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Intellectual disability - microarray and sequencing v5.557 CEP295 Achchuthan Shanmugasundram Phenotypes for gene: CEP295 were changed from Seckel syndrome 11, OMIM # 620767 to Seckel syndrome 11, OMIM:620767
Intellectual disability - microarray and sequencing v5.556 CEP295 Achchuthan Shanmugasundram Classified gene: CEP295 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.556 CEP295 Achchuthan Shanmugasundram Gene: cep295 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.555 CEP295 Achchuthan Shanmugasundram reviewed gene: CEP295: Rating: AMBER; Mode of pathogenicity: None; Publications: 38154379; Phenotypes: Seckel syndrome 11, OMIM:620767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.555 DOCK4 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: DOCK4.
Intellectual disability - microarray and sequencing v5.555 DOCK4 Achchuthan Shanmugasundram Classified gene: DOCK4 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.555 DOCK4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:38526744 reported seven unrelated individuals with heterozygous variants and with developmental delay or intellectual disability, of which four had ID. Three of them with ID had heterozygous variants, while one had compound heterozygous variants. There is also some functional evidence available.

Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.555 DOCK4 Achchuthan Shanmugasundram Gene: dock4 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.554 DOCK4 Achchuthan Shanmugasundram Phenotypes for gene: DOCK4 were changed from neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.554 DOCK4 Achchuthan Shanmugasundram Phenotypes for gene: DOCK4 were changed from DOCK4-related neurodevelopmental disorder (MONDO:0060490) to neuronevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.553 DOCK4 Achchuthan Shanmugasundram reviewed gene: DOCK4: Rating: GREEN; Mode of pathogenicity: None; Publications: 38526744; Phenotypes: neuronevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.553 GTF3C5 Achchuthan Shanmugasundram Publications for gene: GTF3C5 were set to 38520561; 35503477
Intellectual disability - microarray and sequencing v5.552 GTF3C5 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, the gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.552 GTF3C5 Achchuthan Shanmugasundram edited their review of gene: GTF3C5: Changed publications to: 35503477, 38520561
Intellectual disability - microarray and sequencing v5.552 GTF3C5 Achchuthan Shanmugasundram Classified gene: GTF3C5 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.552 GTF3C5 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:35503477 reported a proband with profound developmental delay and PMID:38520561 reported three families with syndromic intellectual disability (ID was mild in one family). There is also functional evidence and evidence from zebrafish model in support of the disease association.

Hence, the gene can be promoted to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.552 GTF3C5 Achchuthan Shanmugasundram Gene: gtf3c5 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.551 GTF3C5 Achchuthan Shanmugasundram Phenotypes for gene: GTF3C5 were changed from neurodevelopmental disorder MONDO:0700092, GTF3C5-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.550 GTF3C5 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: GTF3C5.
Intellectual disability - microarray and sequencing v5.550 GTF3C5 Achchuthan Shanmugasundram reviewed gene: GTF3C5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal ciliopathies v3.23 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Childhood onset dystonia, chorea or related movement disorder v3.78 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Neurological ciliopathies v3.20 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Ophthalmological ciliopathies v3.7 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Intellectual disability - microarray and sequencing v5.550 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
Rare multisystem ciliopathy disorders v1.172 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
DDG2P v3.90 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome to Stromme syndrome, OMIM:243605
Fetal anomalies v3.169 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605 to Stromme syndrome, OMIM:243605
Unexplained young onset end-stage renal disease v3.42 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome to Stromme syndrome, OMIM:243605; Lethal fetal brain malformation-duodenal atresia-bilateral renal hypoplasia syndrome
CAKUT v1.177 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Stromme syndrome, 243605; bilateral renal hypoplasia; Duodenal atresia; Hydronephrosis to Stromme syndrome, OMIM:243605
Limb disorders v4.23 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from Polydactyly; Stromme syndrome 243605 to Stromme syndrome, OMIM:243605
Severe microcephaly v4.88 CENPF Arina Puzriakova Phenotypes for gene: CENPF were changed from MPD; microcephalic primordial dwarfism; Stromme syndrome, 243605; Microcephaly to Stromme syndrome, OMIM:243605; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.549 GMNN Arina Puzriakova Phenotypes for gene: GMNN were changed from Meier-Gorlin syndrome 6, 616835 to Meier-Gorlin syndrome 6, OMIM:616835
Clefting v4.111 GMNN Arina Puzriakova Phenotypes for gene: GMNN were changed from Meier-Gorlin syndrome 6, 616835 to Meier-Gorlin syndrome 6, OMIM:616835
Severe microcephaly v4.87 GMNN Arina Puzriakova Phenotypes for gene: GMNN were changed from MPD; microcephalic primordial dwarfism; Meier-Gorlin syndrome 6, 616835; MGORS6; primordial dwarfism to Meier-Gorlin syndrome 6, OMIM:616835; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.548 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; INSULIN-LIKE GROWTH FACTOR I DEFICIENCY (IGF1 DEFICIENCY) to Insulin-like growth factor I deficiency, OMIM:608747
Monogenic hearing loss v4.39 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency,608747; GrowthretardationwithdeafnessandmentalretardationduetoIGF1deficiency,608747 to Insulin-like growth factor I deficiency, OMIM:608747
DDG2P v3.89 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from INSULIN-LIKE GROWTH FACTOR I DEFICIENCY 608747 to Insulin-like growth factor I deficiency, OMIM:608747
Fetal anomalies v3.168 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from INSULIN-LIKE GROWTH FACTOR I DEFICIENCY to Insulin-like growth factor I deficiency, OMIM:608747
IUGR and IGF abnormalities v1.69 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; Insulin-Like Growth Factor I Deficiency to Insulin-like growth factor I deficiency, OMIM:608747
Silver Russell syndrome v1.13 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency 608747 to Insulin-like growth factor I deficiency, OMIM:608747
Severe microcephaly v4.86 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; MPD; microcephalic primordial dwarfism to Insulin-like growth factor I deficiency, OMIM:608747; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.547 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from LIG4 syndrome, OMIM:606593 to LIG4 syndrome, OMIM:606593
Haematological malignancies cancer susceptibility v4.5 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from Class: miscellaneous; Ligase IV syndrome; Lymphoma; ALL to LIG4 syndrome, OMIM:606593; Ligase IV syndrome; Lymphoma; ALL
Intellectual disability - microarray and sequencing v5.547 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from LIG4 syndrome, 606593{Multiple myeloma, resistance to}, 254500Severe combined immunodeficiency with sensitivity to ionizing radiation, 602450; LIG4 SYNDROME to LIG4 syndrome, OMIM:606593
Growth failure in early childhood v3.95 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from microcephaly, growth retardation, immunodeficiency, developmental delay to LIG4 syndrome, OMIM:606593; microcephaly, growth retardation, immunodeficiency, developmental delay
Fetal anomalies v3.167 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from SEVERE COMBINED IMMUNODEFICIENCY AUTOSOMAL RECESSIVE T-CELL-NEGATIVE/B-CELL-NEGATIVE/NK-CELL-POSITIVE WITH SENSITIVITY TO IONIZING RADIATION; LIG4 SYNDROME to LIG4 syndrome, OMIM:606593
Cytopenia - NOT Fanconi anaemia v3.34 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from 606593 LIG4 syndrome to LIG4 syndrome, OMIM:606593
IUGR and IGF abnormalities v1.68 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from microcephaly, growth retardation, immunodeficiency, developmental delay to LIG4 syndrome, OMIM:606593; microcephaly, growth retardation, immunodeficiency, developmental delay
Haematological malignancies for rare disease v1.18 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from Class: miscellaneous; Ligase IV syndrome; Lymphoma; ALL to LIG4 syndrome, OMIM:606593; Class: miscellaneous; Ligase IV syndrome; Lymphoma; ALL
Infantile enterocolitis & monogenic inflammatory bowel disease v1.44 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from SCID; LIG4 syndrome 606593 to LIG4 syndrome, OMIM:606593
Severe microcephaly v4.85 LIG4 Arina Puzriakova Phenotypes for gene: LIG4 were changed from MPD; microcephalic primordial dwarfism; LIG4 syndrome, 606593; microcephaly to LIG4 syndrome, OMIM:606593; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.546 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from Meier-Gorlin syndrome 1, 224690; MEIER-GORLIN SYNDROME 1 to Meier-Gorlin syndrome 1, OMIM:224690
Skeletal dysplasia v4.65 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from Meier-Gorlin syndrome 1 224690; Meier-Gorlin syndrome 1 224690 to Meier-Gorlin syndrome 1, OMIM:224690
Fetal anomalies v3.166 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from MEIER-GORLIN SYNDROME 1 to Meier-Gorlin syndrome 1, OMIM:224690
Limb disorders v4.22 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from Meier-Gorlin syndrome 1 to Meier-Gorlin syndrome 1, OMIM:224690
Deafness and congenital structural abnormalities v1.27 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from Bilateral Microtia; 224690; Meier Gorlin EPS; causes microtia and syndromic features; Meier-Gorlin syndrome 1 to Meier-Gorlin syndrome 1, OMIM:224690; Bilateral Microtia
IUGR and IGF abnormalities v1.67 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from microtia, beaked nose, patellar aplasia/hypoplasia, mammary hypoplasia, micrognathia to Meier-Gorlin syndrome 1, OMIM:224690; microtia, beaked nose, patellar aplasia/hypoplasia, mammary hypoplasia, micrognathia
Severe microcephaly v4.84 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from MPD; microcephalic primordial dwarfism; Meier-Gorlin syndrome 1, 224690 to Meier-Gorlin syndrome 1, OMIM:224690; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.545 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from Meier-Gorlin syndrome 2, 613800 to Meier-Gorlin syndrome 2, OMIM:613800
Fetal anomalies v3.165 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from MEIER-GORLIN SYNDROME 2 to Meier-Gorlin syndrome 2, OMIM:613800
Skeletal dysplasia v4.64 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from Meier-Gorlin syndrome 2 613800; Meier-Gorlin syndrome 2 613800 to Meier-Gorlin syndrome 2, OMIM:613800
Deafness and congenital structural abnormalities v1.26 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from Bilateral Microtia; 613800; Meier-Gorlin EPS; causes syndromic features to Meier-Gorlin syndrome 2, OMIM:613800; Bilateral Microtia
IUGR and IGF abnormalities v1.66 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia to Meier-Gorlin syndrome 2, OMIM:613800; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia
Severe microcephaly v4.83 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from MPD; microcephalic primordial dwarfism; Meier-Gorlin syndrome 2, 613800 to Meier-Gorlin syndrome 2, OMIM:613800; Microcephalic primordial dwarfism
Breast cancer pertinent cancer susceptibility v2.8 PTEN Dmitrijs Rots reviewed gene: PTEN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: PHTS; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure in early childhood v3.94 PAPPA2 Melissa Connolly reviewed gene: PAPPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555216, Durkie et al, 2024 https://www.acgs.uk.com/media/12533/uk-practice-guidelines-for-variant-classification-v12-2024.pdf; Phenotypes: Short stature, dysmorphism, mild microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v3.94 PAPPA2 Melissa Connolly Deleted their review
Growth failure in early childhood v3.94 PAPPA2 Melissa Connolly reviewed gene: PAPPA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555216, Durkie et al, 2024 https://www.acgs.uk.com/media/12533/uk-practice-guidelines-for-variant-classification-v12-2024.pdf; Phenotypes: Short stature, frontal bossing, prognathism, juvenile cataracts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.31 COASY Achchuthan Shanmugasundram Classified gene: COASY as Amber List (moderate evidence)
Arthrogryposis v5.31 COASY Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for promoting this gene to green rating in the next GMS review.
Arthrogryposis v5.31 COASY Achchuthan Shanmugasundram Gene: coasy has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.30 COASY Achchuthan Shanmugasundram Phenotypes for gene: COASY were changed from Pontocerebellar hypoplasia, type 12, OMIM:618266; pontocerebellar hypoplasia, type 12, MONDO:0032643 to Neurodegeneration with brain iron accumulation 6, OMIM:615643; Pontocerebellar hypoplasia, type 12, OMIM:618266; arthrogryposis, MONDO:0008779
Arthrogryposis v5.29 COASY Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: COASY.
Tag Q2_24_NHS_review tag was added to gene: COASY.
Arthrogryposis v5.29 COASY Achchuthan Shanmugasundram reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 35499143, 36495139; Phenotypes: Neurodegeneration with brain iron accumulation 6, OMIM:615643, Pontocerebellar hypoplasia, type 12, OMIM:618266, arthrogryposis, MONDO:0008779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.29 PIP5K1C Achchuthan Shanmugasundram Phenotypes for gene: PIP5K1C were changed from Lethal congenital contractural syndrome 3 611369 to Lethal congenital contractural syndrome 3, OMIM:611369
Arthrogryposis v5.28 PIP5K1C Achchuthan Shanmugasundram Publications for gene: PIP5K1C were set to 17701898
Arthrogryposis v5.27 PIP5K1C Achchuthan Shanmugasundram Classified gene: PIP5K1C as Amber List (moderate evidence)
Arthrogryposis v5.27 PIP5K1C Achchuthan Shanmugasundram Added comment: Comment on list classification: As there are three unrelated cases with biallelic variants (two unrelated cases with the same homozygous variant and two foetuses from one family with compound heterozygous variants), this gene can be promoted to green rating in the next GMS update.
Arthrogryposis v5.27 PIP5K1C Achchuthan Shanmugasundram Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.26 PIP5K1C Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PIP5K1C.
Tag Q2_24_NHS_review tag was added to gene: PIP5K1C.
Arthrogryposis v5.26 PIP5K1C Achchuthan Shanmugasundram reviewed gene: PIP5K1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 17701898, 38491417; Phenotypes: Lethal congenital contractural syndrome 3, OMIM:611369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.26 TRIP4 Achchuthan Shanmugasundram reviewed gene: TRIP4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31794073; Phenotypes: Spinal muscular atrophy with congenital bone fractures 1, OMIM:616866, ?Muscular dystrophy, congenital, Davignon-Chauveau type, OMIM:617066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.26 COASY Achchuthan Shanmugasundram Publications for gene: COASY were set to 11980892; 25778941; 24360804; 27021474; 28489334; 30089828; 36495139
Ectodermal dysplasia v3.29 TWIST2 Dmitrijs Rots gene: TWIST2 was added
gene: TWIST2 was added to Ectodermal dysplasia. Sources: Expert Review
Mode of inheritance for gene: TWIST2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TWIST2 were set to Focal facial dermal dysplasia 3, Setleis type
Review for gene: TWIST2 was set to GREEN
Added comment: Included as differential for ectodermal dysplasia
Sources: Expert Review
Arthrogryposis v5.25 SLC18A3 Achchuthan Shanmugasundram Classified gene: SLC18A3 as Amber List (moderate evidence)
Arthrogryposis v5.25 SLC18A3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, PMID:34943989 reports an additional patient with compound heterozygous variants in SLC18A3 gene and presenting with arthrogryposis congenital (AMC). Hence, there is sufficient evidence available for promoting this gene to green rating in the next GMS review.
Arthrogryposis v5.25 SLC18A3 Achchuthan Shanmugasundram Gene: slc18a3 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.24 SLC18A3 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: SLC18A3.
Tag Q2_24_NHS_review tag was added to gene: SLC18A3.
Arthrogryposis v5.24 SLC18A3 Achchuthan Shanmugasundram edited their review of gene: SLC18A3: Changed phenotypes to: Myasthenic syndrome, congenital, 21, presynaptic, OMIM:617239, arthrogryposis, MONDO:0008779
Arthrogryposis v5.24 SLC18A3 Achchuthan Shanmugasundram Phenotypes for gene: SLC18A3 were changed from Myasthenic syndrome, congenital, 21, presynaptic, 617239; arthrogryposis to Myasthenic syndrome, congenital, 21, presynaptic, OMIM:617239; arthrogryposis, MONDO:0008779
Arthrogryposis v5.23 SLC18A3 Achchuthan Shanmugasundram Publications for gene: SLC18A3 were set to 28188302; 27590285; 31059209
Arthrogryposis v5.22 SLC18A3 Achchuthan Shanmugasundram reviewed gene: SLC18A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v4.63 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from Meier-Gorlin syndrome 3 613803; Meier-Gorlin syndrome 3 613803 to Meier-Gorlin syndrome 3, OMIM:613803
Intellectual disability - microarray and sequencing v5.544 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from Meier-Gorlin syndrome 3, 613803 to Meier-Gorlin syndrome 3, OMIM:613803
Fetal anomalies v3.164 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from MEIER-GORLIN SYNDROME 3 to Meier-Gorlin syndrome 3, OMIM:613803
Deafness and congenital structural abnormalities v1.25 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from Bilateral Microtia; 613803; Meier-Gorlin EPS; causes syndromic features; Meier-Gorlin syndrome 3 to Meier-Gorlin syndrome 3, OMIM:613803; Bilateral Microtia
IUGR and IGF abnormalities v1.65 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia to Meier-Gorlin syndrome 3, OMIM:613803; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia
Severe microcephaly v4.82 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from MPD; microcephalic primordial dwarfism; Meier-Gorlin syndrome 3, 613803 to Meier-Gorlin syndrome 3, OMIM:613803; Microcephalic primordial dwarfism
Insulin resistance (including lipodystrophy) v1.17 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II 210720; Osteodysplastic Primordial Dwarfism of Majewski Tyoe 2; Severe Insulin Resistance to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720; Insulin resistance, HP:0000855
IUGR and IGF abnormalities v1.64 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Seckel syndrome, MOPD type II - growth restrction, microcephaly, prominent nose, micrognathia, squeaky voice, insulin resistance to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Limb disorders v4.21 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II 210720 to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Skeletal dysplasia v4.62 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II 210720 to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
DDG2P v3.88 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE II 210720 to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Fetal anomalies v3.163 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE II to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Intellectual disability - microarray and sequencing v5.543 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from Microcephalic osteodysplastic primordial dwarfism, type II, 210720 -3; MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE II to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Growth failure in early childhood v3.94 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from MOPDII; Seckel syndrome, MOPD type II - growth restrction, microcephaly, prominent nose, micrognathia, squeaky voice, insulin resistance, 210720 to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720
Severe microcephaly v4.81 PCNT Arina Puzriakova Phenotypes for gene: PCNT were changed from MPD; microcephalic primordial dwarfism; Microcephalic Osteodysplastic Primordial Dwarfism; Microcephalic osteodysplastic primordial dwarfism, type II, 210720 to Microcephalic osteodysplastic primordial dwarfism, type II, OMIM:210720; Microcephalic primordial dwarfism
Retinal disorders v4.90 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651 to Lowry-Wood syndrome, OMIM:226960; Roifman syndrome, OMIM:616651
Intellectual disability - microarray and sequencing v5.542 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Gene2Phenotype confirmed gene with ID HPO to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651
Early onset or syndromic epilepsy v4.196 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I 210710 to Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710
Growth failure in early childhood v3.93 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from MOPD I to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710
Fetal anomalies v3.162 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I to Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710
Cytopenia - NOT Fanconi anaemia v3.33 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Roifman syndrome, 616651; Microcephalic osteodysplastic primordial dwarfism, type I, 210710 to Roifman syndrome, OMIM:616651
Bleeding and platelet disorders v3.10 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I / Roifman syndrome to Roifman syndrome, OMIM:616651
Inherited bleeding disorders v1.178 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Platelet disorder; Roifman Syndrome with thrombocytopenia and Primary immunodeficiency to Roifman syndrome, OMIM:616651; Roifman Syndrome with thrombocytopenia and Primary immunodeficiency
Skeletal dysplasia v4.61 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Roifman syndrome 616651; Microcephalic osteodysplastic primordial dwarfism, type I 210710 to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651
Limb disorders v4.20 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I 210710; Roifman syndrome 616651 to Lowry-Wood syndrome, OMIM:226960; Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Roifman syndrome, OMIM:616651
Primary immunodeficiency or monogenic inflammatory bowel disease v4.202 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly, short stature; Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly; Combined immunodeficiencies with associated or syndromic features to Roifman syndrome, OMIM:616651; Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly
COVID-19 research v1.142 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly; Combined immunodeficiencies with associated or syndromic features; Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly, short stature to Roifman syndrome, OMIM:616651; Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly
Severe microcephaly v4.80 RNU4ATAC Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Microcephalic osteodysplastic primordial dwarfism, type I; Microcephalic osteodysplastic primordial dwarfism, type I, 210710; MPD; microcephalic primordial dwarfism to Microcephalic osteodysplastic primordial dwarfism, type I, OMIM:210710; Lowry-Wood syndrome, OMIM:226960; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.541 TRAIP Arina Puzriakova Phenotypes for gene: TRAIP were changed from Seckel syndrome 9, 616777 to Seckel syndrome 9, OMIM:616777
Cerebral vascular malformations v3.16 TRAIP Arina Puzriakova Phenotypes for gene: TRAIP were changed from Seckel syndrome 9 616777 to Seckel syndrome 9, OMIM:616777
Fetal anomalies v3.161 TRAIP Arina Puzriakova Phenotypes for gene: TRAIP were changed from Seckel syndrome 9 to Seckel syndrome 9, OMIM:616777
Severe microcephaly v4.79 TRAIP Arina Puzriakova Phenotypes for gene: TRAIP were changed from MPD; microcephalic primordial dwarfism; Seckel syndrome 9, 616777; Microcephaly to Seckel syndrome 9, OMIM:616777; Microcephalic primordial dwarfism
Mitochondrial disorders v4.169 XRCC4 Arina Puzriakova Mode of inheritance for gene: XRCC4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.169 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from Short stature, microcephaly, and endocrine dysfunction 616541 to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
Growth failure in early childhood v3.92 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from short stature, microcephaly, hypothyroidism, diabetes mellitus, progressive ataxia, hypergonadotrophic hypogonadism to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
Fetal anomalies v3.160 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from PRIMORDIAL DWARFISM to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
Skeletal dysplasia v4.60 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from Short stature, microcephaly, and endocrine dysfunction 616541 to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
Intellectual disability - microarray and sequencing v5.540 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from PRIMORDIAL DWARFISM to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541
IUGR and IGF abnormalities v1.63 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from short stature, microcephaly, hypothyroidism, diabetes mellitus, progressive ataxia, hypergonadotrophic hypogonadism to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541; Short stature, microcephaly, hypothyroidism, diabetes mellitus, progressive ataxia, hypergonadotrophic hypogonadism
Severe microcephaly v4.78 XRCC4 Arina Puzriakova Phenotypes for gene: XRCC4 were changed from MPD; microcephalic primordial dwarfism; Short stature, microcephaly, and endocrine dysfunction, 616541 to Short stature, microcephaly, and endocrine dysfunction, OMIM:616541; Microcephalic primordial dwarfism
Severe microcephaly v4.77 ATRIP Arina Puzriakova Publications for gene: ATRIP were set to
Severe microcephaly v4.76 ATRIP Arina Puzriakova Mode of inheritance for gene: ATRIP was changed from to BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v3.91 ATRIP Arina Puzriakova Phenotypes for gene: ATRIP were changed from microcephaly, micrognathia, small ear lobes, dental crowding to Microcephalic primordial dwarfism; Microcephaly, micrognathia, small ear lobes, dental crowding
Severe microcephaly v4.75 ATRIP Arina Puzriakova Phenotypes for gene: ATRIP were changed from MPD; microcephalic primordial dwarfism; severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism to Microcephalic primordial dwarfism; Severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism
Intellectual disability - microarray and sequencing v5.539 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from MEIER-GORLIN SYNDROME 5 to Meier-Gorlin syndrome 5, OMIM:613805
Growth failure in early childhood v3.90 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from ?Meier-Gorlin syndrome 5, 613805; patellar hypoplasia/aplasia, microtia, meier-gorlin syndrome, mammary hypoplasia to Meier-Gorlin syndrome 5, OMIM:613805; patellar hypoplasia/aplasia, microtia, meier-gorlin syndrome, mammary hypoplasia
Skeletal dysplasia v4.59 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from Meier-Gorlin syndrome 5 613805 to Meier-Gorlin syndrome 5, OMIM:613805
Fetal anomalies v3.159 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from MEIER-GORLIN SYNDROME 5 to Meier-Gorlin syndrome 5, OMIM:613805
Deafness and congenital structural abnormalities v1.24 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from Bilateral Microtia; 613805; Meier-Gorlin syndrome 5, 613805; Neurology panel; Bilateral Microtia, 613805; Causes Meier-Gorlin EPS; syndromic features to Meier-Gorlin syndrome 5, OMIM:613805; Bilateral Microtia
IUGR and IGF abnormalities v1.62 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from patellar hypoplasia/aplasia, microtia, meier-gorlin syndrome, mammary hypoplasia to Meier-Gorlin syndrome 5, OMIM:613805; patellar hypoplasia/aplasia, microtia, meier-gorlin syndrome, mammary hypoplasia
Severe microcephaly v4.74 CDC6 Arina Puzriakova Phenotypes for gene: CDC6 were changed from MPD; microcephalic primordial dwarfism; ?Meier-Gorlin syndrome 5, 613805 to Meier-Gorlin syndrome 5, OMIM:613805; Microcephalic primordial dwarfism
Severe microcephaly v4.73 CENPE Arina Puzriakova Phenotypes for gene: CENPE were changed from ?Microcephaly 13, primary, autosomal recessive, 616051; MPD; microcephalic primordial dwarfism to ?Microcephaly 13, primary, autosomal recessive, OMIM:616051; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.538 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from MEIER-GORLIN SYNDROME 4 to Meier-Gorlin syndrome 4, OMIM:613804
Skeletal dysplasia v4.58 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from Meier-Gorlin syndrome 4 613804 to Meier-Gorlin syndrome 4, OMIM:613804
Fetal anomalies v3.158 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from MEIER-GORLIN SYNDROME 4 to Meier-Gorlin syndrome 4, OMIM:613804
Deafness and congenital structural abnormalities v1.23 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from Bilateral Microtia; 613804; Meier-Gorlin syndrome 4, 613804; Causes Meier-Gorlin EPS; syndromic features; Short stature, small head size, the ears may be low-set or rotated backward (+/-microtia). Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge to Meier-Gorlin syndrome 4, OMIM:613804; Short stature, small head size, the ears may be low-set or rotated backward (+/-microtia). Additional features can include a small mouth (microstomia), an underdeveloped lower jaw (micrognathia), full lips, and a narrow nose with a high nasal bridge
IUGR and IGF abnormalities v1.61 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from micrognathia, microtia, patellar hypoplasia/aplasia, mammary hypoplasia to Meier-Gorlin syndrome 4, OMIM:613804; micrognathia, microtia, patellar hypoplasia/aplasia, mammary hypoplasia
Severe microcephaly v4.72 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from MPD; microcephalic primordial dwarfism; Meier-Gorlin syndrome 4, 613804 to Meier-Gorlin syndrome 4, OMIM:613804; Microcephalic primordial dwarfism
Monogenic diabetes v2.58 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Bloom syndrome to Bloom syndrome, OMIM:210900
Pigmentary skin disorders v3.12 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Bloom syndrome to Bloom syndrome, OMIM:210900
Primary ovarian insufficiency v1.68 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Bloom syndrome 210900 to Bloom syndrome, OMIM:210900
IUGR and IGF abnormalities v1.60 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Bloom syndrome, 210900 to Bloom syndrome, OMIM:210900
Haematological malignancies for rare disease v1.17 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Class: BM failure syndrome (typ AR); Bloom syndrome; leukaemia; lymphoma; skin squamous cell; other tumour types; Lymphoma; ALL; MDS; AML; Leukaemia; Carcinomas to Bloom syndrome, OMIM:210900; Class: BM failure syndrome (typ AR); Bloom syndrome; leukaemia; lymphoma; skin squamous cell; other tumour types; Lymphoma; ALL; MDS; AML; Leukaemia; Carcinomas
Severe microcephaly v4.71 BLM Arina Puzriakova Phenotypes for gene: BLM were changed from Bloom syndrome, OMIM:210900 to Bloom syndrome, OMIM:210900; Microcephalic primordial dwarfism
Hereditary haemorrhagic telangiectasia v3.6 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from Cutaneous telangiectasia and cancer syndrome, familial, 614564 (biallelic) to ?Cutaneous telangiectasia and cancer syndrome, familial, OMIM:614564
Intellectual disability - microarray and sequencing v5.537 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from Seckel syndrome 1, 210600Cutaneous telangiectasia and cancer syndrome, familial, 614564; SECKEL SYNDROME TYPE 1 (SCKL1) to Seckel syndrome 1, OMIM:210600
Clefting v4.110 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from SECKEL SYNDROME 1; SCKL1 to Seckel syndrome 1, OMIM:210600
Clefting v4.110 ATR Arina Puzriakova Mode of inheritance for gene: ATR was changed from to BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.70 ATR Arina Puzriakova Publications for gene: ATR were set to
Severe microcephaly v4.69 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from MPD; microcephalic primordial dwarfism; Seckel syndrome 1, 210600; MICROCEPHALIC PRIMORDIAL DWARFISM I to Seckel syndrome 1, OMIM:210600; Microcephalic primordial dwarfism
Intellectual disability - microarray and sequencing v5.536 FEM1B Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications to: 31036916, 38465576; Changed phenotypes to: Syndromic disease MONDO:0002254, FEM1B-related
Fetal anomalies v3.157 USP14 Zornitza Stark gene: USP14 was added
gene: USP14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP14 were set to 38469793
Phenotypes for gene: USP14 were set to Syndromic disease MONDO:0002254, USP14-related
Review for gene: USP14 was set to AMBER
Added comment: PMID 38469793: biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. The fetus and the newborn had extensive brain malformations.
Sources: Literature
Intellectual disability - microarray and sequencing v5.536 RNU4-2 Zornitza Stark gene: RNU4-2 was added
gene: RNU4-2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU4-2 were set to 38645094
Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related
Review for gene: RNU4-2 was set to GREEN
Added comment: Over 100 individuals reported with NND and heterozygous variants in a 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III). The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). Variants in this region likely explain 0.41% of individuals with NDD.
Sources: Literature
Intellectual disability - microarray and sequencing v5.536 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Intellectual disability - microarray and sequencing v5.536 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Childhood onset dystonia, chorea or related movement disorder v3.77 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Childhood onset dystonia, chorea or related movement disorder v3.77 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Childhood onset hereditary spastic paraplegia v4.43 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Childhood onset hereditary spastic paraplegia v4.43 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Severe microcephaly v4.68 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Severe microcephaly v4.68 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Ataxia and cerebellar anomalies - narrow panel v4.64 ACBD6 Arina Puzriakova Added comment: Comment on phenotypes: This gene now has a relevant phenotype listed in OMIM (MIM# 620785)
Ataxia and cerebellar anomalies - narrow panel v4.64 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder, MONDO:0700092 to Neurodevelopmental disorder with progressive movement abnormalities, OMIM:620785
Paediatric disorders - additional genes v3.10 PLD1 Arina Puzriakova changed review comment from: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.; to: Comment on list classification: This Green gene was signed off in Mar 2023 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.157 PLD1 Arina Puzriakova changed review comment from: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.; to: Comment on list classification: This Green gene was signed off in Mar 2023 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Paediatric disorders - additional genes v3.10 PLD1 Arina Puzriakova Classified gene: PLD1 as Green List (high evidence)
Paediatric disorders - additional genes v3.10 PLD1 Arina Puzriakova Added comment: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Paediatric disorders - additional genes v3.10 PLD1 Arina Puzriakova Gene: pld1 has been classified as Green List (High Evidence).
Fetal anomalies v3.157 PLD1 Arina Puzriakova Classified gene: PLD1 as Green List (high evidence)
Fetal anomalies v3.157 PLD1 Arina Puzriakova Added comment: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.157 PLD1 Arina Puzriakova Gene: pld1 has been classified as Green List (High Evidence).
Fetal anomalies v3.156 PLD1 Arina Puzriakova Tag Q2_24_demote_red tag was added to gene: PLD1.
Tag Q2_24_expert_review tag was added to gene: PLD1.
Paediatric disorders - additional genes v3.9 PLD1 Arina Puzriakova Tag Q2_24_demote_red tag was added to gene: PLD1.
Tag Q2_24_expert_review tag was added to gene: PLD1.
Paediatric disorders - additional genes v3.9 PLD1 Arina Puzriakova commented on gene: PLD1: Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Paediatric or syndromic cardiomyopathy v3.47 PLD1 Arina Puzriakova Classified gene: PLD1 as Green List (high evidence)
Paediatric or syndromic cardiomyopathy v3.47 PLD1 Arina Puzriakova Added comment: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Paediatric or syndromic cardiomyopathy v3.47 PLD1 Arina Puzriakova Gene: pld1 has been classified as Green List (High Evidence).
Fetal anomalies v3.156 PLD1 Arina Puzriakova commented on gene: PLD1: Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Paediatric or syndromic cardiomyopathy v3.46 PLD1 Arina Puzriakova Tag Q2_24_demote_red tag was added to gene: PLD1.
Tag Q2_24_expert_review tag was added to gene: PLD1.
Tag Q2_24_NHS_review tag was added to gene: PLD1.
Early onset or syndromic epilepsy v4.195 GLI3 Arina Puzriakova Mode of inheritance for gene: GLI3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v4.194 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Skeletal ciliopathies v3.22 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Joubert Syndrome and Senior-Loken Syndrome 24 gene panel to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Childhood onset dystonia, chorea or related movement disorder v3.76 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Joubert Syndrome and Senior-Loken Syndrome 24 gene panel to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Neurological ciliopathies v3.19 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Joubert Syndrome and Senior-Loken Syndrome 24 gene panel to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Ophthalmological ciliopathies v3.6 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Joubert Syndrome and Senior-Loken Syndrome 24 gene panel to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Rare multisystem ciliopathy disorders v1.171 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Joubert Syndrome and Senior-Loken Syndrome 24 gene panel to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Growth failure in early childhood v3.89 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome to Pallister-Hall syndrome, OMIM:146510
Clefting v4.109 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome, 146510 to Pallister-Hall syndrome, OMIM:146510
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.180 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome 175700; 175700 to Greig cephalopolysyndactyly syndrome, OMIM:175700
Unexplained young onset end-stage renal disease v3.41 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome; Pallister-Hall syndrome 146510 to Pallister-Hall syndrome, OMIM:146510
CAKUT v1.176 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome to Pallister-Hall syndrome, OMIM:146510
Unexplained kidney failure in young people v1.119 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Pallister-Hall syndrome 146510 to Pallister-Hall syndrome, OMIM:146510
Fetal anomalies v3.156 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from PALLISTER-HALL SYNDROME; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; PREAXIAL POLYDACTYLY TYPE IV; POSTAXIAL POLYDACTYLY TYPE A to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510; Polydactyly, postaxial, types A1 and B, OMIM:174200; Polydactyly, preaxial, type IV, OMIM:174700
Skeletal dysplasia v4.57 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome 175700; Polydactyly, postaxial, types A1 and B 174200; Polydactyly, preaxial, type IV 174700; Pallister-Hall syndrome 146510; {Hypothalamic hamartomas, somatic} 241800 to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510; Polydactyly, postaxial, types A1 and B, OMIM:174200; Polydactyly, preaxial, type IV, OMIM:174700
Limb disorders v4.19 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome 175700; Pallister-Hall syndrome 146510; Polydactyly, postaxial, types A1 and B 174200; Polydactyly, preaxial, type IV 174700; {Hypothalamic hamartomas, somatic} 241800; Polydactyly to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510; Polydactyly, postaxial, types A1 and B, OMIM:174200; Polydactyly, preaxial, type IV, OMIM:174700
Pituitary hormone deficiency v3.12 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome (175700); Pallister-Hall syndrome (146510) to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Intellectual disability - microarray and sequencing v5.535 GLI3 Arina Puzriakova Tag Q2_24_demote_amber tag was added to gene: GLI3.
Tag Q2_24_NHS_review tag was added to gene: GLI3.
Intellectual disability - microarray and sequencing v5.535 GLI3 Arina Puzriakova Phenotypes for gene: GLI3 were changed from Greig cephalopolysyndactyly syndrome, 175700Pallister-Hall syndrome, 146510Polydactyly, preaxial, type IV, 174700Polydactyly, postaxial, types A1 and B, 174200{Hypothalamic hamartomas, somatic}, 241800; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME to Greig cephalopolysyndactyly syndrome, OMIM:175700; Pallister-Hall syndrome, OMIM:146510
Intellectual disability - microarray and sequencing v5.534 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to
Intellectual disability - microarray and sequencing v5.533 GLI3 Arina Puzriakova Classified gene: GLI3 as Green List (high evidence)
Intellectual disability - microarray and sequencing v5.533 GLI3 Arina Puzriakova Added comment: Comment on list classification: Reassessed in view of the Red review by Tracy Lester on this Green gene

