v3.1510 PPIL1 Arina Puzriakova Tag for-review was removed from gene: PPIL1.
Intellectual disability v3.1510 FBRSL1 Arina Puzriakova Tag for-review was removed from gene: FBRSL1.
Hereditary ataxia, adult onset v2.142 TMEM106B Eleanor Williams Publications for gene: TMEM106B were set to
Hereditary ataxia, adult onset v2.141 TMEM106B Eleanor Williams Tag for-review was removed from gene: TMEM106B.
Hereditary ataxia, adult onset v2.141 TMEM106B Sarah Leigh commented on gene: TMEM106B
Hereditary ataxia, adult onset v2.140 TMEM106B Eleanor Williams Source Expert Review Amber was added to TMEM106B.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 RNU7-1 Ivone Leong Tag for-review was removed from gene: RNU7-1.
White matter disorders and cerebral calcification - childhood onset v1.223 NUP188 Ivone Leong Tag watchlist was removed from gene: NUP188.
White matter disorders and cerebral calcification - childhood onset v1.223 NUP188 Ivone Leong Tag for-review was removed from gene: NUP188.
Tag watchlist tag was added to gene: NUP188.
White matter disorders and cerebral calcification - childhood onset v1.223 SCAF4 Ivone Leong Tag for-review was removed from gene: SCAF4.
White matter disorders and cerebral calcification - childhood onset v1.223 AP4B1 Ivone Leong Tag for-review was removed from gene: AP4B1.
White matter disorders and cerebral calcification - childhood onset v1.223 TMEM106B Ivone Leong Tag for-review was removed from gene: TMEM106B.
White matter disorders and cerebral calcification - childhood onset v1.223 STN1 Ivone Leong Tag for-review was removed from gene: STN1.
White matter disorders and cerebral calcification - childhood onset v1.223 STN1 Sarah Leigh commented on gene: STN1: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
White matter disorders and cerebral calcification - childhood onset v1.223 TMEM106B Sarah Leigh commented on gene: TMEM106B
White matter disorders and cerebral calcification - childhood onset v1.223 AP4B1 Sarah Leigh commented on gene: AP4B1
White matter disorders and cerebral calcification - childhood onset v1.223 SCAF4 Sarah Leigh commented on gene: SCAF4
White matter disorders and cerebral calcification - childhood onset v1.223 NUP188 Sarah Leigh commented on gene: NUP188
White matter disorders and cerebral calcification - childhood onset v1.223 RNU7-1 Sarah Leigh commented on gene: RNU7-1
White matter disorders and cerebral calcification - childhood onset v1.223 STN1 Ivone Leong Source Expert Review Green was added to STN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 TMEM106B Ivone Leong Source Expert Review Green was added to TMEM106B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 AP4B1 Ivone Leong Source Expert Review Green was added to AP4B1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 SCAF4 Ivone Leong Source Expert Review Green was added to SCAF4.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 NUP188 Ivone Leong Source Expert Review Green was added to NUP188.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
White matter disorders and cerebral calcification - childhood onset v1.223 RNU7-1 Ivone Leong Source Expert Review Green was added to RNU7-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Holoprosencephaly v2.25 SMC1A Ivone Leong Tag for-review was removed from gene: SMC1A.
Holoprosencephaly v2.25 STAG2 Ivone Leong Tag for-review was removed from gene: STAG2.
Holoprosencephaly v2.25 STAG2 Sarah Leigh commented on gene: STAG2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Holoprosencephaly v2.25 SMC1A Sarah Leigh commented on gene: SMC1A
Holoprosencephaly v2.24 STAG2 Ivone Leong Source Expert Review Green was added to STAG2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Holoprosencephaly v2.24 SMC1A Ivone Leong Source Expert Review Green was added to SMC1A.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.125 RNU7-1 Ivone Leong Tag for-review was removed from gene: RNU7-1.
Hereditary spastic paraplegia, childhood onset v2.125 PCYT2 Ivone Leong Tag for-review was removed from gene: PCYT2.