Rarely, individuals with Greig cephalopolysyndactyly syndrome or GLI3-Related Pallister-Hall syndrome have been found to have intellectual disability (PMID: 12414818; 14708104; 14608643; 34296525). This is usually observed in the most severely affected individuals and those with large deletions encompassing GLI3. The majority of patients have normal psychomotor development or only some mild delays. All GLI3-related disorders are more likely to be recognised in context of other features such as skeletal abnormalities.

Overall, I therefore agree that this gene could be demoted to Amber at the next GMS panel update.
Intellectual disability - microarray and sequencing v5.533 GLI3 Arina Puzriakova Gene: gli3 has been classified as Green List (High Evidence).
Pigmentary skin disorders v3.11 BLM Dmitrijs Rots gene: BLM was added
gene: BLM was added to Pigmentary skin disorders. Sources: Expert Review
Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLM were set to PMID: 32972601
Phenotypes for gene: BLM were set to Bloom syndrome
Penetrance for gene: BLM were set to Complete
Review for gene: BLM was set to GREEN
Added comment: Included in the review PMID: 32972601 as differential for cafe-au-lait
Sources: Expert Review
Pigmentary skin disorders v3.11 SMARCB1 Dmitrijs Rots gene: SMARCB1 was added
gene: SMARCB1 was added to Pigmentary skin disorders. Sources: Expert Review
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCB1 were set to PMID: 32972601
Phenotypes for gene: SMARCB1 were set to Schwannomatosis-1, susceptibility to
Penetrance for gene: SMARCB1 were set to Incomplete
Review for gene: SMARCB1 was set to GREEN
Added comment: Included in the review PMID: 32972601 as differential for cafe-au-lait
Sources: Expert Review
Intellectual disability - microarray and sequencing v5.532 CPA6 Arina Puzriakova Tag refuted tag was added to gene: CPA6.
Intellectual disability - microarray and sequencing v5.532 CPA6 Arina Puzriakova commented on gene: CPA6
Severe microcephaly v4.67 SASS6 Zornitza Stark edited their review of gene: SASS6: Added comment: Two additional families:

PMID: 38501757
1x compound het for a fs and +3 splice variant.

Using cDNA RT-ed from mother's RNA, exons 13-15 were amplified and exon 14 was found to be skipped resulting in c.1546_1674del and p.516_558del

PMID: 36739862
1x family, compound het for 2 missense
Functional studies not performed; Changed rating: GREEN; Changed publications to: 24951542, 30639237, 38501757, 36739862
Intellectual disability - microarray and sequencing v5.532 KCNB2 Zornitza Stark gene: KCNB2 was added
gene: KCNB2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder MONDO:0700092, KCNB2-related
Review for gene: KCNB2 was set to GREEN
Added comment: 7 individuals, all missense
5 de novo + 1x inherited from father who has hypotonia + 1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature
Intellectual disability - microarray and sequencing v5.532 GTF3C5 Zornitza Stark gene: GTF3C5 was added
gene: GTF3C5 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C5 were set to 38520561; 35503477
Phenotypes for gene: GTF3C5 were set to neurodevelopmental disorder MONDO:0700092, GTF3C5-related
Review for gene: GTF3C5 was set to GREEN
Added comment: 4 families/probands with syndromic ID. Loss of function is the expected mechanism.
PMID: 38520561 - Biallelic variants identified (3 missense & 1 stopgain) in 4 individuals from 3 families presenting with multisystem developmental syndrome including the features: growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Gene-disease relationship supported by: reduced protein expression in patient cells, yeast assays, and a zebrafish model
PMID: 35503477 - 1 proband with biallelic missense variants and hypomelanosis of Ito, seizures, growth retardation, abnormal brain MRI, developmental delay, and facial dysmorphism
Sources: Literature
Intellectual disability - microarray and sequencing v5.532 DOCK4 Zornitza Stark gene: DOCK4 was added
gene: DOCK4 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOCK4 were set to 38526744
Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder (MONDO:0060490)
Review for gene: DOCK4 was set to GREEN
Added comment: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Sources: Literature
Intellectual disability - microarray and sequencing v5.532 PLXNB2 Zornitza Stark gene: PLXNB2 was added
gene: PLXNB2 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to 38458752
Phenotypes for gene: PLXNB2 were set to Syndromic disease MONDO:0002254, PLXNB2 -related
Review for gene: PLXNB2 was set to GREEN
Added comment: 8 individuals from 6 families with core features of amelogenesis imperfecta and sensorineural hearing loss. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. WES and WGS identified biallelic pathogenic variants in PLXNB2 (missense, nonsense, splice and a multiexon deletion variants). Variants segregated with disease.

PLXNB2 is a large transmembrane semaphorin receptor protein, and semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Plxnb2 expression was detected in differentiating ameloblasts in mice. Human phenotype overlaps with that seen in Plxnb2 knockout mice.
Sources: Literature
Monogenic hearing loss v4.38 KIAA1024L Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: KIAA1024L.
Monogenic hearing loss v4.38 KIAA1024L Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the association of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Monogenic hearing loss v4.38 KIAA1024L Achchuthan Shanmugasundram Classified gene: KIAA1024L as Amber List (moderate evidence)
Monogenic hearing loss v4.38 KIAA1024L Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene to green rating in the next GMS review.
Monogenic hearing loss v4.38 KIAA1024L Achchuthan Shanmugasundram Gene: kiaa1024l has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.37 KIAA1024L Achchuthan Shanmugasundram commented on gene: KIAA1024L: The new gene name for KIAA1024L is MINAR2 and 'new-gene-name' tag has been added to flag this.
Monogenic hearing loss v4.37 KIAA1024L Achchuthan Shanmugasundram gene: KIAA1024L was added
gene: KIAA1024L was added to Monogenic hearing loss. Sources: Literature
new-gene-name tags were added to gene: KIAA1024L.
Mode of inheritance for gene: KIAA1024L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1024L were set to 35727972
Phenotypes for gene: KIAA1024L were set to Deafness, autosomal recessive 120, OMIM:620238
Review for gene: KIAA1024L was set to GREEN
Added comment: PMID:35727972 reported 13 patients from four unrelated families with non-syndromic sensorineural hearing loss. Four of these patients had prelingual onset of severe to profound, progressive bilateral hearing loss. The other nine patients had congenital onset of severe to profound bilateral hearing loss, which was not progressive on one patient, while data was not available for the other.

Three different homozygous variants (c.144G > A/ p.Trp48Ter, c.412_419delCGGTTTTG/ p.Arg138Valfs*10 and c.393G > T/ p.Lys131Asn) were identified in MINAR2/ KIAA1024L gene in these patients.

There is some functional evidence available for the p.Lys131Asn variant. In addition, mice with loss of function of the Minar2 protein present with rapidly progressive sensorineural hearing loss.

This gene has also been associated with relevant phenotype in OMIM (MIM #620238).
Sources: Literature
Intellectual disability - microarray and sequencing v5.532 CEP295 Zornitza Stark edited their review of gene: CEP295: Changed rating: GREEN
Intellectual disability - microarray and sequencing v5.532 CEP295 Zornitza Stark gene: CEP295 was added
gene: CEP295 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review
Mode of inheritance for gene: CEP295 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP295 were set to 38154379
Phenotypes for gene: CEP295 were set to Seckel syndrome 11, OMIM # 620767
Added comment: 4 children from 2 unrelated families with Seckel-like syndrome - severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes. WES identified biallelic pathogenic variants in CEP295 gene (p(Q544∗) and p(R1520∗); p(R55Efs∗49) and p(P562L)).

Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying mechanisms. Depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Loss of CEP295 caused extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts.
Sources: Expert Review
Ataxia and cerebellar anomalies - narrow panel v4.63 ATP2B3 Achchuthan Shanmugasundram Classified gene: ATP2B3 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.63 ATP2B3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Ataxia and cerebellar anomalies - narrow panel v4.63 ATP2B3 Achchuthan Shanmugasundram Gene: atp2b3 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.62 ATP2B3 Achchuthan Shanmugasundram Publications for gene: ATP2B3 were set to
Ataxia and cerebellar anomalies - narrow panel v4.61 ATP2B3 Achchuthan Shanmugasundram Phenotypes for gene: ATP2B3 were changed from Spinocerebellar ataxia, X-linked 1 to ?Spinocerebellar ataxia, X-linked 1, OMIM:302500
Ataxia and cerebellar anomalies - narrow panel v4.60 ATP2B3 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v4.59 ATP2B3 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: ATP2B3.
Ataxia and cerebellar anomalies - narrow panel v4.59 ATP2B3 Achchuthan Shanmugasundram changed review comment from: There are six unrelated cases reported with X-linked recessive variants in ATP2B3 gene and with a phenotype comprising ataxia. However, the onset of the disease was during childhood in three of these cases, while detailed clinical information was not available for the other three cases. There is also functional evidence available.

This gene has already been associated with ataxia in OMIM (MIM #302500), but not yet with any phenotypes in Gene2Phenotype.; to: There are six unrelated cases reported with five different X-linked recessive variants in ATP2B3 gene and with a phenotype comprising ataxia. However, the onset of the disease was during childhood in three of these cases, while detailed clinical information was not available for the other three cases. There is also functional evidence available.

This gene has already been associated with ataxia in OMIM (MIM #302500), but not yet with any phenotypes in Gene2Phenotype.
Ataxia and cerebellar anomalies - narrow panel v4.59 ATP2B3 Achchuthan Shanmugasundram reviewed gene: ATP2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 25953895, 28807751, 36207321; Phenotypes: ?Spinocerebellar ataxia, X-linked 1, OMIM:302500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary ataxia with onset in adulthood v4.34 ATP2B3 Achchuthan Shanmugasundram changed review comment from: There are six unrelated cases reported with X-linked recessive variants in ATP2B3 gene and with a phenotype comprising ataxia. However, the onset of the disease was during childhood inn three of these cases, while detailed clinical information was not available for the other three cases.; to: There are six unrelated cases reported with X-linked recessive variants in ATP2B3 gene and with a phenotype comprising ataxia. However, the onset of the disease was during childhood in three of these cases, while detailed clinical information was not available for the other three cases.
Hereditary ataxia with onset in adulthood v4.34 ATP2B3 Achchuthan Shanmugasundram Phenotypes for gene: ATP2B3 were changed from Spinocerebellar ataxia, X-linked 1; X-linked spinocerebellar ataxia, 302500 to ?Spinocerebellar ataxia, X-linked 1, OMIM:302500
Hereditary ataxia with onset in adulthood v4.33 ATP2B3 Achchuthan Shanmugasundram Publications for gene: ATP2B3 were set to
Hereditary ataxia with onset in adulthood v4.32 ATP2B3 Achchuthan Shanmugasundram Mode of inheritance for gene: ATP2B3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary ataxia with onset in adulthood v4.31 ATP2B3 Achchuthan Shanmugasundram commented on gene: ATP2B3: There are six unrelated cases reported with X-linked recessive variants in ATP2B3 gene and with a phenotype comprising ataxia. However, the onset of the disease was during childhood inn three of these cases, while detailed clinical information was not available for the other three cases.
Hereditary ataxia with onset in adulthood v4.31 ATP2B3 Achchuthan Shanmugasundram edited their review of gene: ATP2B3: Changed phenotypes to: ?Spinocerebellar ataxia, X-linked 1, OMIM:302500
Hereditary ataxia with onset in adulthood v4.31 ATP2B3 Achchuthan Shanmugasundram reviewed gene: ATP2B3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25953895, 28807751, 36207321; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.532 SMAD3 Achchuthan Shanmugasundram changed review comment from: Two out of six cases with single nucleotide variants from DECIPHER database (https://www.deciphergenomics.org/gene/SMAD3/patient-overlap/snvs )were reported with global developmental delay. However, intellectual disability or global developmental delay were not reported as clinical presentations in patients with Loeys-Dietz syndrome 3 (MIM #613795).; to: Two out of six cases with single nucleotide variants from DECIPHER database (https://www.deciphergenomics.org/gene/SMAD3/patient-overlap/snvs) were reported with global developmental delay. However, intellectual disability or global developmental delay were not reported as clinical presentations in patients with Loeys-Dietz syndrome 3 (MIM #613795). Hence the rating should remain amber with current evidence.
Intellectual disability - microarray and sequencing v5.532 SMAD3 Achchuthan Shanmugasundram reviewed gene: SMAD3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurological segmental overgrowth v2.12 MAX Achchuthan Shanmugasundram Classified gene: MAX as Amber List (moderate evidence)
Neurological segmental overgrowth v2.12 MAX Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by James Poulter, there is sufficient evidence available (three unrelated cases with the same p.Arg60Gln variant and functional studies) for the promotion of this gene to green rating in the next GMS update.
Neurological segmental overgrowth v2.12 MAX Achchuthan Shanmugasundram Gene: max has been classified as Amber List (Moderate Evidence).
Neurological segmental overgrowth v2.11 MAX Achchuthan Shanmugasundram changed review comment from: PMID:38141607 reported three individuals with the same recurrent de novo germline variant in the MAX gene (p.Arg60Gln). Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.; to: PMID:38141607 reported three individuals with the same recurrent de novo germline variant in the MAX gene (p.Arg60Gln). Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.

This gene has been associated with relevant phenotypes in OMIM (MIM #620712).
Neurological segmental overgrowth v2.11 MAX Achchuthan Shanmugasundram Phenotypes for gene: MAX were changed from Macrocephaly; Polydactyly; delayed ophthalmic development; autism to Polydactyly-macrocephaly syndrome, OMIM:620712
Neurological segmental overgrowth v2.10 MAX Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: MAX.
Tag Q2_24_NHS_review tag was added to gene: MAX.
Neurological segmental overgrowth v2.10 MAX Achchuthan Shanmugasundram changed review comment from: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain.

Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.; to: PMID:38141607 reported three individuals with the same recurrent de novo germline variant in the MAX gene (p.Arg60Gln). Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.
Neurological segmental overgrowth v2.10 MAX Achchuthan Shanmugasundram Publications for gene: MAX were set to PMID:38141607
Neurological segmental overgrowth v2.9 MAX Achchuthan Shanmugasundram commented on gene: MAX: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain.

Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae.

Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc.
Neurological segmental overgrowth v2.9 MAX Achchuthan Shanmugasundram reviewed gene: MAX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38141607; Phenotypes: Polydactyly-macrocephaly syndrome, OMIM:620712; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.532 ZFX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with phenotype in OMIM (MIM #301118), but not yet in Gene2Phenotype.
Intellectual disability - microarray and sequencing v5.532 ZFX Achchuthan Shanmugasundram Phenotypes for gene: ZFX were changed from X-linked neurodevelopmental disorder with recurrent facial gestalt to Intellectual developmental disorder, X-linked syndromic 37, OMIM:301118
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Ian Berry, there are now five unrelated families with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Ian Berry, there are now at least nine probands with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: CADM3.
Tag Q2_24_NHS_review tag was added to gene: CADM3.
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram Classified gene: CADM3 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ian Berry, there are now five unrelated families with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram Gene: cadm3 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.93 CADM3 Achchuthan Shanmugasundram Publications for gene: CADM3 were set to 33889941
Hereditary neuropathy or pain disorder v3.92 CADM3 Achchuthan Shanmugasundram reviewed gene: CADM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe Paediatric Disorders v1.184 PRNP Tracy Lester reviewed gene: PRNP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Monogenic hearing loss v4.36 GRXCR2 Sadaf Naz reviewed gene: GRXCR2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33528103, PMID:24619944; Phenotypes: #615837: Deafness, autosomal recessive 101; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Paediatric or syndromic cardiomyopathy v3.46 CASZ1 Achchuthan Shanmugasundram Classified gene: CASZ1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v3.46 CASZ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ludmila Volozonoka, there is sufficient evidence available (three unrelated cases and some functional studies) for the promotion of this gene to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v3.46 CASZ1 Achchuthan Shanmugasundram Gene: casz1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v3.45 CASZ1 Achchuthan Shanmugasundram Phenotypes for gene: CASZ1 were changed from Pediatric Dilated Cardiomyopathy; Pediatric LVNC to dilated cardiomyopathy, MONDO:0005021; left ventricular noncompaction, MONDO:0018901
Paediatric or syndromic cardiomyopathy v3.44 CASZ1 Achchuthan Shanmugasundram changed review comment from: PMID:28099117 reported a patient with a novel heterozygous CASZ1 variant (p.K351X) and with dilated cardiomyopathy (DCM). The variant co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The functional characterisation of the variant with a luciferase reporter assay showed that the variant had no transcriptional activity.

PMID:31268246 reported the identification of a previously unreported de novo heterozygous frameshift variant (p.Val815Profs*14) in CASZ1 in an 11-month-old Chinese boy with DCM and left ventricular noncompaction cardiomyopathy (LVNC).

PMID:36293425 reported a girl with a new de novo frameshift variant (p.Trp1261GlyfsTer29) in CASZ1 gene. DCM was diagnosed for the first time at the age of three months and she died at the age of 1 year 10 months with a diagnosis of dilated cardiomyopathy and decompensation, systemic multiple organ failure, post-anoxic brain damage and gastrointestinal and vaginal bleeding.; to: PMID:28099117 reported a patient with a novel heterozygous CASZ1 variant (p.K351X) and with dilated cardiomyopathy (DCM). The variant co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The functional characterisation of the variant with a luciferase reporter assay showed that the variant had no transcriptional activity.

PMID:31268246 reported the identification of a previously unreported de novo heterozygous frameshift variant (p.Val815Profs*14) in CASZ1 in an 11-month-old Chinese boy with DCM and left ventricular noncompaction cardiomyopathy (LVNC).

PMID:36293425 reported a girl with a new de novo frameshift variant (p.Trp1261GlyfsTer29) in CASZ1 gene. DCM was diagnosed for the first time at the age of three months and she died at the age of 1 year 10 months with a diagnosis of dilated cardiomyopathy and decompensation, systemic multiple organ failure, post-anoxic brain damage and gastrointestinal and vaginal bleeding.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Paediatric or syndromic cardiomyopathy v3.44 CASZ1 Achchuthan Shanmugasundram edited their review of gene: CASZ1: Changed phenotypes to: dilated cardiomyopathy, MONDO:0005021, left ventricular noncompaction, MONDO:0018901
Paediatric or syndromic cardiomyopathy v3.44 CASZ1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: CASZ1.
Paediatric or syndromic cardiomyopathy v3.44 CASZ1 Achchuthan Shanmugasundram reviewed gene: CASZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28099117, 31268246, 36293425; Phenotypes: dilated cardiomyopathy, MONDO:0005021; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.89 MT-ATP6 Achchuthan Shanmugasundram Tag Q2_24_NHS_review tag was added to gene: MT-ATP6.
Retinal disorders v4.89 SLC37A3 Achchuthan Shanmugasundram Tag Q2_24_NHS_review tag was added to gene: SLC37A3.
Retinal disorders v4.89 SLC37A3 Achchuthan Shanmugasundram Classified gene: SLC37A3 as Amber List (moderate evidence)
Retinal disorders v4.89 SLC37A3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Siying Lin, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Retinal disorders v4.89 SLC37A3 Achchuthan Shanmugasundram Gene: slc37a3 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.88 SLC37A3 Achchuthan Shanmugasundram Phenotypes for gene: SLC37A3 were changed from Retinitis pigmentosa; No OMIM entry to retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.87 SLC37A3 Achchuthan Shanmugasundram Publications for gene: SLC37A3 were set to 28041643
Retinal disorders v4.86 SLC37A3 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: SLC37A3.
Retinal disorders v4.86 SLC37A3 Achchuthan Shanmugasundram reviewed gene: SLC37A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: retinitis pigmentosa, MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.86 MT-ATP6 Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: MT-ATP6.
Retinal disorders v4.86 MT-ATP6 Achchuthan Shanmugasundram Classified gene: MT-ATP6 as Amber List (moderate evidence)
Retinal disorders v4.86 MT-ATP6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is ample evidence available for the association of MT-ATP6 gene with retinitis pigmentosa. Hence, this gene can be promoted to green rating in the next GMS review.
Retinal disorders v4.86 MT-ATP6 Achchuthan Shanmugasundram Gene: mt-atp6 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.85 MT-ATP6 Achchuthan Shanmugasundram Phenotypes for gene: MT-ATP6 were changed from Retinitis pigmentosa to NARP syndrome, MONDO:0010794
Retinal disorders v4.84 MT-ATP6 Achchuthan Shanmugasundram Publications for gene: MT-ATP6 were set to
Retinal disorders v4.83 MT-ATP6 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: MT-ATP6.
Retinal disorders v4.83 MT-ATP6 Achchuthan Shanmugasundram reviewed gene: MT-ATP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 11843698, 17568559, 19124644, 22819295, 23266623, 24118886, 27015314, 29054413, 29224958, 36809201; Phenotypes: NARP syndrome, MONDO:0010794; Mode of inheritance: MITOCHONDRIAL
Primary immunodeficiency or monogenic inflammatory bowel disease v4.201 PTCRA Achchuthan Shanmugasundram Classified gene: PTCRA as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.201 PTCRA Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.201 PTCRA Achchuthan Shanmugasundram Gene: ptcra has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.200 PTCRA Achchuthan Shanmugasundram Phenotypes for gene: PTCRA were changed from Autoimmunity; elevated TCRgamma/delta T cells; lymphopenia; low TREC to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783
Primary immunodeficiency or monogenic inflammatory bowel disease v4.199 PTCRA Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PTCRA.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.199 PTCRA Achchuthan Shanmugasundram reviewed gene: PTCRA: Rating: GREEN; Mode of pathogenicity: None; Publications: 38422122; Phenotypes: Autoimmunity, HP:0002960, lymphopenia, MONDO:0003783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.92 GAN Arina Puzriakova Publications for gene: GAN were set to 1106248
Hereditary neuropathy or pain disorder v3.91 GAN Arina Puzriakova Classified gene: GAN as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.91 GAN Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update as the scope of this panel has now been expanded to include complex cases of neuropathy.
Biallelic variants in the GAN gene cause giant axonal neuropathy. This childhood onset polyneuropathy results in progressive neurodegeneration of both the peripheral and central nervous systems. More than 10 unrelated cases have been reported in the literature which is sufficient for making this gene Green (PMIDs: 18595793; 19231187; 20949505; 27852232; 36866531)
Hereditary neuropathy or pain disorder v3.91 GAN Arina Puzriakova Gene: gan has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.531 GAN Arina Puzriakova changed review comment from: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases to date (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.; to: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.
Intellectual disability - microarray and sequencing v5.531 GAN Arina Puzriakova Tag Q2_24_promote_green tag was added to gene: GAN.
Tag Q2_24_NHS_review tag was added to gene: GAN.
Intellectual disability - microarray and sequencing v5.531 GAN Arina Puzriakova Publications for gene: GAN were set to
Intellectual disability - microarray and sequencing v5.530 GAN Arina Puzriakova Classified gene: GAN as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.530 GAN Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in the GAN gene cause giant axonal neuropathy, characterised by abnormalities in the peripheral and central nervous systems. Though extent of CNS involvement can vary, intellectual disability has been reported in at least 3 unrelated cases to date (PMID: 18595793; 19231187). Therefore, this gene should be promoted to Green at the next GMS panel update.
Intellectual disability - microarray and sequencing v5.530 GAN Arina Puzriakova Gene: gan has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.22 COASY Hannah Knight reviewed gene: COASY: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35499143; Phenotypes: Pontocerebellar hypoplasia type 12; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.22 PIP5K1C Hannah Knight reviewed gene: PIP5K1C: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38491417; Phenotypes: Lethal congenital contractural syndrome 3 611369; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.90 GAN Arina Puzriakova Tag Q2_24_promote_green tag was added to gene: GAN.
Tag Q2_24_NHS_review tag was added to gene: GAN.
Arthrogryposis v5.22 SLC18A3 Hannah Knight reviewed gene: SLC18A3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34943989; Phenotypes: Myasthenic syndrome, congenital, 21, presynaptic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.22 TRIP4 Hannah Knight reviewed gene: TRIP4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31794073; Phenotypes: Spinal muscular atrophy with congenital bone fractures 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.529 GAN Arina Puzriakova Mode of inheritance for gene: GAN was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.528 GAN Arina Puzriakova Phenotypes for gene: GAN were changed from to Giant axonal neuropathy-1, OMIM:256850
Hereditary neuropathy v1.477 GAN Arina Puzriakova Phenotypes for gene: GAN were changed from Giant axonal neuropathy-1 to Giant axonal neuropathy-1, OMIM:256850
Hereditary neuropathy or pain disorder v3.90 GAN Arina Puzriakova Phenotypes for gene: GAN were changed from Giant axonal neuropathy-1 to Giant axonal neuropathy-1, OMIM:256850
Intellectual disability - microarray and sequencing v5.527 SEPHS1 Arina Puzriakova Classified gene: SEPHS1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.527 SEPHS1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability - microarray and sequencing v5.527 SEPHS1 Arina Puzriakova Gene: sephs1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.526 SEPHS1 Arina Puzriakova Classified gene: SEPHS1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.526 SEPHS1 Arina Puzriakova Gene: sephs1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.525 SEPHS1 Arina Puzriakova gene: SEPHS1 was added
gene: SEPHS1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Q2_24_promote_green tags were added to gene: SEPHS1.
Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SEPHS1 were set to 38531365
Phenotypes for gene: SEPHS1 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: SEPHS1 was set to GREEN
Added comment: Mullegama et al. (2024) reported 9 individuals from 8 families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight individuals shared different missense variants at the same p.Arg371 residue in SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were confirmed as de novo (one unknown). Functional studies showed that variants at the Arg371 residue impact direct protein-protein interactions of SEPSH1 and enhance cell proliferation by modulating ROS homeostasis.
Sources: Literature
Fetal anomalies v3.155 GRM1 Arina Puzriakova Classified gene: GRM1 as Red List (low evidence)
Fetal anomalies v3.155 GRM1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Zornitza Stark. Could not find any evidence of prenatal phenotypes in patients with GRM1 variants.
Fetal anomalies v3.155 GRM1 Arina Puzriakova Gene: grm1 has been classified as Red List (Low Evidence).
Stickler syndrome v4.4 LRP2 Arina Puzriakova Classified gene: LRP2 as Red List (low evidence)
Stickler syndrome v4.4 LRP2 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.

Only a single family reported with features overlapping those of Stickler syndrome (PMID:23992033), mainly based on their ocular phenotype, including high myopia, vitreous changes, cataract and esotropia. LRP2 variants are typically associated with Donnai-Barrow syndrome and facio-oculo-acoustico-renal syndrome which are not relevant to this panel.
Stickler syndrome v4.4 LRP2 Arina Puzriakova Gene: lrp2 has been classified as Red List (Low Evidence).
Cytopenia - NOT Fanconi anaemia v3.32 FCGR3B Arina Puzriakova Classified gene: FCGR3B as Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v3.32 FCGR3B Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.