Hereditary spastic paraplegia, childhood onset v2.125 STN1 Ivone Leong Tag for-review was removed from gene: STN1.
Hereditary spastic paraplegia, childhood onset v2.125 STN1 Sarah Leigh commented on gene: STN1: The rating of this gene has been updated following NHS Genomic Medicine Serviceapproval.
Hereditary spastic paraplegia, childhood onset v2.125 PCYT2 Sarah Leigh commented on gene: PCYT2
Hereditary spastic paraplegia, childhood onset v2.125 RNU7-1 Sarah Leigh commented on gene: RNU7-1
Hereditary spastic paraplegia, childhood onset v2.124 STN1 Ivone Leong Source Expert Review Green was added to STN1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.124 PCYT2 Ivone Leong Source Expert Review Green was added to PCYT2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.124 RNU7-1 Ivone Leong Source Expert Review Green was added to RNU7-1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v2.74 GFER Ivone Leong Tag for-review was removed from gene: GFER.
Congenital myopathy v2.74 KY Ivone Leong Tag watchlist was removed from gene: KY.
Tag for-review was removed from gene: KY.
Congenital myopathy v2.74 UNC45B Ivone Leong Tag for-review was removed from gene: UNC45B.
Congenital myopathy v2.74 MYH2 Ivone Leong Tag for-review was removed from gene: MYH2.
Congenital myopathy v2.74 MYH2 Sarah Leigh reviewed gene: MYH2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v2.74 UNC45B Sarah Leigh commented on gene: UNC45B: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Congenital myopathy v2.74 KY Sarah Leigh commented on gene: KY: The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.
Congenital myopathy v2.74 GFER Sarah Leigh commented on gene: GFER
Congenital myopathy v2.73 MYH2 Ivone Leong Source Expert list was added to MYH2.
Mode of inheritance for gene MYH2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v2.73 UNC45B Ivone Leong Source Expert Review Green was added to UNC45B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v2.73 KY Ivone Leong Source Expert Review Green was added to KY.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Congenital myopathy v2.73 GFER Ivone Leong Source Expert Review Green was added to GFER.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability v3.1510 CACNB4 Sarah Leigh commented on gene: CACNB4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 CNOT3 Sarah Leigh commented on gene: CNOT3: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 ZNF335 Sarah Leigh commented on gene: ZNF335: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 MFSD2A Sarah Leigh commented on gene: MFSD2A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 MAPRE2 Sarah Leigh commented on gene: MAPRE2: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 SCN1B Sarah Leigh commented on gene: SCN1B
Intellectual disability v3.1510 SCAMP5 Sarah Leigh commented on gene: SCAMP5: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 KAT8 Sarah Leigh commented on gene: KAT8: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 GPC4 Sarah Leigh commented on gene: GPC4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 KDM6B Sarah Leigh commented on gene: KDM6B: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 CDK19 Sarah Leigh commented on gene: CDK19: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 EXT2 Sarah Leigh commented on gene: EXT2: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 TOR1A Sarah Leigh commented on gene: TOR1A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 ABCA2 Sarah Leigh commented on gene: ABCA2
Intellectual disability v3.1510 PIGH Sarah Leigh commented on gene: PIGH
Intellectual disability v3.1510 METTL5 Sarah Leigh commented on gene: METTL5
Intellectual disability v3.1510 LMBRD2 Sarah Leigh commented on gene: LMBRD2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 LIAS Sarah Leigh commented on gene: LIAS
Intellectual disability v3.1510 CSNK1G1 Sarah Leigh commented on gene: CSNK1G1
Intellectual disability v3.1510 ALG14 Sarah Leigh commented on gene: ALG14: After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.
Intellectual disability v3.1510 SLC12A6 Sarah Leigh commented on gene: SLC12A6: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 COG4 Sarah Leigh commented on gene: COG4: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 SCN8A Sarah Leigh commented on gene: SCN8A: Just 2 families reported with possible AR inheritance: v rare - all het parents seem to have features so prob ok to keep as monoallelic only (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 SCN8A Sarah Leigh commented on gene: SCN8A: After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changed
Intellectual disability v3.1510 AGO2 Sarah Leigh commented on gene: AGO2: Green rating is for monoallelic MOI only, many cases reported with speech delay and variable ID (source NHS Genomic Medicine Service).