Also note review from Helen Brittain (Genomics England Clinical Team) on 100K panel Cytopenias and congenital anaemias (159) from 9 Mar 2017:

"Relevant phenotype affects neutrophils only, on a transient basis owing to presence of antibodies in mother and antigen in fetus (as a result of different genetic factors in father and mother.). Therefore not a germline condition associated with mutations in the child."
Cytopenia - NOT Fanconi anaemia v3.32 FCGR3B Arina Puzriakova Gene: fcgr3b has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.19 ADAMTS2 Arina Puzriakova Classified gene: ADAMTS2 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.19 ADAMTS2 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.19 ADAMTS2 Arina Puzriakova Gene: adamts2 has been classified as Red List (Low Evidence).
Dilated and arrhythmogenic cardiomyopathy v2.22 MYZAP Arina Puzriakova Tag Q2_24_promote_green tag was added to gene: MYZAP.
Dilated and arrhythmogenic cardiomyopathy v2.22 MYZAP Arina Puzriakova Deleted their comment
Dilated and arrhythmogenic cardiomyopathy v2.22 MYZAP Arina Puzriakova Publications for gene: MYZAP were set to 34899865; 20093627; 35840178
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Classified gene: MYZAP as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Added comment: Comment on list classification: New gene added to the panel by Aleš Maver. MYZAP is not yet associated with any phenotype in OMIM or Gene2Phenoype. At least three unrelated families have been reported with biallelic LOF variants in MYZAP and a phenotype of DCM (PMIDs: 34899865; 35840178; 38436102). Studies in zebrafish and mice demonstrate the link between MYZAP and cardiomyopathy (PMIDs: 20093627; 24698889). Overall, the evidence is sufficient to promote this gene to Green at the next GMS panel update.
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Gene: myzap has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Classified gene: MYZAP as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Added comment: Comment on list classification: New gene added to the panel by Aleš Maver. MYZAP is not yet associated with any phenotype in OMIM or Gene2Phenoype. At least three unrelated families have been reported with biallelic LOF variants in MYZAP and a phenotype of DCM (PMIDs: 34899865; 35840178; 38436102). Studies in zebrafish and mice demonstrate the link between MYZAP and cardiomyopathy (PMIDs: 20093627; 24698889). Overall, the evidence is sufficient to promote this gene to Green at the next GMS panel update.
Dilated and arrhythmogenic cardiomyopathy v2.21 MYZAP Arina Puzriakova Gene: myzap has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism (GMS) v3.18 NDNF Arina Puzriakova Classified gene: NDNF as Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v3.18 NDNF Arina Puzriakova Added comment: Comment on list classification: Gene was re-reviewed in light of an Amber review by Zornitza Stark (Australian Genomics) on a Green gene. At least five unrelated cases have been reported, as well as mouse and zebrafish studies showing Ndnf deficiency leads to anomalies in GnRH neuron migration. Pedigree analysis does indicate variable expressivity and incomplete penetrance, although this is relatively common in dominant forms of HH. Furthermore, inclusion of NDNF on this panel has already been reviewed and approved by the NHS specialist group and therefore the Green rating is being maintained.
Hypogonadotropic hypogonadism (GMS) v3.18 NDNF Arina Puzriakova Gene: ndnf has been classified as Green List (High Evidence).
Hypogonadotropic hypogonadism (GMS) v3.17 NDNF Arina Puzriakova Phenotypes for gene: NDNF were changed from Congenital hypogonadotropic hypogonadism (CHH); Hypogonadotropic hypogonadism 25 with anosmia, 618841 to Hypogonadotropic hypogonadism 25 with anosmia, OMIM:618841
Hypogonadotropic hypogonadism (GMS) v3.16 NDNF Arina Puzriakova Publications for gene: NDNF were set to 31883645
Hypogonadotropic hypogonadism (GMS) v3.15 NDNF Arina Puzriakova commented on gene: NDNF: PMID: 36245975 (2022) - another male patient with idiopathic hypogonadotropin hypogonadism identified harbouring a paternally inherited NDNF variant (c.1439T>A, p.Ile480Asn)
Hereditary spastic paraplegia v1.311 RTN2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are sufficient number of cases with biallelic variants and lower limb spasticity, the MOI has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Hereditary spastic paraplegia v1.311 RTN2 Achchuthan Shanmugasundram Mode of inheritance for gene: RTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.310 RTN2 Achchuthan Shanmugasundram Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant to Spastic paraplegia 12, autosomal dominant, OMIM:604805; distal hereditary motor neuropathy, MONDO:0018894; Lower limb spasticity, HP:0002061
Hereditary spastic paraplegia v1.309 RTN2 Achchuthan Shanmugasundram Publications for gene: RTN2 were set to Montenegro et al. (2012)
Hereditary spastic paraplegia v1.308 RTN2 Achchuthan Shanmugasundram reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38527963; Phenotypes: distal hereditary motor neuropathy, MONDO:0018894, Lower limb spasticity, HP:0002061; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v4.42 RTN2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are sufficient number of cases with biallelic variants and lower limb spasticity, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset hereditary spastic paraplegia v4.42 RTN2 Achchuthan Shanmugasundram Mode of inheritance for gene: RTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v4.41 RTN2 Achchuthan Shanmugasundram Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant, 604805 to Spastic paraplegia 12, autosomal dominant, OMIM:604805; distal hereditary motor neuropathy, MONDO:0018894; Lower limb spasticity, HP:0002061
Childhood onset hereditary spastic paraplegia v4.40 RTN2 Achchuthan Shanmugasundram Publications for gene: RTN2 were set to 22232211; 24123792; 28362824
Childhood onset hereditary spastic paraplegia v4.39 RTN2 Achchuthan Shanmugasundram Tag Q2_24_MOI tag was added to gene: RTN2.
Tag Q2_24_NHS_review tag was added to gene: RTN2.
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain, and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.39 RTN2 Achchuthan Shanmugasundram reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38527963; Phenotypes: distal hereditary motor neuropathy, MONDO:0018894, Lower limb spasticity, HP:0002061; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Rare genetic inflammatory skin disorders v3.18 COL5A2 Arina Puzriakova Classified gene: COL5A2 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.18 COL5A2 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.18 COL5A2 Arina Puzriakova Gene: col5a2 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.17 COL5A1 Arina Puzriakova Classified gene: COL5A1 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.17 COL5A1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.17 COL5A1 Arina Puzriakova Gene: col5a1 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.16 COL4A5 Arina Puzriakova Classified gene: COL4A5 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.16 COL4A5 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.16 COL4A5 Arina Puzriakova Gene: col4a5 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.15 COL4A4 Arina Puzriakova Classified gene: COL4A4 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.15 COL4A4 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.15 COL4A4 Arina Puzriakova Gene: col4a4 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.14 COL4A3 Arina Puzriakova Classified gene: COL4A3 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.14 COL4A3 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.14 COL4A3 Arina Puzriakova Gene: col4a3 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.13 COL3A1 Arina Puzriakova Classified gene: COL3A1 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.13 COL3A1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.13 COL3A1 Arina Puzriakova Gene: col3a1 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.12 COL1A2 Arina Puzriakova Classified gene: COL1A2 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.12 COL1A2 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.12 COL1A2 Arina Puzriakova Gene: col1a2 has been classified as Red List (Low Evidence).
Rare genetic inflammatory skin disorders v3.11 COL1A1 Arina Puzriakova Classified gene: COL1A1 as Red List (low evidence)
Rare genetic inflammatory skin disorders v3.11 COL1A1 Arina Puzriakova Added comment: Comment on list classification: Demoted from Amber to Red inline with review by Dmitrijs Rots.
Rare genetic inflammatory skin disorders v3.11 COL1A1 Arina Puzriakova Gene: col1a1 has been classified as Red List (Low Evidence).
Autoinflammatory disorders v1.17 IL17RA Arina Puzriakova Tag watchlist tag was added to gene: IL17RA.
Autoinflammatory disorders v1.17 IL17RA Arina Puzriakova Classified gene: IL17RA as Amber List (moderate evidence)
Autoinflammatory disorders v1.17 IL17RA Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants have been found patients with immunodeficiency, presenting as chronic mucocutaneous candidiasis (PMID: 21350122).

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease so it is plausible that the interleukin-17A receptor (IL-17RA) could contribute to the same pathway.

Literature review did reveal multiple mouse models where IL-17RA was shown to promote the inflammatory response (PMID: 38060620; 30364284; 35844540; 38451335); however, there is no evidence of human cases where a variant in the IL17RA gene caused an autoinflammatory disorder. Therefore rating as Amber with a watchlist tag, awaiting further evidence.
Autoinflammatory disorders v1.17 IL17RA Arina Puzriakova Gene: il17ra has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.199 IL17RA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Candidiasis, familial, 5;Chronic mucocutaneous candidiasis (CMC);Immunodeficiency 51, 613953;Defects in Intrinsic and Innate Immunity;CMC, folliculitis;Defects in Intrinsic and Innate Immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v4.199 IL17RA Arina Puzriakova Phenotypes for gene: IL17RA were changed from Candidiasis, familial, 5; Chronic mucocutaneous candidiasis (CMC); Immunodeficiency 51, 613953; Defects in Intrinsic and Innate Immunity; CMC, folliculitis; Defects in Intrinsic and Innate Immunity to Immunodeficiency 51, OMIM:613953
Autoinflammatory disorders v1.16 IL17RA Arina Puzriakova Phenotypes for gene: IL17RA were changed from Immunodeficiency-51 to Immunodeficiency 51, OMIM:613953
Likely inborn error of metabolism - targeted testing not possible v4.137 ADA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Combined B and T cell defect;Adenosine deaminase deficiency (Disorders of purine metabolism);SCID;Infantile enterocolitis & monogenic inflammatory bowel disease
Likely inborn error of metabolism - targeted testing not possible v4.137 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Likely inborn error of metabolism - targeted testing not possible v4.136 ADA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Combined B and T cell defect;Adenosine deaminase deficiency (Disorders of purine metabolism);SCID;Infantile enterocolitis & monogenic inflammatory bowel disease
Likely inborn error of metabolism - targeted testing not possible v4.136 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Combined B and T cell defect; Adenosine deaminase deficiency (Disorders of purine metabolism); SCID; Infantile enterocolitis & monogenic inflammatory bowel disease to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Primary immunodeficiency or monogenic inflammatory bowel disease v4.198 ADA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Severe combined immunodeficiency due to ADA deficiency (some mosiacism noted);Severe combined immunodeficiency due to ADA deficiency, 102700;T-B- SCID;T-B+ SCID;Adenosine deaminase (ADA) deficiency;Atypical Severe Combined Immunodeficiency (Atypical SCID);Omenn syndrome;Severe combined immunodeficiency (SCID);Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects;Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v4.198 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency (some mosiacism noted); Severe combined immunodeficiency due to ADA deficiency, 102700; T-B- SCID; T-B+ SCID; Adenosine deaminase (ADA) deficiency; Atypical Severe Combined Immunodeficiency (Atypical SCID); Omenn syndrome; Severe combined immunodeficiency (SCID); Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects; Immunodeficiencies affecting cellular and humoral immunity to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Fetal anomalies v3.154 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Combined B and T cell defect; Adenosine deaminase deficiency (Disorders of purine metabolism); SCID; Infantile enterocolitis & monogenic inflammatory bowel disease to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Fetal anomalies v3.153 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from ADENOSINE DEAMINASE DEFICIENCY to Combined B and T cell defect; Adenosine deaminase deficiency (Disorders of purine metabolism); SCID; Infantile enterocolitis & monogenic inflammatory bowel disease
Undiagnosed metabolic disorders v1.617 ADA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Adenosine deaminase deficiency (Disorders of purine metabolism);Combined B and T cell defect;Infantile enterocolitis & monogenic inflammatory bowel disease;SCID
Undiagnosed metabolic disorders v1.617 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Adenosine deaminase deficiency (Disorders of purine metabolism); Combined B and T cell defect; Infantile enterocolitis & monogenic inflammatory bowel disease; SCID to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Intellectual disability - microarray and sequencing v5.524 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, 102700; Adenosine deaminase deficiency, partial, 102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Severe combined immunodeficiency with adenosine deaminase deficiency v1.3 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700 to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700
Severe combined immunodeficiency with adenosine deaminase deficiency v1.2 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Autoinflammatory disorders v1.15 ADA Arina Puzriakova Phenotypes for gene: ADA were changed from T(-), B(-), NK(-) severe combin immunodeficiency to Severe combined immunodeficiency due to ADA deficiency, OMIM:102700; Adenosine deaminase deficiency, partial, OMIM:102700
Bleeding and platelet disorders v3.9 GP6 Arina Puzriakova Phenotypes for gene: GP6 were changed from 614201 Bleeding disorder, platelet-type, 11 to Bleeding disorder, platelet-type, 11, OMIM:614201
Inherited bleeding disorders v1.177 GP6 Arina Puzriakova Phenotypes for gene: GP6 were changed from Bleeding diathesis due to glycoprotein VI deficiency to Bleeding disorder, platelet-type, 11, OMIM:614201
Autoinflammatory disorders v1.14 GP6 Arina Puzriakova Phenotypes for gene: GP6 were changed from Platlet-type bleeding disorder-11 to Bleeding disorder, platelet-type, 11, OMIM:614201
Autoinflammatory disorders v1.13 GP6 Arina Puzriakova Classified gene: GP6 as Red List (low evidence)
Autoinflammatory disorders v1.13 GP6 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with bleeding disorder caused by defective platelet activation and aggregation in response to collagen. Could not find evidence of an autoinflammatory component observed in patients and therefore rating as Red on this panel
Autoinflammatory disorders v1.13 GP6 Arina Puzriakova Gene: gp6 has been classified as Red List (Low Evidence).
Autoinflammatory disorders v1.12 ADA Arina Puzriakova Classified gene: ADA as Red List (low evidence)
Autoinflammatory disorders v1.12 ADA Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Lauma Freimane (Children's Clinical University Hospital). Biallelic variants are associated with partial ADA deficiency or severe combined immunodeficiency (SCID) due to ADA deficiency with multiple unrelated cases reported.

Despite ADA null mice displaying severe pulmonary inflammation, could not find evidence of an autoinflammatory component observed in patients and therefore rating as Red on this panel
Autoinflammatory disorders v1.12 ADA Arina Puzriakova Gene: ada has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram Classified gene: RTN2 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of RTN2 biallelic variants with distal hereditary motor neuropathy. Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram Gene: rtn2 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.88 RTN2 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: RTN2.
Hereditary neuropathy or pain disorder v3.88 RTN2 Achchuthan Shanmugasundram gene: RTN2 was added
gene: RTN2 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: RTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTN2 were set to 38527963
Phenotypes for gene: RTN2 were set to distal hereditary motor neuropathy, MONDO:0018894
Review for gene: RTN2 was set to GREEN
Added comment: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Fetal anomalies v3.152 NRXN2 Sarah Leigh Classified gene: NRXN2 as Red List (low evidence)
Fetal anomalies v3.152 NRXN2 Sarah Leigh Added comment: Comment on list classification: There insufficient evidence between NRXN2 variants and autism for this gene to be rated amber.
Fetal anomalies v3.152 NRXN2 Sarah Leigh Gene: nrxn2 has been classified as Red List (Low Evidence).
Iron metabolism disorders - NOT common HFE mutations v2.6 CYBRD1 Sarah Leigh Publications for gene: CYBRD1 were set to 15338274; 27884173
Iron metabolism disorders - NOT common HFE mutations v2.5 CYBRD1 Sarah Leigh edited their review of gene: CYBRD1: Added comment: It would appear that there are no CYBRD1 rare SNVs associated with iron metabolism.  However, PMID: 37632052 concludes that the coexistence of minor alleles of HDAC3 rs976552 and CYBRD1 rs884409 is linked with higher prevalence of hepatocellular carcinoma.

Furthermore, HFE p.C282Y variant together with the CYBRD1 polymorphism rs884409 reduces CYBRD1 promoter activity by 30% (PMID: 19673882).; Changed rating: AMBER
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent heterozygous LIM2 p.R130C variant (PMIDs: 32202185; 33078099; 33708862; 33923544; 35736209). These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.; to: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with cataracts due to a recurrent heterozygous LIM2 p.R130C variant (PMIDs: 32202185; 33078099; 33708862; 33923544; 35736209). These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent LIM2 p.R130C variant (PMIDs: 32202185; 33078099; 33708862; 33923544; 35736209). These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.; to: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent heterozygous LIM2 p.R130C variant (PMIDs: 32202185; 33078099; 33708862; 33923544; 35736209). These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova Tag recurrent-variant tag was added to gene: LIM2.
Tag Q2_24_MOI tag was added to gene: LIM2.
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova changed review comment from: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent LIM2 p.R130C variant. These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.; to: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent LIM2 p.R130C variant (PMIDs: 32202185; 33078099; 33708862; 33923544; 35736209). These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova Added comment: Comment on mode of inheritance: The MOI should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update. At least 9 unrelated multigenerational families have been identified with congenital cataracts due to a recurrent LIM2 p.R130C variant. These families come from different ancestries (British, Chinese, Spanish, Japanese) and haplotype analysis in families from shared ancestries has suggested the variant likely arose due to independent founder events in each family. The evidence therefore supports this MOI being included in future analyses.
Bilateral congenital or childhood onset cataracts v4.12 LIM2 Arina Puzriakova Mode of inheritance for gene: LIM2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.87 CADM3 Ian Berry reviewed gene: CADM3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38074074, 33889941; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bilateral congenital or childhood onset cataracts v4.11 LIM2 Arina Puzriakova Publications for gene: LIM2 were set to Ponnam et al (2008) Mol Vis 14:1204-1208; Pras et al (2002) Am J Hum genet 70:1363-7
Bilateral congenital or childhood onset cataracts v4.10 LIM2 Arina Puzriakova Phenotypes for gene: LIM2 were changed from Cortical Pulverulent Cataract; Cataract 19, 615277 to Cataract 19, multiple types, OMIM:615277
Structural eye disease v3.77 LIM2 Arina Puzriakova Phenotypes for gene: LIM2 were changed from Cataract 19, 615277 to Cataract 19, multiple types, OMIM:615277
Intellectual disability - microarray and sequencing v5.523 FRYL Arina Puzriakova Classified gene: FRYL as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.523 FRYL Arina Puzriakova Added comment: Comment on list classification: Rating Amber as overall the evidence is borderline. Only one recent study (PMID:38479391) has reported an disease association for FRYL, with variable phenotypes and results from functional studies, as well as variants in other genes in several cases. Additional studies are required to conclusively corroborate causality (added watchlist tag).
Intellectual disability - microarray and sequencing v5.523 FRYL Arina Puzriakova Gene: fryl has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.522 FRYL Arina Puzriakova gene: FRYL was added
gene: FRYL was added to Intellectual disability - microarray and sequencing. Sources: Literature
watchlist tags were added to gene: FRYL.
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: FRYL was set to AMBER
Added comment: New association linking this gene to disease which is not yet listed in OMIM or Gene2Phenotype. There are no sequence variants in Decipher and ClinVar shows only a single pathogenic frameshift variant (c.1224del, p.Lys409fs) for FRYL-associated neurodevelopmental disorder, amongst multiple SNVs which are mostly missense VUS or B/LB.

Pan et al., 2024 (PMID: 38479391) reported 14 individuals with heterozygous variant in FRYL who presented with DD/ID, dysmorphic features, and other congenital anomalies in multiple systems. Except for DD/ID which was the only universal feature, observed phenotypes were variable and nonspecific.

Variants were confirmed de novo in all except one individual (duo testing excluded paternal inheritance although it was present at low frequency in gnomAD). Variant types include missense (5), fs/stop-gain (8) and canonical splice (1). Modelling 4/5 patient missense variants using flies showed that only one serves as a severe LoF variant, two others behave as partial LoF variants, and one variant had no functional impact (only variant not confirmed as de novo indicating this is a VUS). Four individuals also had P/LP variants in other genes (SF3B4, DHCR7, SLC6A19, SDHA) which could at least partially explain their phenotypes, and a further four harboured additional VUSs.
Sources: Literature
RASopathies v1.81 RRAS Sarah Leigh Classified gene: RRAS as Green List (high evidence)
RASopathies v1.81 RRAS Sarah Leigh Gene: rras has been classified as Green List (High Evidence).
RASopathies v1.80 RRAS Sarah Leigh Tag Q2_24_promote_green was removed from gene: RRAS.
RASopathies v1.80 RRAS Sarah Leigh Tag Q2_24_promote_green tag was added to gene: RRAS.
Fetal anomalies v3.151 RRAS Sarah Leigh Tag Q2_24_promote_green tag was added to gene: RRAS.
Cytopenia - NOT Fanconi anaemia v3.31 RRAS Sarah Leigh Tag Q2_24_promote_green tag was added to gene: RRAS.
RASopathies v1.80 RRAS Sarah Leigh Publications for gene: RRAS were set to 24705357
RASopathies v1.79 RRAS Sarah Leigh edited their review of gene: RRAS: Added comment: RRAS variants have not associated with a phenotype in OMIM or MONDO, but Gen2Phen lists a strong association between RRAS variants and RRAS-related atypical Noonan syndrome. Three germline RRAS variants have been reported (PMID: 24705357; 32815881; 34935735), associated with a RASopathy, which includes myelodysplastic syndrome and contributes to leukaemogenesis.; Changed rating: GREEN; Changed publications to: 24705357, 32815881, 34935735
Fetal anomalies v3.151 RRAS Sarah Leigh edited their review of gene: RRAS: Added comment: RRAS variants have not associated with a phenotype in OMIM or MONDO, but Gen2Phen lists a strong association between RRAS variants and RRAS-related atypical Noonan syndrome. Three germline RRAS variants have been reported (PMID: 24705357; 32815881; 34935735), associated with a RASopathy, which includes myelodysplastic syndrome and contributes to leukaemogenesis.; Changed rating: GREEN; Changed publications to: 24705357, 32815881, 34935735
Cytopenia - NOT Fanconi anaemia v3.31 RRAS Sarah Leigh Publications for gene: RRAS were set to 34935735
Cytopenia - NOT Fanconi anaemia v3.30 RRAS Sarah Leigh commented on gene: RRAS: RRAS variants have not associated with a phenotype in OMIM or MONDO, but Gen2Phen lists a strong association between RRAS variants and RRAS-related atypical Noonan syndrome. Three germline RRAS variants have been reported (PMID: 24705357; 32815881; 34935735), associated with a RASopathy, which includes myelodysplastic syndrome and contributes to leukaemogenesis.
RASopathies v1.79 RRAS Sarah Leigh Added comment: Comment on phenotypes: Phenotype from Gen2Phen
RASopathies v1.79 RRAS Sarah Leigh Phenotypes for gene: RRAS were changed from Noonan syndrome to RRAS-related atypical Noonan syndrome
Fetal anomalies v3.151 RRAS Sarah Leigh Added comment: Comment on phenotypes: Phenotype from Gen2Phen
Fetal anomalies v3.151 RRAS Sarah Leigh Phenotypes for gene: RRAS were changed from ATYPICAL NOONAN SYNDROME to RRAS-related atypical Noonan syndrome
Fetal anomalies v3.150 RRAS Sarah Leigh Publications for gene: RRAS were set to
Cytopenia - NOT Fanconi anaemia v3.30 RRAS Sarah Leigh edited their review of gene: RRAS: Added comment: RRAS variants have not associated with a phenotype in OMIM or MONDO, but Gen2Phen lists a strong association between RRAS variants and RRAS-related atypical Noonan syndrome. Three germline RRAS variants have been reported (PMID: 24705357; 32815881; 34935735), associated with a RASopathy, which includes myelodysplastic syndrome and contributes to leukaemogenesis.; Changed rating: GREEN; Changed publications to: 24705357, 32815881, 34935735; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cytopenia - NOT Fanconi anaemia v3.30 RRAS Sarah Leigh Added comment: Comment on phenotypes: RRAS-related atypical Noonan syndrome phenotype from Gen2Phen
Cytopenia - NOT Fanconi anaemia v3.30 RRAS Sarah Leigh Phenotypes for gene: RRAS were changed from Pediatric Myelodysplastic Syndrome to RRAS-related atypical Noonan syndrome
Cytopenia - NOT Fanconi anaemia v3.29 RRAS Sarah Leigh Publications for gene: RRAS were set to PMID: 34935735
Cytopenia - NOT Fanconi anaemia v3.28 RRAS Sarah Leigh Classified gene: RRAS as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.28 RRAS Sarah Leigh Gene: rras has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v4.31 NAA60 Sarah Leigh commented on gene: NAA60: NAA60 should be green on the Hereditary ataxia with onset in adulthood as four of the families described in table 1 (PMID: 38480682), also displayed either cerebellar syndrome (which often includes ataxia) or cerebellar ataxia (personal communication from Helen Brittain (Genomics England Clinical Fellow).
Adult onset neurodegenerative disorder v4.47 NAA60 Sarah Leigh changed review comment from: To date, NAA60 variants are not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38480682 reports six NAA60 variants in six unrelated cases with an autosomal recessive primary familial brain calcification (PFBC). Table 2 in PMID: 38480682 outlines the extent of the calcification seen in the patient's CT scans. Functional studies show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro, and loss of function by the NAA60 variants results in a reduced level of surface SLC20A2, thereby, reducing the extracellular phosphate uptake. The authors conclude, that this study provides a possible biochemical explanation of the involvement of NAA60 variants in PFBC development (PMID: 38480682).
Sources: Literature; to: To date, NAA60 variants are not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38480682 reports six NAA60 variants in six unrelated cases with an autosomal recessive primary familial brain calcification (PFBC); signs of Parkinsonian presentation was evident in three families reported. Table 2 in PMID: 38480682 outlines the extent of the calcification seen in the patient's CT scans. Functional studies show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro, and loss of function by the NAA60 variants results in a reduced level of surface SLC20A2, thereby, reducing the extracellular phosphate uptake. The authors conclude, that this study provides a possible biochemical explanation of the involvement of NAA60 variants in PFBC development (PMID: 38480682).
Sources: Literature
Hereditary ataxia with onset in adulthood v4.31 NAA60 Sarah Leigh Tag Q2_24_MOI tag was added to gene: NAA60.
Adult onset neurodegenerative disorder v4.47 NAA60 Sarah Leigh Tag Q2_24_MOI tag was added to gene: NAA60.
White matter disorders and cerebral calcification - narrow panel v3.35 NAA60 Sarah Leigh Tag Q2_24_MOI tag was added to gene: NAA60.
Hereditary ataxia with onset in adulthood v4.31 NAA60 Sarah Leigh Entity copied from White matter disorders and cerebral calcification - narrow panel v3.35
Hereditary ataxia with onset in adulthood v4.31 NAA60 Sarah Leigh gene: NAA60 was added
gene: NAA60 was added to Hereditary ataxia with onset in adulthood. Sources: Literature,Expert Review Amber
Q2_24_promote_green, Q2_24_NHS_review tags were added to gene: NAA60.
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to NAA60 associated autosomal recessive primary familial brain calcifications
Adult onset neurodegenerative disorder v4.47 NAA60 Sarah Leigh Entity copied from White matter disorders and cerebral calcification - narrow panel v3.35
Adult onset neurodegenerative disorder v4.47 NAA60 Sarah Leigh gene: NAA60 was added
gene: NAA60 was added to Adult onset neurodegenerative disorder. Sources: Literature,Expert Review Amber
Q2_24_promote_green, Q2_24_NHS_review tags were added to gene: NAA60.
Mode of inheritance for gene: NAA60 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to NAA60 associated autosomal recessive primary familial brain calcifications
White matter disorders and cerebral calcification - narrow panel v3.35 NAA60 Sarah Leigh changed review comment from: To date, NAA60 variants are not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38480682 reports six NAA60 variants in six unrelated cases with an autosomal recessive primary familial brain calcification (PFBC). Table 2 in PMID: 38480682 outlines the extent of the calcification seen in the patient's CT scans. Functional studies show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro, and loss of function by the NAA60 variants results in a reduced level of surface SLC20A2, thereby, reducing the extracellular phosphate uptake. The authors conclude, that this study provides a possible biochemical explanation of the involvement of NAA60 variants in PFBC development (PMID: 38480682).
Sources: Literature; to: To date, NAA60 variants are not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38480682 reports six NAA60 variants in six unrelated cases with an autosomal recessive primary familial brain calcification (PFBC). Table 2 in PMID: 38480682 outlines the extent of the calcification seen in the patient's CT scans. Functional studies show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro, and loss of function by the NAA60 variants results in a reduced level of surface SLC20A2, thereby, reducing the extracellular phosphate uptake. The authors conclude, that this study provides a possible biochemical explanation of the involvement of NAA60 variants in PFBC development (PMID: 38480682).
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v3.35 NAA60 Sarah Leigh Mode of inheritance for gene: NAA60 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v4.30 BTD Achchuthan Shanmugasundram Phenotypes for gene: BTD were changed from Biotinidase deficiency, OMIM:253260 to Biotinidase deficiency, OMIM:253260; optic atrophy, MONDO:0003608
Optic neuropathy v4.29 BTD Achchuthan Shanmugasundram edited their review of gene: BTD: Changed phenotypes to: Biotinidase deficiency, OMIM:253260, optic atrophy, MONDO:0003608
Optic neuropathy v4.29 BTD Achchuthan Shanmugasundram Classified gene: BTD as Amber List (moderate evidence)
Optic neuropathy v4.29 BTD Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Optic neuropathy v4.29 BTD Achchuthan Shanmugasundram Gene: btd has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.28 BTD Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: BTD.
Optic neuropathy v4.28 BTD Achchuthan Shanmugasundram gene: BTD was added
gene: BTD was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: BTD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BTD were set to 26203071; 29025919; 32235217; 33364171
Phenotypes for gene: BTD were set to Biotinidase deficiency, OMIM:253260
Review for gene: BTD was set to GREEN
Added comment: PMID:26203071 - A 22-year-old man presented with a disabling extensive myelopathy and bilateral optic neuropathy which mimicked the findings of a (seronegative) neuromyelitis optica. A novel homozygous BTD variant (p.Ala439Asp) and a known variant (c.1413T>C/ p.Cys471Cys) were identified in this patient.

PMID:29025919 - Two unrelated individuals with adult-onset biotinidase deficiency had severe, but reversible optic neuropathy. They were identified with compound heterozygous variants (patient 1: p.Phe232Cys/ p.Leu440Pro; patient 2: p.Gln456His/ p.Arg538Cys).

PMID:32235217 - A 49-year-old man was reported with progressive optic atrophy, peripheral neuropathy, and systemic weakness and fatigue due to biotinidase deficiency. This patient was reported with compound heterozygous variants (p.Ala171Thr/ p.Asp444His)

PMID:33364171 - Two adult brothers were reported with biallelic BTD variants. Both of them presented with lower limb neuropathy and one had progressive optic neuropathy.
Sources: Literature
Possible mitochondrial disorder - nuclear genes v3.105 SLIRP Achchuthan Shanmugasundram Classified gene: SLIRP as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.105 SLIRP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with compound heterozygous SLIRP variants and the gene should be rated red.
Possible mitochondrial disorder - nuclear genes v3.105 SLIRP Achchuthan Shanmugasundram Gene: slirp has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.104 SLIRP Achchuthan Shanmugasundram reviewed gene: SLIRP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v3.15 COL5A1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: COL5A1.
Cerebral vascular malformations v3.15 COL5A1 Achchuthan Shanmugasundram Classified gene: COL5A1 as Amber List (moderate evidence)
Cerebral vascular malformations v3.15 COL5A1 Achchuthan Shanmugasundram Gene: col5a1 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v3.14 COL5A1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of heterozygous COL5A1 variants with this panel. However, there are only two cases reported with compound heterozygous variants. Hence the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Cerebral vascular malformations v3.14 COL5A1 Achchuthan Shanmugasundram Mode of inheritance for gene: COL5A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.13 COL5A1 Achchuthan Shanmugasundram Phenotypes for gene: COL5A1 were changed from Fibromuscular dysplasia, multifocal to Ehlers-Danlos syndrome, classic type, 1, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329
Cerebral vascular malformations v3.12 COL5A1 Achchuthan Shanmugasundram Publications for gene: COL5A1 were set to PMID: 32938213
Cerebral vascular malformations v3.11 COL5A1 Achchuthan Shanmugasundram edited their review of gene: COL5A1: Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v3.11 COL5A1 Achchuthan Shanmugasundram edited their review of gene: COL5A1: Changed phenotypes to: Ehlers-Danlos syndrome, classic type, 1, OMIM:130000, Fibromuscular dysplasia, multifocal, OMIM:619329
Cerebral vascular malformations v3.11 COL5A1 Achchuthan Shanmugasundram changed review comment from: PMID:17053184 - Of 15 patients from seven families with spontaneous cervical artery dissections (CAD) recruited in this study, two patients from a family carried a rare variant in COL5A1 (p.Asp192Asn). One of them also carried a rare variant in COL5A2.

PMID:31903434 - Among 43 patients with cervical artery dissection (CeAD) analysed in this study, one patient had classic Ehlers Danlos syndrome due to two different missense variants in COL5A1 (p.Arg65Trp and p.Val172Phe), while another patient had missense variants in COL5A2 (p.Pro1103Leu) and COL5A1 (p.Thr1757Met).

PMID:32938213 - Four unrelated individuals were reported with the same heterozygous variant in COL5A1 (p.Gly514Ser) and they presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. The existence of a common haplotype among all four probands suggest founder effect.

PMID:33189937 - A 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS was identified with two COL5A1 missense variants in trans configuration (p.Gly530Ser and p.Pro1379Ser).

PMID:35911880; to: PMID:17053184 - Of 15 patients from seven families with spontaneous cervical artery dissections (CAD) recruited in this study, two patients from a family carried a rare variant in COL5A1 (p.Asp192Asn). One of them also carried a rare variant in COL5A2.

PMID:31903434 - Among 43 patients with cervical artery dissection (CeAD) analysed in this study, one patient had classic Ehlers Danlos syndrome due to two different missense variants in COL5A1 (p.Arg65Trp and p.Val172Phe), while another patient had missense variants in COL5A2 (p.Pro1103Leu) and COL5A1 (p.Thr1757Met).

PMID:32938213 - Four unrelated individuals were reported with the same heterozygous variant in COL5A1 (p.Gly514Ser) and they presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. The existence of a common haplotype among all four probands suggest founder effect.

PMID:33189937 - A 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS was identified with two COL5A1 missense variants in trans configuration (p.Gly530Ser and p.Pro1379Ser).

PMID:35911880 - A female was reported with postpartum arterial dissection involving all four cervicocephalic arteries resulting in acute cerebral infarction. She was identified with a heterozygous COL5A1 gene variant (p.Asp1648Gly).

This gene has been associated with relevant phenotypes in OMIM and Gene2Phenotype.
Cerebral vascular malformations v3.11 COL5A1 Achchuthan Shanmugasundram reviewed gene: COL5A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 17053184, 31903434, 32938213, 33189937, 35911880; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v4.36 GRAP Achchuthan Shanmugasundram commented on gene: GRAP: As reviewed by Barbara Vona, two unrelated families were reported with the same homozygous missense variant. There is some functional data available as well.

This gene has been associated with relevant phenotype in OMIM (MIM #618456).
Monogenic hearing loss v4.36 GRAP Achchuthan Shanmugasundram Classified gene: GRAP as Red List (low evidence)
Monogenic hearing loss v4.36 GRAP Achchuthan Shanmugasundram Gene: grap has been classified as Red List (Low Evidence).
Monogenic hearing loss v4.35 GRAP Achchuthan Shanmugasundram Phenotypes for gene: GRAP were changed from Non-syndromic hearing loss to Deafness, autosomal recessive 114, OMIM:618456
Monogenic hearing loss v4.34 GRAP Achchuthan Shanmugasundram reviewed gene: GRAP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 114, OMIM:618456; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.34 GRAP Achchuthan Shanmugasundram Publications for gene: GRAP were set to PMID: 30610177
Proteinuric renal disease v4.12 RCAN1 Achchuthan Shanmugasundram commented on gene: RCAN1: As reviewed by Zornitza Stark, whole-genome sequencing performed on 320 individuals from 201 families with familial and sporadic nephrotic syndrome (NS)/ focal segmental glomerulosclerosis (FSGS) identified two variants in RCAN1 gene in two families with autosomal dominant FSGS/ steroid-resistant nephrotic syndrome (SRNS). In addition, there is some functional data available.

This gene has not been associated with any phenotypes either in OMIM or in Gene2Phenotype.

This gene can be rated amber with current evidence.
Proteinuric renal disease v4.12 RCAN1 Achchuthan Shanmugasundram Classified gene: RCAN1 as Amber List (moderate evidence)
Proteinuric renal disease v4.12 RCAN1 Achchuthan Shanmugasundram Gene: rcan1 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v4.11 RCAN1 Achchuthan Shanmugasundram Phenotypes for gene: RCAN1 were changed from FSGS; proteinuria to focal segmental glomerulosclerosis, MONDO:0100313; nephrotic syndrome, MONDO:0005377
Proteinuric renal disease v4.10 RCAN1 Achchuthan Shanmugasundram reviewed gene: RCAN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: focal segmental glomerulosclerosis, MONDO:0100313, nephrotic syndrome, MONDO:0005377; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuric renal disease v4.10 PRDM15 Achchuthan Shanmugasundram Classified gene: PRDM15 as Amber List (moderate evidence)
Proteinuric renal disease v4.10 PRDM15 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (six unrelated individuals with three different biallelic variants, mouse and Xenopus models and functional data) for the promotion of this gene to green rating in the next GMS update.
Proteinuric renal disease v4.10 PRDM15 Achchuthan Shanmugasundram Gene: prdm15 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v4.9 PRDM15 Achchuthan Shanmugasundram Phenotypes for gene: PRDM15 were changed from Steroid resistant nephrotic syndrome; Holoprosencephaly to steroid-resistant nephrotic syndrome, MONDO:0044765
Proteinuric renal disease v4.8 PRDM15 Achchuthan Shanmugasundram Publications for gene: PRDM15 were set to 31950080
Proteinuric renal disease v4.7 PRDM15 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PRDM15.
Proteinuric renal disease v4.7 PRDM15 Achchuthan Shanmugasundram reviewed gene: PRDM15: Rating: GREEN; Mode of pathogenicity: None; Publications: 33593823; Phenotypes: steroid-resistant nephrotic syndrome, MONDO:0044765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic neuropathy v4.27 PDXK Achchuthan Shanmugasundram Classified gene: PDXK as Amber List (moderate evidence)
Optic neuropathy v4.27 PDXK Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
Optic neuropathy v4.27 PDXK Achchuthan Shanmugasundram Gene: pdxk has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.26 PDXK Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PDXK.
Hereditary neuropathy or pain disorder v3.87 PDXK Achchuthan Shanmugasundram Classified gene: PDXK as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.87 PDXK Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.87 PDXK Achchuthan Shanmugasundram Gene: pdxk has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.86 PDXK Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: PDXK.
Optic neuropathy v4.26 PDXK Achchuthan Shanmugasundram gene: PDXK was added
gene: PDXK was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to 31187503; 32522499
Phenotypes for gene: PDXK were set to Neuropathy, hereditary motor and sensory, type VIC, with optic atrophy, OMIM:618511
Review for gene: PDXK was set to GREEN
Added comment: PMID:31187503 - Five individuals from two unrelated families were reported with biallelic PDXK variants and with primary axonal polyneuropathy and optic atrophy. This association was also supported by results from cell-based functional assays. The biochemical profile can be rescued with PLP supplementation associated with clinical improvement.

PMID:32522499 - Two affected siblings with a novel biallelic missense PDXK variant were reported with a similar phenotype as reported in PMID:31187503 with earlier onset. Functional analysis showed that this variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels.

This gene has been associated with relevant phenotypes in OMIM (MIM #618511), but not yet in Gene2Phenotype.
Sources: Literature
Hereditary neuropathy or pain disorder v3.86 PDXK Achchuthan Shanmugasundram gene: PDXK was added
gene: PDXK was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to 31187503; 32522499
Phenotypes for gene: PDXK were set to Neuropathy, hereditary motor and sensory, type VIC, with optic atrophy, OMIM:618511
Review for gene: PDXK was set to GREEN
Added comment: PMID:31187503 - Five individuals from two unrelated families were reported with biallelic PDXK variants and with primary axonal polyneuropathy and optic atrophy. This association was also supported by results from cell-based functional assays. The biochemical profile can be rescued with PLP supplementation associated with clinical improvement.

PMID:32522499 - Two affected siblings with a novel biallelic missense PDXK variant were reported with a similar phenotype as reported in PMID:31187503 with earlier onset. Functional analysis showed that this variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels.

This gene has been associated with relevant phenotypes in OMIM (MIM #618511), but not yet in Gene2Phenotype.
Sources: Literature
Fetal anomalies v3.149 NRXN2 Sarah Leigh Publications for gene: NRXN2 were set to
Fetal hydrops v1.64 FZD6 Irina Adamena gene: FZD6 was added
gene: FZD6 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: FZD6 was set to Unknown
Publications for gene: FZD6 were set to PMID: 33082562
Phenotypes for gene: FZD6 were set to Nonimmune hydrops fetalis
Review for gene: FZD6 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 GLMN Irina Adamena gene: GLMN was added
gene: GLMN was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: GLMN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GLMN were set to PMID: 33082562
Phenotypes for gene: GLMN were set to Nonimmune hydrops fetalis
Review for gene: GLMN was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 ITGA9 Irina Adamena gene: ITGA9 was added
gene: ITGA9 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: ITGA9 was set to Unknown
Publications for gene: ITGA9 were set to PMID: 33082562
Phenotypes for gene: ITGA9 were set to Nonimmune hydrops fetalis
Review for gene: ITGA9 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Hereditary neuropathy or pain disorder v3.84 SPG7 Sarah Leigh changed review comment from: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; to: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Kirsty Williams), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).
Fetal hydrops v1.64 CANT1 Irina Adamena gene: CANT1 was added
gene: CANT1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: CANT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CANT1 were set to PMID: 33082562
Phenotypes for gene: CANT1 were set to Nonimmune hydrops fetalis
Review for gene: CANT1 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 PTH1R Irina Adamena reviewed gene: PTH1R: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 GPI Irina Adamena gene: GPI was added
gene: GPI was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: GPI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPI were set to PMID: 33082562
Phenotypes for gene: GPI were set to Nonimmune hydrops fetalis
Review for gene: GPI was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 G6PD Irina Adamena gene: G6PD was added
gene: G6PD was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: G6PD was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: G6PD were set to PMID: 33082562
Phenotypes for gene: G6PD were set to Nonimmune hydrops fetalis
Review for gene: G6PD was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 RPL15 Irina Adamena gene: RPL15 was added
gene: RPL15 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: RPL15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RPL15 were set to PMID: 33082562
Phenotypes for gene: RPL15 were set to Nonimmune hydrops fetalis
Review for gene: RPL15 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 PRF1 Irina Adamena gene: PRF1 was added
gene: PRF1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: PRF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRF1 were set to PMID: 33082562
Phenotypes for gene: PRF1 were set to Nonimmune hydrops fetalis
Review for gene: PRF1 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 GATA1 Irina Adamena reviewed gene: GATA1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal hydrops v1.64 SEC23B Irina Adamena gene: SEC23B was added
gene: SEC23B was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: SEC23B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEC23B were set to PMID: 33082562
Phenotypes for gene: SEC23B were set to Nonimmune hydrops fetalis
Review for gene: SEC23B was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 CDAN1 Irina Adamena reviewed gene: CDAN1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 SPTB Irina Adamena gene: SPTB was added
gene: SPTB was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: SPTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTB were set to PMID: 33082562
Phenotypes for gene: SPTB were set to Nonimmune hydrops fetalis
Review for gene: SPTB was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 SLC4A1 Irina Adamena gene: SLC4A1 was added
gene: SLC4A1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: SLC4A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC4A1 were set to PMID: 33082562
Phenotypes for gene: SLC4A1 were set to Nonimmune hydrops fetalis
Review for gene: SLC4A1 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Congenital muscular dystrophy v4.23 FHL1 Sarah Leigh changed review comment from: In response to Zornitza Starks' review, are the phenotypes of Reducing body myopathy, X-linked 1a, severe, infantile or early childhood onset (OMIM:300717) and/or Reducing body myopathy, X-linked 1b, with late childhood or adult onset (OMIM:300718), which are associated with FHL1 variants, appropriate for this panel - Congenital muscular dystrophy (R79)?; to: In response to Zornitza Starks' review, Helen Brittain (Genomics England Clinical Fellow) was asked the following question: are the phenotypes of Reducing body myopathy, X-linked 1a, severe, infantile or early childhood onset (OMIM:300717) and/or Reducing body myopathy, X-linked 1b, with late childhood or adult onset (OMIM:300718), which are associated with FHL1 variants, appropriate for this panel - Congenital muscular dystrophy (R79)?
Helen Brittain replied that in PMID: 19181672, the patients present with weakness and a raised CK - this would make clinicians think of a muscular dystrophy primarily. Although technically it may be a myopathy, I think it is enough of a mimic to be included on both the dystrophy and myopathy panels. Therefore this gene should remain green on Congenital muscular dystrophy
Fetal hydrops v1.64 SGPL1 Irina Adamena reviewed gene: SGPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 GBE1 Irina Adamena reviewed gene: GBE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 MT-TL1 Irina Adamena gene: MT-TL1 was added
gene: MT-TL1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL
Publications for gene: MT-TL1 were set to PMID: 33082562
Phenotypes for gene: MT-TL1 were set to Nonimmune hydrops fetalis
Review for gene: MT-TL1 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 MT-TE Irina Adamena gene: MT-TE was added
gene: MT-TE was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene gene: MT-TE was set to MITOCHONDRIAL
Publications for gene: MT-TE were set to PMID: 33082562
Phenotypes for gene: MT-TE were set to Nonimmune hydrops fetalis
Review for gene: MT-TE was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 MVK Irina Adamena reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 MGAT2 Irina Adamena gene: MGAT2 was added
gene: MGAT2 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: MGAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MGAT2 were set to PMID: 33082562
Phenotypes for gene: MGAT2 were set to Nonimmune hydrops fetalis
Review for gene: MGAT2 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 SLC17A5 Irina Adamena reviewed gene: SLC17A5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 GLB1 Irina Adamena reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 GUSB Irina Adamena reviewed gene: GUSB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 GALNS Irina Adamena reviewed gene: GALNS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33082562; Phenotypes: Nonimmune hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 SCN5A Irina Adamena gene: SCN5A was added
gene: SCN5A was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: SCN5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN5A were set to PMID: 33082562
Phenotypes for gene: SCN5A were set to Nonimmune hydrops fetalis
Review for gene: SCN5A was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 KCNH2 Irina Adamena gene: KCNH2 was added
gene: KCNH2 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: KCNH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH2 were set to PMID: 33082562
Phenotypes for gene: KCNH2 were set to Nonimmune hydrops fetalis
Review for gene: KCNH2 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 ALPK3 Irina Adamena gene: ALPK3 was added
gene: ALPK3 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: ALPK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALPK3 were set to PMID: 33082562
Phenotypes for gene: ALPK3 were set to Nonimmune hydrops fetalis
Review for gene: ALPK3 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 MYH7 Irina Adamena gene: MYH7 was added
gene: MYH7 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: MYH7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH7 were set to PMID: 33082562
Phenotypes for gene: MYH7 were set to Nonimmune hydrops fetalis
Review for gene: MYH7 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 LAMB2 Irina Adamena gene: LAMB2 was added
gene: LAMB2 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: LAMB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMB2 were set to PMID: 33082562
Phenotypes for gene: LAMB2 were set to Nonimmune hydrops fetalis
Review for gene: LAMB2 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v3.34 NAA60 Sarah Leigh Classified gene: NAA60 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v3.34 NAA60 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - narrow panel v3.34 NAA60 Sarah Leigh Gene: naa60 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.33 NAA60 Sarah Leigh gene: NAA60 was added
gene: NAA60 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Q2_24_promote_green, Q2_24_NHS_review tags were added to gene: NAA60.
Mode of inheritance for gene: NAA60 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NAA60 were set to 38480682
Phenotypes for gene: NAA60 were set to NAA60 associated autosomal recessive primary familial brain calcifications
Review for gene: NAA60 was set to GREEN
Added comment: To date, NAA60 variants are not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38480682 reports six NAA60 variants in six unrelated cases with an autosomal recessive primary familial brain calcification (PFBC). Table 2 in PMID: 38480682 outlines the extent of the calcification seen in the patient's CT scans. Functional studies show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro, and loss of function by the NAA60 variants results in a reduced level of surface SLC20A2, thereby, reducing the extracellular phosphate uptake. The authors conclude, that this study provides a possible biochemical explanation of the involvement of NAA60 variants in PFBC development (PMID: 38480682).
Sources: Literature
Fetal hydrops v1.64 CDC42 Irina Adamena gene: CDC42 was added
gene: CDC42 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC42 were set to PMID: 33082562
Phenotypes for gene: CDC42 were set to Nonimmune hydrops fetalis
Review for gene: CDC42 was set to GREEN
Added comment: Gene with strong evidence for fetal hydrops (PMID: 33082562)
Sources: Literature
Fetal hydrops v1.64 SLC30A5 Irina Adamena changed review comment from: Four affected children with homozygous loss of function variants in SLC30A5 gene with cardiomyopathy, hydrops fetalis, or cystic hygroma.; to: Four affected children with homozygous loss of function variants in SLC30A5 gene with cardiomyopathy, hydrops fetalis, or cystic hygroma (PMID: 33547425).
Fetal hydrops v1.64 ANGPT2 Irina Adamena reviewed gene: ANGPT2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34876502; Phenotypes: Hydrops fetalis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.64 SLC30A5 Irina Adamena reviewed gene: SLC30A5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33547425; Phenotypes: hydrops fetalis, cardiomyopathy, cystic hygroma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.33 NLRP12 Achchuthan Shanmugasundram Classified gene: NLRP12 as Amber List (moderate evidence)
Monogenic hearing loss v4.33 NLRP12 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases) for the association of NLRP12 with sensorineural hearing loss and hence this gene can be promoted to green rating in the next GMS review.
Monogenic hearing loss v4.33 NLRP12 Achchuthan Shanmugasundram Gene: nlrp12 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.32 NLRP12 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: NLRP12.
Monogenic hearing loss v4.32 NLRP12 Achchuthan Shanmugasundram changed review comment from: PMID:18230725 - Two unrelated families from Guadeloupe were reported with a periodic fever syndrome and with monoallelic NLRP12 variants. Of these, twin boys from family 1 had bilateral sensorineural hearing loss.