Intellectual disability v3.1510 AGO2 Sarah Leigh commented on gene: AGO2
Intellectual disability v3.1510 PNPT1 Sarah Leigh commented on gene: PNPT1
Intellectual disability v3.1510 SCO1 Sarah Leigh commented on gene: SCO1
Intellectual disability v3.1510 FA2H Sarah Leigh commented on gene: FA2H: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 COX6B1 Sarah Leigh commented on gene: COX6B1
Intellectual disability v3.1510 MPI Sarah Leigh commented on gene: MPI
Intellectual disability v3.1510 VAMP1 Sarah Leigh commented on gene: VAMP1
Intellectual disability v3.1510 TRIM32 Sarah Leigh commented on gene: TRIM32
Intellectual disability v3.1510 MGP Sarah Leigh commented on gene: MGP: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 LGI4 Sarah Leigh commented on gene: LGI4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 HYLS1 Sarah Leigh commented on gene: HYLS1
Intellectual disability v3.1510 HADH Sarah Leigh commented on gene: HADH
Intellectual disability v3.1510 FLVCR1 Sarah Leigh commented on gene: FLVCR1
Intellectual disability v3.1510 ATL1 Sarah Leigh commented on gene: ATL1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 ANKH Sarah Leigh commented on gene: ANKH: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 AFG3L2 Sarah Leigh commented on gene: AFG3L2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KCNC3 Sarah Leigh commented on gene: KCNC3
Intellectual disability v3.1510 ALKBH8 Sarah Leigh commented on gene: ALKBH8
Intellectual disability v3.1510 SOX3 Sarah Leigh commented on gene: SOX3
Intellectual disability v3.1510 PRKD1 Sarah Leigh commented on gene: PRKD1
Intellectual disability v3.1510 GPSM2 Sarah Leigh commented on gene: GPSM2
Intellectual disability v3.1510 DDOST Sarah Leigh commented on gene: DDOST
Intellectual disability v3.1510 CYP2U1 Sarah Leigh commented on gene: CYP2U1
Intellectual disability v3.1510 AGPS Sarah Leigh commented on gene: AGPS
Intellectual disability v3.1510 TMEM106B Sarah Leigh commented on gene: TMEM106B
Intellectual disability v3.1510 NEMF Sarah Leigh commented on gene: NEMF
Intellectual disability v3.1510 MPP5 Sarah Leigh commented on gene: MPP5
Intellectual disability v3.1510 MAPK1 Sarah Leigh commented on gene: MAPK1
Intellectual disability v3.1510 LMNB1 Sarah Leigh commented on gene: LMNB1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KIF21B Sarah Leigh commented on gene: KIF21B
Intellectual disability v3.1510 JARID2 Sarah Leigh commented on gene: JARID2
Intellectual disability v3.1510 FAM50A Sarah Leigh commented on gene: FAM50A
Intellectual disability v3.1510 CEP120 Sarah Leigh commented on gene: CEP120
Intellectual disability v3.1510 ZNF526 Sarah Leigh commented on gene: ZNF526
Intellectual disability v3.1510 TFE3 Sarah Leigh commented on gene: TFE3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PIGQ Sarah Leigh commented on gene: PIGQ: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 KAT5 Sarah Leigh commented on gene: KAT5
Intellectual disability v3.1510 ZNF335 Sarah Leigh commented on gene: ZNF335
Intellectual disability v3.1510 ZIC1 Sarah Leigh commented on gene: ZIC1
Intellectual disability v3.1510 SETD1A Sarah Leigh commented on gene: SETD1A: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 PET100 Sarah Leigh commented on gene: PET100
Intellectual disability v3.1510 NUDT2 Sarah Leigh commented on gene: NUDT2
Intellectual disability v3.1510 MFSD2A Sarah Leigh commented on gene: MFSD2A
Intellectual disability v3.1510 MAPRE2 Sarah Leigh commented on gene: MAPRE2
Intellectual disability v3.1510 CDH2 Sarah Leigh commented on gene: CDH2: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SMG8 Sarah Leigh commented on gene: SMG8