PMID:24064030 - Six unrelated Italian patients were reported with familial cold autoinflammatory syndrome 2 and NLRP12 variants, of which one patient had sensorineural hearing loss.

PMID:31820221 - Three cases presenting with NLRP12 - autoinflammatory disorder were reported, where one had sensorineural deafness.
Sources: Literature; to: PMID:18230725 - Two unrelated families from Guadeloupe were reported with a periodic fever syndrome and with monoallelic NLRP12 variants. Of these, twin boys from family 1 had bilateral sensorineural hearing loss.

PMID:24064030 - Six unrelated Italian patients were reported with familial cold autoinflammatory syndrome 2 and NLRP12 variants, of which one patient had sensorineural hearing loss.

PMID:31820221 - Three cases presenting with NLRP12 - autoinflammatory disorder were reported, where one had sensorineural deafness.

NLRP12 has been associated with Familial cold autoinflammatory syndrome 2 (MIM #611762) in OMIM and sensorineural deafness has been listed as one of the clinical presentations of this phenotype.

Sources: Literature
Monogenic hearing loss v4.32 NLRP12 Achchuthan Shanmugasundram gene: NLRP12 was added
gene: NLRP12 was added to Monogenic hearing loss. Sources: Literature
Mode of inheritance for gene: NLRP12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NLRP12 were set to 18230725; 24064030; 31820221
Phenotypes for gene: NLRP12 were set to Familial cold autoinflammatory syndrome 2, OMIM:611762; sensorineural hearing loss disorder, MONDO:0020678
Review for gene: NLRP12 was set to GREEN
Added comment: PMID:18230725 - Two unrelated families from Guadeloupe were reported with a periodic fever syndrome and with monoallelic NLRP12 variants. Of these, twin boys from family 1 had bilateral sensorineural hearing loss.

PMID:24064030 - Six unrelated Italian patients were reported with familial cold autoinflammatory syndrome 2 and NLRP12 variants, of which one patient had sensorineural hearing loss.

PMID:31820221 - Three cases presenting with NLRP12 - autoinflammatory disorder were reported, where one had sensorineural deafness.
Sources: Literature
Childhood solid tumours v4.18 KDM3B Achchuthan Shanmugasundram Classified gene: KDM3B as Amber List (moderate evidence)
Childhood solid tumours v4.18 KDM3B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are four cases reported with KDM3B variants and with cancer, of which three cases are childhood solid tumours (two cases with Wilms tumour and one case with Hodgkin lymphoma), while the fourth case had acute myeloid leukaemia in childhood.

Hence, this gene can be promoted to green rating in the next GMS review.
Childhood solid tumours v4.18 KDM3B Achchuthan Shanmugasundram Gene: kdm3b has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v4.17 KDM3B Achchuthan Shanmugasundram Phenotypes for gene: KDM3B were changed from Diets-Jongmans syndrome to Diets-Jongmans syndrome, OMIM:618846
Childhood solid tumours v4.16 KDM3B Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: KDM3B.
Childhood solid tumours v4.16 KDM3B Achchuthan Shanmugasundram reviewed gene: KDM3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 30885698, 30929739; Phenotypes: Diets-Jongmans syndrome, OMIM:618846; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.521 DENND5B Sarah Leigh Classified gene: DENND5B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.521 DENND5B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability - microarray and sequencing v5.521 DENND5B Sarah Leigh Gene: dennd5b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.520 DENND5B Sarah Leigh Tag Q2_24_promote_green tag was added to gene: DENND5B.
Tag Q2_24_NHS_review tag was added to gene: DENND5B.
Early onset or syndromic epilepsy v4.193 DENND5B Sarah Leigh Classified gene: DENND5B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.193 DENND5B Sarah Leigh Gene: dennd5b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.192 DENND5B Sarah Leigh edited their review of gene: DENND5B: Changed rating: AMBER
Early onset or syndromic epilepsy v4.192 DENND5B Sarah Leigh gene: DENND5B was added
gene: DENND5B was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DENND5B were set to 38387458
Phenotypes for gene: DENND5B were set to DENND5B associated neurodevelopmental disorder
Review for gene: DENND5B was set to GREEN
Added comment: DENND5B variants have not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38387458 reports five de novo missense variants in five unrelated cases. The carriers of these DENND5B variants have a neurodevelopmental disorder, which is characterized by psychomotor delay (5/5 cases), intellectual disability, ranging from severe to mild (3/5 cases, although one of the negative cases was a 2 year old child, who was considered to be too young to make the assessment, although the DD/intellectual disability phenotype was considered to be moderate in this case), epilepsy (2/5 cases) and hypotonia (4/5 cases). The authors of PMID: 38387458 also report the functional effects of the DENND5B variants, which revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. They conclude that this effect is likely to be caused by the predicted disruption of protein folding in the variant DENND5B peptide.
Sources: Literature
Intellectual disability - microarray and sequencing v5.520 DENND5B Sarah Leigh gene: DENND5B was added
gene: DENND5B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: DENND5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DENND5B were set to 38387458
Phenotypes for gene: DENND5B were set to DENND5B associated neurodevelopmental disorder
Review for gene: DENND5B was set to GREEN
Added comment: DENND5B variants have not previously been associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 38387458 reports five de novo missense variants in five unrelated cases. The carriers of these DENND5B variants have a neurodevelopmental disorder, which is characterized by psychomotor delay (5/5 cases), intellectual disability, ranging from severe to mild (3/5 cases, although one of the negative cases was a 2 year old child, who was considered to be too young to make the assessment, although the DD/intellectual disability phenotype was considered to be moderate in this case), epilepsy (2/5 cases) and hypotonia (4/5 cases). The authors of PMID: 38387458 also report the functional effects of the DENND5B variants, which revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. They conclude that this effect is likely to be caused by the predicted disruption of protein folding in the variant DENND5B peptide.
Sources: Literature
Intellectual disability - microarray and sequencing v5.519 TBC1D2B Sarah Leigh Tag watchlist was removed from gene: TBC1D2B.
Tag Q2_24_promote_green tag was added to gene: TBC1D2B.
Tag Q2_24_NHS_review tag was added to gene: TBC1D2B.
Intellectual disability - microarray and sequencing v5.519 TBC1D2B Sarah Leigh Classified gene: TBC1D2B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.519 TBC1D2B Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability - microarray and sequencing v5.519 TBC1D2B Sarah Leigh Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.518 TBC1D2B Sarah Leigh reviewed gene: TBC1D2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh edited their review of gene: TBC1D2B: Added comment: TBC1D2B variants have been associated with Neurodevelopmental disorder with seizures and gingival overgrowth (OMIM:619323) and as definitive Gen2Phen gene for TBC1D2B-related neurodevelopmental disorder. So far, 11 TBC1D2B variants have been reported in 8 unrelated families. Global developmental delay (HP:0001263) was reported in 5/8 families, mental deterioration (HP:0001268) was seen in 5/8 families and seizures (HP:0001250) were reported in 8/8 families (four of these were controlled with medication)(PMID: 38374468).; Changed rating: GREEN
Intellectual disability - microarray and sequencing v5.518 TBC1D2B Sarah Leigh Publications for gene: TBC1D2B were set to 32623794
Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh Publications for gene: TBC1D2B were set to 32623794
Intellectual disability - microarray and sequencing v5.517 TBC1D2B Sarah Leigh Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM:619323; neurodevelopmental disorder with seizures and gingival overgrowth, MONDO:0859148
Early onset or syndromic epilepsy v4.190 TBC1D2B Sarah Leigh Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM:619323; neurodevelopmental disorder with seizures and gingival overgrowth, MONDO:0859148
Ichthyosis and erythrokeratoderma v3.28 DBR1 Achchuthan Shanmugasundram Classified gene: DBR1 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.28 DBR1 Achchuthan Shanmugasundram Gene: dbr1 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.27 DBR1 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: DBR1.
Ichthyosis and erythrokeratoderma v3.27 DBR1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant.; to: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant. There is functional data available. This gene can only be rated amber with the current evidence.

The 'founder-effect' tag is added to this gene.
Ichthyosis and erythrokeratoderma v3.27 DBR1 Achchuthan Shanmugasundram Classified gene: DBR1 as No list
Ichthyosis and erythrokeratoderma v3.27 DBR1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant.
Ichthyosis and erythrokeratoderma v3.27 DBR1 Achchuthan Shanmugasundram Gene: dbr1 has been removed from the panel.
Ichthyosis and erythrokeratoderma v3.26 DBR1 Achchuthan Shanmugasundram edited their review of gene: DBR1: Changed phenotypes to: ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v3.26 DBR1 Achchuthan Shanmugasundram Phenotypes for gene: DBR1 were changed from Ichthyosis (MONDO#0019269), DBR1-related to ichthyosis, MONDO:0019269
Ichthyosis and erythrokeratoderma v3.25 DBR1 Achchuthan Shanmugasundram reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inherited ichthyosis, MONDO:0015947; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v3.12 ADAMTSL2 Achchuthan Shanmugasundram Classified gene: ADAMTSL2 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v3.12 ADAMTSL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, six families were reported with the same monoallelic variant and with Ehlers-Danlos syndrome. However, there is no functional data and it is not clear whether it is a founder variant. Hence, this gene can only be rated amber with the current evidence in this panel.
Ehlers Danlos syndrome with a likely monogenic cause v3.12 ADAMTSL2 Achchuthan Shanmugasundram Gene: adamtsl2 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v3.11 ADAMTSL2 Achchuthan Shanmugasundram reviewed gene: ADAMTSL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, MONDO:0020066; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital adrenal hypoplasia v3.11 KDM1A Achchuthan Shanmugasundram Phenotypes for gene: KDM1A were changed from Food-dependent Cushing syndrome (FDCS) to Cleft palate, psychomotor retardation, and distinctive facial features, OMIM:616728; congenital adrenal hyperplasia, MONDO:0018479
Congenital adrenal hypoplasia v3.10 KDM1A Achchuthan Shanmugasundram Classified gene: KDM1A as Red List (low evidence)
Congenital adrenal hypoplasia v3.10 KDM1A Achchuthan Shanmugasundram Gene: kdm1a has been classified as Red List (Low Evidence).
Congenital adrenal hypoplasia v3.9 KDM1A Achchuthan Shanmugasundram reviewed gene: KDM1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cleft palate, psychomotor retardation, and distinctive facial features, OMIM:616728, congenital adrenal hyperplasia, MONDO:0018479; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare genetic inflammatory skin disorders v3.10 GNB1 Achchuthan Shanmugasundram Classified gene: GNB1 as Amber List (moderate evidence)
Rare genetic inflammatory skin disorders v3.10 GNB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are five cases reported with cutaneous mastocytosis.

Cutaneous mastocytosis has also been reported as one of the clinical presentations of the OMIM phenotype Intellectual developmental disorder, autosomal dominant 42 (MIM #616973).

Hence, this gene can be promoted to green rating in the next GMS review.
Rare genetic inflammatory skin disorders v3.10 GNB1 Achchuthan Shanmugasundram Gene: gnb1 has been classified as Amber List (Moderate Evidence).
Rare genetic inflammatory skin disorders v3.9 GNB1 Achchuthan Shanmugasundram Phenotypes for gene: GNB1 were changed from Cutaneous mastocytosis; Intellectual developmental disorder, autosomal dominant 42 to Intellectual developmental disorder, autosomal dominant 42, OMIM:616973; cutaneous mastocytosis, MONDO:0019023
Rare genetic inflammatory skin disorders v3.8 GNB1 Achchuthan Shanmugasundram Publications for gene: GNB1 were set to 35119134
Rare genetic inflammatory skin disorders v3.7 GNB1 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: GNB1.
Rare genetic inflammatory skin disorders v3.7 GNB1 Achchuthan Shanmugasundram reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29174093, 30194818, 35119134; Phenotypes: Intellectual developmental disorder, autosomal dominant 42, OMIM:616973, cutaneous mastocytosis, MONDO:0019023; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v3.11 SECISBP2 Achchuthan Shanmugasundram Tag Q2_24_NHS_review tag was added to gene: SECISBP2.
Thoracic aortic aneurysm or dissection (GMS) v3.11 SECISBP2 Achchuthan Shanmugasundram Classified gene: SECISBP2 as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v3.11 SECISBP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases and animal models) for the promotion of this gene to green rating in the next GMS review.
Thoracic aortic aneurysm or dissection (GMS) v3.11 SECISBP2 Achchuthan Shanmugasundram Gene: secisbp2 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v3.10 SECISBP2 Achchuthan Shanmugasundram Phenotypes for gene: SECISBP2 were changed from Growth retardation; sensorineural hearing loss; muscular dystrophy; thoracic aortic aneurysm; raised circulating thyroxine and low plasma selenium to Thyroid hormone metabolism, abnormal, 1, OMIM:609698; thoracic aortic aneurysm
Thoracic aortic aneurysm or dissection (GMS) v3.9 SECISBP2 Achchuthan Shanmugasundram Publications for gene: SECISBP2 were set to PMID 38042913; PMID 21084748
Thoracic aortic aneurysm or dissection (GMS) v3.8 SECISBP2 Achchuthan Shanmugasundram Tag Q2_24_promote_green tag was added to gene: SECISBP2.
Thoracic aortic aneurysm or dissection (GMS) v3.8 SECISBP2 Achchuthan Shanmugasundram reviewed gene: SECISBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38042913; Phenotypes: Thyroid hormone metabolism, abnormal, 1, OMIM:609698; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.83 RP1L1 Arina Puzriakova Added comment: Comment on mode of inheritance: This gene is associated with occult macular dystrophy (monoallelic variants) and retinitis pigmentosa (biallelic variants) (https://omim.org/entry/608581) with sufficient cases reported for each phenotype. Currently the monoallelic phenotype is not represented on any GMS panels.

Following curation and consultation with the Genomics England clinical team, there was agreement that macular dystrophy is part of the phenotypic target for this panel. Based on previous reviews, it is not clear why the monoallelic MOI was overwritten and therefore this gene will be flagged for specialist review to determine whether the MOI should stay as 'biallelic' or be updated to 'both mono- and biallelic'.
Retinal disorders v4.83 RP1L1 Arina Puzriakova Mode of inheritance for gene: RP1L1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.82 RP1L1 Arina Puzriakova Tag Q2_24_MOI tag was added to gene: RP1L1.
Tag Q2_24_expert_review tag was added to gene: RP1L1.
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.31 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.30 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051; 32631815
Monogenic hearing loss v4.30 RIPOR2 Achchuthan Shanmugasundram Publications for gene: RIPOR2 were set to 17150207; 24958875; 9055809; 9205841; 24958875; 27269051
Monogenic hearing loss v4.29 RIPOR2 Achchuthan Shanmugasundram Phenotypes for gene: RIPOR2 were changed from Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515 to Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515
Monogenic hearing loss v4.29 RIPOR2 Achchuthan Shanmugasundram Phenotypes for gene: RIPOR2 were changed from ?Deafness, autosomal recessive 104 , OMIM:616515 to Deafness, autosomal dominant 21, OMIM:607017; ?Deafness, autosomal recessive 104, OMIM:616515
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Classified gene: RIPOR2 as Amber List (moderate evidence)
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Added comment: Comment on list classification: Only one variant was reported with both monoallelic and biallelic inheritance. There is some functional data for both modes of inheritance. Although there are 12 unrelated cases reported with the same monoallelic variant, this variant was suggested to be founder variant. Hence, this gene can only be rated amber with the current evidence for both modes of inheritance.
Monogenic hearing loss v4.28 RIPOR2 Achchuthan Shanmugasundram Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram changed review comment from: Biallelic variants:
PMID:24958875 reported six affected members from a single Turkish family with a homozygous splice site variant in the RIPOR2 gene (c.102-1G-A) and with deafness. In addition, morpholino knockdown of the orthologous gene in zebrafish embryos resulted in a significant reduction in the number of saccular hair cells and neuromasts, and caused hearing loss.

Monoallelic variants:
PMID:32631815 reported a heterozygous 12 nucleotide in-frame deletion (c.1696_1707del, p.Gln566_Lys569del) in RIPOR2 that was detected in 12 families of Dutch origin with non-syndromic hearing loss.

In total, the variant was detected in 59/63 affected participants, but also in five unaffected subjects from three family. Age of onset was highly variable, from congenital to 70 years (mean age: 30.6 years) - unaffected family members who harboured the variant were aged 23, 40, 49, 50, and 51 years, respectively. The authors speculated that the four affected subjects without the variant represent phenocopies. The presence of an identical variant in 12 families of common origin, as well as haplotype analysis, indicates a founder effect.

Functional analysis of this variant showed aberrant localisation of RIPOR2 variant protein in early postnatal mouse hair cells, ex vivo; and failure to rescue the stereocilia defects of Ripor2 knockout mice, in contrast to the rescue effect observed in cells expressing wild-type RIPOR2.; to: Biallelic variants:
PMID:24958875 reported six affected members from a single Turkish family with a homozygous splice site variant in the RIPOR2 gene (c.102-1G-A) and with deafness. In addition, morpholino knockdown of the orthologous gene in zebrafish embryos resulted in a significant reduction in the number of saccular hair cells and neuromasts, and caused hearing loss.

Monoallelic variants:
PMID:32631815 reported a heterozygous 12 nucleotide in-frame deletion (c.1696_1707del, p.Gln566_Lys569del) in RIPOR2 that was detected in 12 families of Dutch origin with non-syndromic hearing loss.

In total, the variant was detected in 59/63 affected participants, but also in five unaffected subjects from three family. Age of onset was highly variable, from congenital to 70 years (mean age: 30.6 years) - unaffected family members who harboured the variant were aged 23, 40, 49, 50, and 51 years, respectively. The authors speculated that the four affected subjects without the variant represent phenocopies. The presence of an identical variant in 12 families of common origin, as well as haplotype analysis, indicates a founder effect. Hence, the 'founder-effect' tag was added.