Intellectual disability v3.1510 LSS Sarah Leigh commented on gene: LSS
Intellectual disability v3.1510 KCNMA1 Sarah Leigh commented on gene: KCNMA1
Intellectual disability v3.1510 H3F3B Sarah Leigh commented on gene: H3F3B
Intellectual disability v3.1510 H3F3A Sarah Leigh commented on gene: H3F3A
Intellectual disability v3.1510 KDM4B Sarah Leigh commented on gene: KDM4B
Intellectual disability v3.1510 BICRA Sarah Leigh commented on gene: BICRA
Intellectual disability v3.1510 ZFHX4 Sarah Leigh commented on gene: ZFHX4
Intellectual disability v3.1510 SHMT2 Sarah Leigh commented on gene: SHMT2
Intellectual disability v3.1510 NARS Sarah Leigh commented on gene: NARS
Intellectual disability v3.1510 MORC2 Sarah Leigh commented on gene: MORC2
Intellectual disability v3.1510 LARS Sarah Leigh commented on gene: LARS
Intellectual disability v3.1510 POLR1C Sarah Leigh commented on gene: POLR1C
Intellectual disability v3.1510 NUS1 Sarah Leigh commented on gene: NUS1
Intellectual disability v3.1510 PUM1 Sarah Leigh commented on gene: PUM1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RALGAPA1 Sarah Leigh commented on gene: RALGAPA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 RARS Sarah Leigh commented on gene: RARS: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 CEP55 Sarah Leigh commented on gene: CEP55
Intellectual disability v3.1510 CTU2 Sarah Leigh commented on gene: CTU2
Intellectual disability v3.1510 TRAPPC4 Sarah Leigh commented on gene: TRAPPC4
Intellectual disability v3.1510 UGP2 Sarah Leigh commented on gene: UGP2
Intellectual disability v3.1510 CXorf56 Sarah Leigh commented on gene: CXorf56
Intellectual disability v3.1510 KAT8 Sarah Leigh commented on gene: KAT8
Intellectual disability v3.1510 SLC5A6 Sarah Leigh commented on gene: SLC5A6: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SNX27 Sarah Leigh commented on gene: SNX27: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 WNT1 Sarah Leigh commented on gene: WNT1
Intellectual disability v3.1510 YIF1B Sarah Leigh commented on gene: YIF1B
Intellectual disability v3.1510 VARS2 Sarah Leigh commented on gene: VARS2
Intellectual disability v3.1510 UGDH Sarah Leigh commented on gene: UGDH
Intellectual disability v3.1510 TTC5 Sarah Leigh commented on gene: TTC5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 TRNT1 Sarah Leigh commented on gene: TRNT1
Intellectual disability v3.1510 TNRC6B Sarah Leigh commented on gene: TNRC6B
Intellectual disability v3.1510 TET3 Sarah Leigh commented on gene: TET3: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 TENM3 Sarah Leigh commented on gene: TENM3
Intellectual disability v3.1510 TASP1 Sarah Leigh commented on gene: TASP1
Intellectual disability v3.1510 SUZ12 Sarah Leigh commented on gene: SUZ12: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SUPT16H Sarah Leigh commented on gene: SUPT16H
Intellectual disability v3.1510 SPTBN4 Sarah Leigh commented on gene: SPTBN4
Intellectual disability v3.1510 SPOP Sarah Leigh commented on gene: SPOP
Intellectual disability v3.1510 SOX6 Sarah Leigh commented on gene: SOX6: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SLC1A1 Sarah Leigh commented on gene: SLC1A1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SLC12A2 Sarah Leigh commented on gene: SLC12A2
Intellectual disability v3.1510 SFXN4 Sarah Leigh commented on gene: SFXN4: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Intellectual disability v3.1510 SBF1 Sarah Leigh commented on gene: SBF1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.