Functional analysis of this variant showed aberrant localisation of RIPOR2 variant protein in early postnatal mouse hair cells, ex vivo; and failure to rescue the stereocilia defects of Ripor2 knockout mice, in contrast to the rescue effect observed in cells expressing wild-type RIPOR2.
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram edited their review of gene: RIPOR2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: RIPOR2.
Monogenic hearing loss v4.27 RIPOR2 Achchuthan Shanmugasundram reviewed gene: RIPOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24958875, 32631815; Phenotypes: Deafness, autosomal dominant 21, OMIM:607017, ?Deafness, autosomal recessive 104, OMIM:616515; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe Paediatric Disorders v1.184 CNTNAP2 Tracy Lester reviewed gene: CNTNAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.515 ASCC3 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Intellectual developmental disorder, autosomal recessive 81, OMIM:620700)
Intellectual disability - microarray and sequencing v5.515 ASCC3 Arina Puzriakova Phenotypes for gene: ASCC3 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual developmental disorder, autosomal recessive 81, OMIM:620700
DDG2P v3.86 ASCC3 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Intellectual developmental disorder, autosomal recessive 81, OMIM:620700)
DDG2P v3.86 ASCC3 Arina Puzriakova Phenotypes for gene: ASCC3 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual developmental disorder, autosomal recessive 81, OMIM:620700
Congenital myopathy v4.37 ASCC3 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Intellectual developmental disorder, autosomal recessive 81, OMIM:620700)
Congenital myopathy v4.37 ASCC3 Arina Puzriakova Phenotypes for gene: ASCC3 were changed from congenital myopathy, MONDO:0019952 to Intellectual developmental disorder, autosomal recessive 81, OMIM:620700
Intellectual disability - microarray and sequencing v5.514 ASCC3 Arina Puzriakova Tag gene-checked was removed from gene: ASCC3.
DDG2P v3.85 ASCC3 Arina Puzriakova Tag gene-checked was removed from gene: ASCC3.
Congenital myopathy v4.36 ASCC3 Arina Puzriakova Tag gene-checked was removed from gene: ASCC3.
Renal ciliopathies v3.5 DLG5 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Yuksel-Vogel-Bauser syndrome, OMIM:620703)
Renal ciliopathies v3.5 DLG5 Arina Puzriakova Phenotypes for gene: DLG5 were changed from DLG5-associated developmental disorder (monoallelic); DLG5-associated developmental disorder (biallelic) to Yuksel-Vogel-Bauser syndrome, OMIM:620703
Unexplained young onset end-stage renal disease v3.40 DLG5 Arina Puzriakova Phenotypes for gene: DLG5 were changed from DLG5-associated developmental disorder (monoallelic); DLG5-associated developmental disorder (biallelic) to Yuksel-Vogel-Bauser syndrome, OMIM:620703
Renal ciliopathies v3.4 DLG5 Arina Puzriakova Tag gene-checked was removed from gene: DLG5.
Intellectual disability - microarray and sequencing v5.514 PTRHD1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747)
Intellectual disability - microarray and sequencing v5.514 PTRHD1 Arina Puzriakova Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747
Parkinson Disease and Complex Parkinsonism v1.121 PTRHD1 Arina Puzriakova Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, OMIM:620747
Intellectual disability - microarray and sequencing v5.513 PTRHD1 Arina Puzriakova Tag gene-checked was removed from gene: PTRHD1.
DDG2P v3.85 FZD5 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Microphthalmia/coloboma 11, OMIM:620731)
DDG2P v3.85 FZD5 Arina Puzriakova Phenotypes for gene: FZD5 were changed from Autosomal Dominant Coloboma to Microphthalmia/coloboma 11, OMIM:620731
Structural eye disease v3.76 FZD5 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Microphthalmia/coloboma 11, OMIM:620731)
Structural eye disease v3.76 FZD5 Arina Puzriakova Phenotypes for gene: FZD5 were changed from Coloboma, None to Microphthalmia/coloboma 11, OMIM:620731
Fetal anomalies v3.147 FZD5 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Microphthalmia/coloboma 11, OMIM:620731)
Fetal anomalies v3.147 FZD5 Arina Puzriakova Phenotypes for gene: FZD5 were changed from Autosomal Dominant Coloboma to Microphthalmia/coloboma 11, OMIM:620731
Ocular coloboma v1.47 FZD5 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Microphthalmia/coloboma 11, OMIM:620731)
Ocular coloboma v1.47 FZD5 Arina Puzriakova Phenotypes for gene: FZD5 were changed from Coloboma to Microphthalmia/coloboma 11, OMIM:620731
Structural eye disease v3.75 FZD5 Arina Puzriakova Tag gene-checked was removed from gene: FZD5.
DDG2P v3.84 FZD5 Arina Puzriakova Tag gene-checked was removed from gene: FZD5.
Ocular coloboma v1.46 FZD5 Arina Puzriakova Tag gene-checked was removed from gene: FZD5.
Intellectual disability - microarray and sequencing v5.513 SLC32A1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Developmental and epileptic encephalopathy 114, OMIM:620774)
Intellectual disability - microarray and sequencing v5.513 SLC32A1 Arina Puzriakova Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 114, OMIM:620774
Early onset or syndromic epilepsy v4.188 SLC32A1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has relevant phenotypes listed in OMIM (Developmental and epileptic encephalopathy 114, OMIM:620774 and Generalized epilepsy with febrile seizures plus, type 12, OMIM:620755)
Early onset or syndromic epilepsy v4.188 SLC32A1 Arina Puzriakova Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to Developmental and epileptic encephalopathy 114, OMIM:620774; Generalized epilepsy with febrile seizures plus, type 12, OMIM:620755
DDG2P v3.84 SLC32A1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Developmental and epileptic encephalopathy 114, OMIM:620774)
DDG2P v3.84 SLC32A1 Arina Puzriakova Phenotypes for gene: SLC32A1 were changed from SLC32A1-associated developmental and epileptic encephalopathy to Developmental and epileptic encephalopathy 114, OMIM:620774
Intellectual disability - microarray and sequencing v5.512 SLC32A1 Arina Puzriakova Tag gene-checked was removed from gene: SLC32A1.
Early onset or syndromic epilepsy v4.187 SLC32A1 Arina Puzriakova Tag gene-checked was removed from gene: SLC32A1.
DDG2P v3.83 SLC32A1 Arina Puzriakova Tag gene-checked was removed from gene: SLC32A1.
DDG2P v3.83 BRD4 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Cornelia de Lange syndrome 6, OMIM:620568)
DDG2P v3.83 BRD4 Arina Puzriakova Phenotypes for gene: BRD4 were changed from CORNELIA DE LANGE-LIKE SYNDROME to Cornelia de Lange syndrome 6, OMIM:620568
Severe microcephaly v4.67 BRD4 Arina Puzriakova Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome, MONDO:0016033 to Cornelia de Lange syndrome 6, OMIM:620568
Intellectual disability - microarray and sequencing v5.512 BRD4 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Cornelia de Lange syndrome 6, OMIM:620568)
Intellectual disability - microarray and sequencing v5.512 BRD4 Arina Puzriakova Phenotypes for gene: BRD4 were changed from Intellectual disability; Microcephaly; Abnormal heart morphology; Abnormality of the face to Cornelia de Lange syndrome 6, OMIM:620568
DDG2P v3.82 BRD4 Arina Puzriakova Tag gene-checked was removed from gene: BRD4.
Intellectual disability - microarray and sequencing v5.511 BRD4 Arina Puzriakova Tag gene-checked was removed from gene: BRD4.
Intellectual disability - microarray and sequencing v5.511 CAPRIN1 Arina Puzriakova Publications for gene: CAPRIN1 were set to 23849776; 35979925; 36136249
Early onset or syndromic epilepsy v4.187 CAPRIN1 Arina Puzriakova Publications for gene: CAPRIN1 were set to 35979925
DDG2P v3.82 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
DDG2P v3.82 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636 to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Intellectual disability - microarray and sequencing v5.510 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
Intellectual disability - microarray and sequencing v5.510 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behaviour; Seizures to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Early onset or syndromic epilepsy v4.186 CAPRIN1 Arina Puzriakova Added comment: Comment on phenotypes: Gene-checked tag removed as this gene now has a phenotype listed in OMIM (Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636)
Early onset or syndromic epilepsy v4.186 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Global developmental delay; Delayed speech and language development; Intellectual disability; Autistic behavior; Seizures to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
Intellectual disability - microarray and sequencing v5.509 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
Early onset or syndromic epilepsy v4.185 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
DDG2P v3.81 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from AUTISM OR INTELLECTUAL DISABILITY to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
DDG2P v3.80 CAPRIN1 Arina Puzriakova Tag gene-checked was removed from gene: CAPRIN1.
Ataxia and cerebellar anomalies - narrow panel v4.59 CAPRIN1 Arina Puzriakova Phenotypes for gene: CAPRIN1 were changed from Cerebellar ataxia, MONDO:0000437; Early-onset ataxia to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, OMIM:620636
DDG2P v3.80 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
DDG2P v3.80 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from WNK3-related neurodevelopmental disorder to WNK3-related neurodevelopmental disorder; Prieto syndrome, OMIM:309610
Autism v0.36 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Early onset or syndromic epilepsy v4.185 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Intellectual disability - microarray and sequencing v5.509 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X-linked intellectual disability, MONDO:0100284 to Prieto syndrome, OMIM:309610; Intellectual disability, MONDO:0001071
Early onset or syndromic epilepsy v4.185 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from X-linked intellectual disability, MONDO:0100284 to Prieto syndrome, OMIM:309610; Intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.508 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Malformations of cortical development v4.26 WNK3 Arina Puzriakova Phenotypes for gene: WNK3 were changed from Intellectual disability, MONDO:0001071 to Prieto syndrome, OMIM:309610; Intellectual disability, MONDO:0001071
Malformations of cortical development v4.25 WNK3 Arina Puzriakova Tag gene-checked was removed from gene: WNK3.
Intellectual disability - microarray and sequencing v5.508 C12orf4 Arina Puzriakova Phenotypes for gene: C12orf4 were changed from Autosomal recessive intellectual disability to Intellectual developmental disorder, autosomal recessive 66, OMIM:618221
Severe Paediatric Disorders v1.183 C12orf4 Arina Puzriakova Phenotypes for gene: C12orf4 were changed from Mental retardation, autosomal recessive 66, 618221 to Intellectual developmental disorder, autosomal recessive 66, OMIM:618221
Severe Paediatric Disorders v1.182 C12orf4 Arina Puzriakova commented on gene: C12orf4
Intellectual disability - microarray and sequencing v5.507 C12orf4 Arina Puzriakova commented on gene: C12orf4
Severe Paediatric Disorders v1.182 C12orf4 Arina Puzriakova Tag new-gene-name tag was added to gene: C12orf4.
Intellectual disability - microarray and sequencing v5.507 C12orf4 Arina Puzriakova Tag new-gene-name tag was added to gene: C12orf4.
Mosaic skin disorders - deep sequencing v2.47 MVD Arina Puzriakova Tag Q2_24_promote_green tag was added to gene: MVD.
Mosaic skin disorders - deep sequencing v2.47 MVD Arina Puzriakova Classified gene: MVD as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.47 MVD Arina Puzriakova Added comment: Comment on list classification: At least 5 individuals reported (PMID: 30942823; 33491095) which meets the criteria for classifying this gene-disease association as Green at the next GMS panel update.
Mosaic skin disorders - deep sequencing v2.47 MVD Arina Puzriakova Gene: mvd has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.46 MVD Arina Puzriakova commented on gene: MVD
Mosaic skin disorders - deep sequencing v2.46 MVD Arina Puzriakova Publications for gene: MVD were set to 30942823
Mosaic skin disorders - deep sequencing v2.45 MVD Arina Puzriakova Phenotypes for gene: MVD were changed from Linear porokeratosis to Porokeratosis 7, multiple types, OMIM:614714
Rare genetic inflammatory skin disorders v3.7 MVD Arina Puzriakova Phenotypes for gene: MVD were changed from POROKERATOSIS 7, MULTIPLE TYPES, OMIM:614714 to Porokeratosis 7, multiple types, OMIM:614714
Familial disseminated superficial actinic porokeratosis v1.3 MVD Arina Puzriakova Phenotypes for gene: MVD were changed from Porokeratosis 7, multiple types, 614714; actinic/non-actinic disseminated superficial porokeratosis; POROK7; DSAP/DSP to Porokeratosis 7, multiple types, OMIM:614714
Skeletal dysplasia v4.55 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti 308300; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency 300301 to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Primary lymphoedema v3.11 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency 300301 to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Intellectual disability - microarray and sequencing v5.507 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, type II, 308300Ectodermal dysplasia, hypohidrotic, with immune deficiency, 300291Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301Immunodeficiency, isolated, 300584{Atypical mycobacteriosis, familial}, 300636Invasive pneumococcal disease, recurrent isolated, 2, 300640; INCONTINENTIA PIGMENTI (IP) to Incontinentia pigmenti, OMIM:308300
Incontinentia pigmenti v1.2 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, OMIM:308300
Structural eye disease v3.75 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, IP, 308300 to Incontinentia pigmenti, OMIM:308300
Retinal disorders v4.82 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
Early onset or syndromic epilepsy v4.184 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
Mosaic skin disorders - deep sequencing v2.44 IKBKG Arina Puzriakova changed review comment from: Comment on list classification: Incontinentia pigmenti (IP) is a X-linked dominant disorder associated with variants in the IKBKG gene. IP is mostly lethal in males in utero, and only very rare surviving male cases have somatic mosaicism. Phenotypically, cutaneous lesions manifest in Blaschkoid distribution.

Overall 'R327 Mosaic skin disorders - deep sequencing' represents the most likely diagnostic route for these cases and therefore a Green rating on this panel would be appropriate.; to: Comment on list classification: Incontinentia pigmenti (IP) is a X-linked dominant disorder associated with variants in the IKBKG gene. IP is mostly lethal in males in utero, and only very rare surviving male cases have somatic mosaicism. Phenotypically, cutaneous lesions manifest in Blaschkoid distribution.

Overall 'R327 Mosaic skin disorders - deep sequencing' represents a plausible route for referral and diagnosis for these cases and therefore a Green rating on this panel would be appropriate.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.197 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Immunodeficiency 33, 300636; Ectodermal dysplasia, hypohidrotic, with immune deficiency 300291; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Immunodeficiency, isolated, 300584; Invasive pneumococcal disease, recurrent isolated, 2,300640; Defects of TLR/NFkappa-B signalling; Anhidrotic ectodermal dysplasia (in some), various infections (bacteria, mycobacteria, viruses and fungi), colitis, conical teeth, variable defects of skin, hair and teeth, monocyte dysfunction; Combined immunodeficiencies with associated or syndromic features to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291; Immunodeficiency 33, OMIM:300636
Rare genetic inflammatory skin disorders v3.6 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti; Incontinentia pigmenti, Ectodermal dysplasia to Incontinentia pigmenti, OMIM:308300
Ectodermal dysplasia without a known gene mutation v1.28 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, type II, 308300; Ectodermal dysplasia, hypohidrotic, with immune deficiency, 300291; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Immunodeficiency, isolated, 300584; {Atypical mycobacteriosis, familial}, 300636:Invasive pneumococcal disease, recurrent isolated, 2, 300640; Ectodermal Dysplasia, Hypohidrotic, With Immune Deficiency to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Ectodermal dysplasia v3.29 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Ectodermal Dysplasia, Hypohidrotic, With Immune Deficiency; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; {Atypical mycobacteriosis, familial}, 300636:Invasive pneumococcal disease, recurrent isolated, 2, 300640; Immunodeficiency, isolated, 300584; Ectodermal dysplasia, hypohidrotic, with immune deficiency, 300291; Incontinentia pigmenti, type II, 308300 to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Gastrointestinal epithelial barrier disorders v1.75 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Immunodeficiency 33, 300636; Immunodeficiency, isolated, 300584 to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Infantile enterocolitis & monogenic inflammatory bowel disease v1.43 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Ectodermal X-linked dysplasia, hypohidrotic, with immune deficiency 300291 to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291
Mosaic skin disorders - deep sequencing v2.44 IKBKG Arina Puzriakova Classified gene: IKBKG as Amber List (moderate evidence)
Mosaic skin disorders - deep sequencing v2.44 IKBKG Arina Puzriakova Added comment: Comment on list classification: Incontinentia pigmenti (IP) is a X-linked dominant disorder associated with variants in the IKBKG gene. IP is mostly lethal in males in utero, and only very rare surviving male cases have somatic mosaicism. Phenotypically, cutaneous lesions manifest in Blaschkoid distribution.

Overall 'R327 Mosaic skin disorders - deep sequencing' represents the most likely diagnostic route for these cases and therefore a Green rating on this panel would be appropriate.
Mosaic skin disorders - deep sequencing v2.44 IKBKG Arina Puzriakova Gene: ikbkg has been classified as Amber List (Moderate Evidence).
Mosaic skin disorders - deep sequencing v2.43 IKBKG Arina Puzriakova Tag somatic tag was added to gene: IKBKG.
Tag Q2_24_promote_green tag was added to gene: IKBKG.
Mosaic skin disorders - deep sequencing v2.43 IKBKG Arina Puzriakova Publications for gene: IKBKG were set to
Mosaic skin disorders - deep sequencing v2.42 IKBKG Arina Puzriakova Phenotypes for gene: IKBKG were changed from Ectodermal dysplasia and immunodeficiency 1, 300291; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Incontinentia pigmenti, 308300 to Incontinentia pigmenti, OMIM:308300
Retinal disorders v4.81 SAMD7 Arina Puzriakova commented on gene: SAMD7
Rare genetic inflammatory skin disorders v3.5 ADAMTS2 Dmitrijs Rots reviewed gene: ADAMTS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Thoracic aortic aneurysm or dissection (GMS) v3.8 SECISBP2 krishna chatterjee gene: SECISBP2 was added
gene: SECISBP2 was added to Thoracic aortic aneurysm or dissection (GMS). Sources: Literature
Mode of inheritance for gene: SECISBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SECISBP2 were set to PMID 38042913; PMID 21084748
Phenotypes for gene: SECISBP2 were set to Growth retardation; sensorineural hearing loss; muscular dystrophy; thoracic aortic aneurysm; raised circulating thyroxine and low plasma selenium
Penetrance for gene: SECISBP2 were set to Complete
Review for gene: SECISBP2 was set to GREEN
Added comment: Biallelic defects in this gene cause a multi system disorder with deficiency of most human selenoproteins. Phenotypes listed here are associated with a biochemical signature of elevated circulating T4 (thyroxine) and low plasma selenium.

Since some pathogenic variants can be in non-coding regions and cryptic, we suggest a high index of suspicion even in cases of aortic aneurysm with an apparently monoallelic SECISBP2 defect. In such cases, we advocate measuring circulating T4 and selenium; if these biomarker levels are abnormal a cryptic mutation on the other allele should be sought.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.39 RTN2 Nour Elkhateeb reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38527963; Phenotypes: Weakness in the distal upper and lower limbs, Lower limb spasticity, Hyperreflexia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.308 RTN2 Nour Elkhateeb changed review comment from: A recent publication has been described seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) with pyramidal features.; to: A recent publication has been described seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) with pyramidal features.
Hereditary spastic paraplegia v1.308 RTN2 Nour Elkhateeb changed review comment from: A recent publication has described seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) with pyramidal features.; to: A recent publication has been described seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) with pyramidal features.
Hereditary spastic paraplegia v1.308 RTN2 Nour Elkhateeb reviewed gene: RTN2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 38527963; Phenotypes: Weakness in the distal upper and lower limbs, Lower limb spasticity, Hyperreflexia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.332 FGF14 Evan Reid reviewed gene: FGF14: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMC10844931; Phenotypes: Adult onset cerebellar ataxia, adult onsent episodic ataxia, cerebellar oculomotor disturbances, vestibulopathy, peripheral neuropathy, dysautonomia, spasticity, parkinsonism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hydrocephalus v4.4 HYLS1 Arina Puzriakova Tag founder-effect tag was added to gene: HYLS1.
Intellectual disability - microarray and sequencing v5.506 ZFX Tracy Lester reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: Intellectual disability, developmental delay, behavioural abnormalities, hypotonia, dysmorphic facies; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.506 CLEC16A Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: CLEC16A.
Intellectual disability - microarray and sequencing v5.506 GLI3 Tracy Lester reviewed gene: GLI3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Cystic kidney disease v4.24 CLCN5 John Sayer gene: CLCN5 was added
gene: CLCN5 was added to Cystic kidney disease. Sources: Literature
Mode of inheritance for gene: CLCN5 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: CLCN5 were set to 7922301; 37641036
Phenotypes for gene: CLCN5 were set to cystic kdiney disease; cortical cysts; medullary cysts; nephrocalcinosis; low molecular weight proteinuria; hypercalciuria
Penetrance for gene: CLCN5 were set to Complete
Review for gene: CLCN5 was set to GREEN
Added comment: Oliver Wrong noted kidney cysts in 33% of his cohort and I think Dent disease is such a difficult diagnosis to make, adding it to the cystic panel will identify new cases presenting with mild cystic kidney disease
Sources: Literature
Growth failure in early childhood v3.87 ISCA-37406-Loss Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes;610543
Growth failure in early childhood v3.87 ISCA-37406-Loss Arina Puzriakova Phenotypes for Region: ISCA-37406-Loss were changed from PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes; 610543 to Chromosome 16p13.3 deletion syndrome, OMIM:610543
Growth failure in early childhood v3.86 ISCA-37397-Loss Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: uterine didelphys;language delay;Hyptonia;prematurity;clinodactyly;ADHD;Goldenhar syndrome;developmental delay;611867;diaphragmatic hernia;DiGeorge syndrome (DGS);velocardiofacial syndrome;mild skeletal abnormalities;Seizures;global developmental delay;prenatal and postnatal growth delay;micropephaly;cardiovascular defects
Growth failure in early childhood v3.86 ISCA-37397-Loss Arina Puzriakova Phenotypes for Region: ISCA-37397-Loss were changed from uterine didelphys; language delay; Hyptonia; prematurity; clinodactyly; ADHD; Goldenhar syndrome; developmental delay; 611867; diaphragmatic hernia; DiGeorge syndrome (DGS); velocardiofacial syndrome; mild skeletal abnormalities; Seizures; global developmental delay; prenatal and postnatal growth delay; micropephaly; cardiovascular defects to Chromosome 22q11.2 deletion syndrome, distal, OMIM:611867
Growth failure in early childhood v3.85 ISCA-37392-Loss Arina Puzriakova Triplosensitivity Score for ISCA-37392-Loss was changed from to None.
Phenotypes for Region: ISCA-37392-Loss were changed from 194050; Williams syndrome to Williams-Beuren syndrome, OMIM:194050
Growth failure in early childhood v3.82 RBBP8 Arina Puzriakova Publications for gene: RBBP8 were updated from 24389050, 21998596 to 24389050; 21998596
Growth failure in early childhood v3.81 LIG4 Arina Puzriakova Publications for gene: LIG4 were updated from 11779494, 16088910, to 11779494; 16088910
Growth failure in early childhood v3.80 LIG1 Arina Puzriakova Publications for gene: LIG1 were updated from 1581963, 1351188 to 1581963; 1351188
Growth failure in early childhood v3.79 H19 Arina Puzriakova Mode of inheritance for gene: H19 was changed from Other - please specifiy in evaluation comments to Other
Growth failure in early childhood v3.76 RAPSN Arina Puzriakova Phenotypes for gene: RAPSN were changed from Fetal Akinesia Deformation Sequence; Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency, 608931Myasthenic syndrome, congenital, associated with facial dysmorphism and acetylcholine receptordeficiency, 608931Fetal akinesia deformation sequence, 208150 to Fetal akinesia deformation sequence 2, OMIM:618388; Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency, OMIM:616326
Growth failure in early childhood v3.75 ORC6 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia
Growth failure in early childhood v3.75 ORC6 Arina Puzriakova Phenotypes for gene: ORC6 were changed from Meier-Gorlin syndrome 3, 613803; Meier-Gorlin; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia to Meier-Gorlin syndrome 3, OMIM:613803
Growth failure in early childhood v3.74 ORC4 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia
Growth failure in early childhood v3.74 ORC4 Arina Puzriakova Phenotypes for gene: ORC4 were changed from Meier-Gorlin; Meier-Gorlin syndrome 2, 613800; micrognathia, patellar aplasia/hypoplasia, microtia, mammary hypoplasia to Meier-Gorlin syndrome 2, OMIM:613800
Growth failure in early childhood v3.73 ORC1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: microtia, beaked nose, patellar aplasia/hypoplasia, mammary hypoplasia, micrognathia
Growth failure in early childhood v3.73 ORC1 Arina Puzriakova Phenotypes for gene: ORC1 were changed from microtia, beaked nose, patellar aplasia/hypoplasia, mammary hypoplasia, micrognathia; Meier-Gorlin; Meier-Gorlin syndrome 1, 224690 to Meier-Gorlin syndrome 1, OMIM:224690
Growth failure in early childhood v3.72 FANCM Arina Puzriakova Phenotypes for gene: FANCM were changed from Fanconi anemia, complementation group M, 614087; Fanconi Anemia; Fanconi anemia to Fanconi anemia, complementation group M, 614087
Growth failure in early childhood v3.71 CDT1 Arina Puzriakova Phenotypes for gene: CDT1 were changed from micrognathia, microtia, patellar hypoplasia/aplasia, mammary hypoplasia; Meier-Gorlin syndrome 4, 613804; Meier-Gorlin to Meier-Gorlin syndrome 4, OMIM:613804
Growth failure in early childhood v3.70 PLK4 Arina Puzriakova Phenotypes for gene: PLK4 were changed from Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171; microcephaly and chorioretinopathy 2, MONDO:0014516 to Microcephaly and chorioretinopathy, autosomal recessive, 2, OMIM:616171
Growth failure in early childhood v3.69 INTS1 Arina Puzriakova Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571, MONDO:0032817 to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571
Growth failure in early childhood v3.68 HMGA2 Arina Puzriakova Phenotypes for gene: HMGA2 were changed from Silver-Russell syndrome 5, OMIM:618908; Silver-Russell syndrome 5, MONDO:0020795 to Silver-Russell syndrome 5, OMIM:618908
Growth failure in early childhood v3.67 COG4 Arina Puzriakova Phenotypes for gene: COG4 were changed from Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407 to Saul-Wilson syndrome, OMIM:618150
Growth failure in early childhood v3.66 ANAPC1 Arina Puzriakova Phenotypes for gene: ANAPC1 were changed from Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368 to Rothmund Thomson syndrome type 1, OMIM:618625
Growth failure in early childhood v3.65 ZNF668 Arina Puzriakova Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, OMIM:620194
Growth failure in early childhood v3.64 VPS50 Arina Puzriakova Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685
Growth failure in early childhood v3.63 SETD5 Arina Puzriakova Phenotypes for gene: SETD5 were changed from Mental retardation, autosomal dominant 23, OMIM:615761; growth retardation; bone fragility to Intellectual developmental disorder, autosomal dominant 23, OMIM:615761
Growth failure in early childhood v3.62 ZFP57 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes include: IUGR;Multi Locus Imprinting Disturbance
Growth failure in early childhood v3.62 ZFP57 Arina Puzriakova Phenotypes for gene: ZFP57 were changed from Diabetes mellitus, transient neonatal 1 OMIM:601410; diabetes mellitus, transient neonatal, 1MONDO:0011073; IUGR; Multi Locus Imprinting Disturbance to Diabetes mellitus, transient neonatal 1, OMIM:601410
Growth failure in early childhood v3.61 UBE2T Arina Puzriakova Phenotypes for gene: UBE2T were changed from Falcon anemia; 616435 Fanconi anemia, complementation group T; Fanconi anemia, complementation group T, 616435 to Fanconi anemia, complementation group T, OMIM:616435
Growth failure in early childhood v3.60 TRIM37 Arina Puzriakova Phenotypes for gene: TRIM37 were changed from Mulibery Nanism, 253250; Mulibrey nanism to Mulibrey nanism, OMIM:253250
Growth failure in early childhood v3.59 TOP3A Arina Puzriakova Phenotypes for gene: TOP3A were changed from MGRISCE2 (Bloom-like syndrome) 618097; Microcephaly, growth restriction, and increased sister chromatid exchange 2; 618097 MGRISCE2 (Bloom-like syndrome) to Microcephaly, growth restriction, and increased sister chromatid exchange 2, OMIM:618097
Intellectual disability - microarray and sequencing v5.506 SRCAP Arina Puzriakova Phenotypes for gene: SRCAP were changed from Floating-Harbor syndrome, 136140; FLOATING-HARBOR SYNDROME to Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, OMIM:619595; Floating-Harbor syndrome, OMIM:136140
Growth failure in early childhood v3.58 SRCAP Arina Puzriakova Phenotypes for gene: SRCAP were changed from Floating Harbor; Floating-Harbor syndrome, 136140 to Floating-Harbor syndrome, OMIM:136140
Growth failure in early childhood v3.57 SPRED2 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): developmental delay;intellectual disability;cardiac defects;short stature;skeletal anomalies;a typical facial gestalt
Growth failure in early childhood v3.57 SPRED2 Arina Puzriakova Phenotypes for gene: SPRED2 were changed from developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Noonan syndrome 14, OMIM:619745
Growth failure in early childhood v3.56 SOS2 Arina Puzriakova Phenotypes for gene: SOS2 were changed from Noonan syndrome 9 to Noonan syndrome 9, OMIM:616559
Growth failure in early childhood v3.55 SOS1 Arina Puzriakova Phenotypes for gene: SOS1 were changed from Rasopathy; Noonan syndrome; Noonan syndrome 4 to Noonan syndrome 4, OMIM:610733
Growth failure in early childhood v3.54 SLX4 Arina Puzriakova Phenotypes for gene: SLX4 were changed from 613951 Fanconi Anemia Fanconi anemia, complementation group P; Fanconi anemia, complementation group P, 613951; Fanconi Anemia to Fanconi anemia, complementation group P, OMIM:613951
Growth failure in early childhood v3.53 SHOX Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Dorsolateral bowed, short radii;Bowing and curving of radius;Radioulnar shortening
Growth failure in early childhood v3.53 SHOX Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582
Growth failure in early childhood v3.52 SHOC2 Arina Puzriakova Phenotypes for gene: SHOC2 were changed from Noonan with loss of anagen hair; Noonan-like syndrome with loose anagen hair to Noonan syndrome-like with loose anagen hair 1, OMIM:607721
Growth failure in early childhood v3.51 RIT1 Arina Puzriakova Phenotypes for gene: RIT1 were changed from Rasopathy; Noonan syndrome 8; Noonan syndrome type 8 to Noonan syndrome 8, OMIM:615355
Growth failure in early childhood v3.50 RAF1 Arina Puzriakova Phenotypes for gene: RAF1 were changed from Rasopathy; Noonan syndrome; LEOPARD syndrome 2; Noonan syndrome 5; LEOPARD syndrome to LEOPARD syndrome 2, OMIM:611554; Noonan syndrome 5, OMIM:611553
Growth failure in early childhood v3.49 PTPN11 Arina Puzriakova Phenotypes for gene: PTPN11 were changed from LEOPARD syndrome 1; LEOPARD syndrome; Noonan syndrome 1; Noonan syndrome to LEOPARD syndrome 1, OMIM:151100; Noonan syndrome 1, OMIM:163950
Growth failure in early childhood v3.48 PPP1CB Arina Puzriakova Phenotypes for gene: PPP1CB were changed from Noonan syndrome-like disorder with loose anagen hair 2, 617506; Rasopathy with developmental delay, short stature and sparse slow-growing hair to Noonan syndrome-like disorder with loose anagen hair 2, OMIM:617506
Growth failure in early childhood v3.47 PLAG1 Arina Puzriakova Phenotypes for gene: PLAG1 were changed from SRS; Silver-Russell syndrome to Silver-Russell syndrome 4, OMIM:618907
Growth failure in early childhood v3.46 PIK3R1 Arina Puzriakova Phenotypes for gene: PIK3R1 were changed from SHORT syndrome, 269880; SHORT to SHORT syndrome, OMIM:269880
Growth failure in early childhood v3.45 PALB2 Arina Puzriakova Phenotypes for gene: PALB2 were changed from Fanconi anemia, complementation group N, 610832; 610832 Fanconi anemia, complementation group N to Fanconi anemia, complementation group N, OMIM:610832
Growth failure in early childhood v3.44 OBSL1 Arina Puzriakova Phenotypes for gene: OBSL1 were changed from 3M; 3-M syndrome 2, 612921 to 3-M syndrome 2, OMIM:612921
Growth failure in early childhood v3.43 NRAS Arina Puzriakova Phenotypes for gene: NRAS were changed from Noonan syndrome; CFC Syndrome; A restricted spectrum of NRAS mutations causes Noonan syndrome. (Nat Genet. 42: 27-29, 2010.); Noonan syndrome 6; Cardio-Facio-cutanenous syndrome to Noonan syndrome 6, OMIM:613224
Growth failure in early childhood v3.42 NHLRC2 Arina Puzriakova Phenotypes for gene: NHLRC2 were changed from FINCA syndrome OMIM:618278 to FINCA syndrome, OMIM:618278
Growth failure in early childhood v3.41 NBN Arina Puzriakova Phenotypes for gene: NBN were changed from Nijmegen; Nijmegen breakage syndrome, 251260 to Nijmegen breakage syndrome, OMIM:251260
Growth failure in early childhood v3.40 NBAS Arina Puzriakova Phenotypes for gene: NBAS were changed from Short stature, optic nerve atrophy, and Pelger-Huet anomaly, 614800 to Short stature, optic nerve atrophy, and Pelger-Huet anomaly, OMIM:614800
Growth failure in early childhood v3.39 MTX2 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): Mandibuloacral dysplasia;lipodystrophy;arterial calcification;growth retardation
Growth failure in early childhood v3.39 MTX2 Arina Puzriakova Phenotypes for gene: MTX2 were changed from Mandibuloacral dysplasia; lipodystrophy; arterial calcification; growth retardation to Mandibuloacral dysplasia progeroid syndrome, OMIM:619127
Growth failure in early childhood v3.38 MAP2K2 Arina Puzriakova Phenotypes for gene: MAP2K2 were changed from CFC syndrome; Cardiofaciocutaneous syndrome 4; Cardiofaciocutaneous syndrome; Cardio-Facio-Cutaneous syndrome type 4; Cardiofaciocutaneous Syndrome; Cardio-Facio-Cutaneous syndrome to Cardiofaciocutaneous syndrome 4, OMIM:615280
Growth failure in early childhood v3.37 MAP2K1 Arina Puzriakova Phenotypes for gene: MAP2K1 were changed from LEOPARD syndrome; CFC syndrome; Cardiofaciocutaneous syndrome; Cardiofaciocutaneous Syndrome; Cardio-Facio-Cutaneous syndrome; Cardiofaciocutaneous syndrome 3; ?Noonan syndrome to Cardiofaciocutaneous syndrome 3, OMIM:615279
Growth failure in early childhood v3.36 LZTR1 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): Noonan syndrome 10;increased nuchal translucency;Prenatal hydrops;cardiac findings
Growth failure in early childhood v3.36 LZTR1 Arina Puzriakova Phenotypes for gene: LZTR1 were changed from Noonan syndrome 10; increased nuchal translucency; Prenatal hydrops; cardiac findings to Noonan syndrome 10, OMIM:616564 (AD); Noonan syndrome 2, OMIM:605275 (AR)
Growth failure in early childhood v3.35 KRAS Arina Puzriakova Phenotypes for gene: KRAS were changed from Rasopathy; Noonan syndrome; CFC syndrome; Cardiofaciocutaneous syndrome 2; Noonan syndrome 3; Cardiofaciocutaneous Syndrome; Cardio-Facio-Cutaneous syndrome to Cardiofaciocutaneous syndrome 2, OMIM:615278; Noonan syndrome 3, OMIM:609942
Growth failure in early childhood v3.34 IGFALS Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes: Short stature;Delayed puberty;Very low IGF-I levels
Growth failure in early childhood v3.34 IGFALS Arina Puzriakova Phenotypes for gene: IGFALS were changed from Acid-labile subunit, deficiency of, OMIM:615961; Short stature; Delayed puberty; Very low IGF-I levels to Acid-labile subunit, deficiency of, OMIM:615961
Growth failure in early childhood v3.33 IGF2 Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): SRS;IUGR;Pre- and post-natal growth failure;?Growth restriction, severe, with distinctive facies, 616489;Silver-Russell phenptype
Growth failure in early childhood v3.33 IGF2 Arina Puzriakova Phenotypes for gene: IGF2 were changed from SRS; IUGR; Pre- and post-natal growth failure; ?Growth restriction, severe, with distinctive facies, 616489; Silver-Russell phenptype to Silver-Russell syndrome 3, OMIM:616489
Growth failure in early childhood v3.32 IGF1 Arina Puzriakova Phenotypes for gene: IGF1 were changed from Insulin-Like Growth Factor I Deficiency; Growth retardation with deafness and mental retardation due to IGF1 deficiency, 608747; IGF1 to Insulin-like growth factor I deficiency, OMIM:608747
Growth failure in early childhood v3.31 HRAS Arina Puzriakova Phenotypes for gene: HRAS were changed from Costello syndrome, 218040; Costello; Costello syndrome to Costello syndrome, OMIM:218040
Growth failure in early childhood v3.30 FGFR3 Arina Puzriakova Phenotypes for gene: FGFR3 were changed from Hypochondroplasia, 146000 to Hypochondroplasia, OMIM:146000; Crouzon syndrome with acanthosis nigricans, OMIM:612247; Thanatophoric dysplasia, type I, OMIM:187600; Thanatophoric dysplasia, type II, OMIM:187601
Growth failure in early childhood v3.29 FANCL Arina Puzriakova Phenotypes for gene: FANCL were changed from Fanconi anemia; Fanconi anemia, complementation group L, 614083; 614083Fanconi anemia, complementation group L; Fanconi Anemia to Fanconi anemia, complementation group L, OMIM:614083
Growth failure in early childhood v3.28 FANCI Arina Puzriakova Phenotypes for gene: FANCI were changed from Fanconi anemia; Fanconi anemia, complementation group I, 609053; 609053 Fanconi anemia, complementation group I; Fanconi Anemia to Fanconi anemia, complementation group I, OMIM:609053
Growth failure in early childhood v3.27 FANCG Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): 614082 Fanconi anemia, complementation group G;pre- and postnatal growth retardation;a typical facial appearance with small head, eyes, and mouth;hypogonadism and reduced fertility;Fanconi anemia, complementation group G, 614082;Fanconi anemia complementation group G;malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii);cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots);hearing loss;and susceptibility to cancer, predominantly acute myeloid leukemia.;Fanconi Anemia;Fanconi anemia;bone marrow failure
Growth failure in early childhood v3.27 FANCG Arina Puzriakova Phenotypes for gene: FANCG were changed from 614082 Fanconi anemia, complementation group G; pre- and postnatal growth retardation; a typical facial appearance with small head, eyes, and mouth; hypogonadism and reduced fertility; Fanconi anemia, complementation group G, 614082; Fanconi anemia complementation group G; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; and susceptibility to cancer, predominantly acute myeloid leukemia.; Fanconi Anemia; Fanconi anemia; bone marrow failure to Fanconi anemia, complementation group G, OMIM:614082
Growth failure in early childhood v3.26 FANCF Arina Puzriakova Phenotypes for gene: FANCF were changed from Fanconi anemia; Fanconi anemia, complementation group F, 603467; 603467 Fanconi anemia, complementation group F; Fanconi Anemia to Fanconi anemia, complementation group F, OMIM:603467
Growth failure in early childhood v3.25 FANCE Arina Puzriakova Phenotypes for gene: FANCE were changed from Fanconi anemia, complementation group E, 600901; Fanconi anemia; 600901 Fanconi anemia, complementation group E; Fanconi Anemia to Fanconi anemia, complementation group E, OMIM:600901
Growth failure in early childhood v3.24 FANCD2 Arina Puzriakova Phenotypes for gene: FANCD2 were changed from Fanconi anemia; Fanconi anemia, complementation group D2, 227646; 227646 Fanconi anemia, complementation group D2; Fanconi Anemia to Fanconi anemia, complementation group D2, OMIM:227646
Growth failure in early childhood v3.23 FANCC Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): pre- and postnatal growth retardation;a typical facial appearance with small head, eyes, and mouth;hypogonadism and reduced fertility;malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii);cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots);hearing loss;and susceptibility to cancer, predominantly acute myeloid leukemia.;Fanconi Anemia;Fanconi anemia, complementation group C, 227645;Fanconi anemia;bone marrow failure;227645 Fanconi anemia, complementation group C
Growth failure in early childhood v3.23 FANCC Arina Puzriakova Phenotypes for gene: FANCC were changed from pre- and postnatal growth retardation; a typical facial appearance with small head, eyes, and mouth; hypogonadism and reduced fertility; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; and susceptibility to cancer, predominantly acute myeloid leukemia.; Fanconi Anemia; Fanconi anemia, complementation group C, 227645; Fanconi anemia; bone marrow failure; 227645 Fanconi anemia, complementation group C to Fanconi anemia, complementation group C, OMIM:227645
Growth failure in early childhood v3.22 FANCB Arina Puzriakova Phenotypes for gene: FANCB were changed from Fanconi Anemia Type B; VACTERL Association with Hydrocephalus; 300514 Fanconi anemia, complementation group B; Fanconi Anemia, X-Linked; Fanconi Anaemia; Fanconi anemia; Falcon anemia; Fanconi anemia, complementation group B, 300514 to Fanconi anemia, complementation group B, OMIM:300514
Growth failure in early childhood v3.21 FANCA Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): pre- and postnatal growth retardation;a typical facial appearance with small head, eyes, and mouth;hypogonadism and reduced fertility;malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii);Fanconi anemia, complementation group A, 227650;cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots);hearing loss;and susceptibility to cancer, predominantly acute myeloid leukemia.;Fanconi Anemia;227650 Fanconi anemia complementation group A;Fanconi anemia;bone marrow failure
Growth failure in early childhood v3.21 FANCA Arina Puzriakova Phenotypes for gene: FANCA were changed from pre- and postnatal growth retardation; a typical facial appearance with small head, eyes, and mouth; hypogonadism and reduced fertility; malformations of the kidneys, heart, and skeleton (absent or abnormal thumbs and radii); Fanconi anemia, complementation group A, 227650; cutaneous abnormalities (hyper- or hypopigmentation and cafe-au-lait spots); hearing loss; and susceptibility to cancer, predominantly acute myeloid leukemia.; Fanconi Anemia; 227650 Fanconi anemia complementation group A; Fanconi anemia; bone marrow failure to Fanconi anemia, complementation group A, OMIM:227650
Growth failure in early childhood v3.20 ERCC4 Arina Puzriakova Phenotypes for gene: ERCC4 were changed from Fanconi anemia, complementation group Q, 615272; 615272 Fanconi anemia, complementation group Q to Fanconi anemia, complementation group Q, OMIM:615272
Growth failure in early childhood v3.19 CUL7 Arina Puzriakova Phenotypes for gene: CUL7 were changed from 3-M syndrome 1, 273750; 3M to 3-M syndrome 1, OMIM:273750
Growth failure in early childhood v3.18 CEP57 Arina Puzriakova Phenotypes for gene: CEP57 were changed from Mosaic variegated aneuploidy syndrome 2, 614114 to Mosaic variegated aneuploidy syndrome 2, OMIM:614114
Growth failure in early childhood v3.17 CDKN1C Arina Puzriakova Added comment: Comment on phenotypes: Previous phenotypes (overwritten): SRS/BWS;Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies;Beckwith-Wiedemann syndrome, 130650
Growth failure in early childhood v3.17 CDKN1C Arina Puzriakova Phenotypes for gene: CDKN1C were changed from SRS/BWS; Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies; Beckwith-Wiedemann syndrome, 130650 to IMAGE syndrome, OMIM:614732
Growth failure in early childhood v3.16 CCDC8 Arina Puzriakova Phenotypes for gene: CCDC8 were changed from 3-M syndrome 3, 614205; 3M to 3-M syndrome 3, OMIM:614205
Growth failure in early childhood v3.15 CBL Arina Puzriakova Phenotypes for gene: CBL were changed from Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia; NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MEYLOMONOCYTIC LEUKEMIA to Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, OMIM:613563
Growth failure in early childhood v3.14 BRAF Arina Puzriakova Phenotypes for gene: BRAF were changed from LEOPARD syndrome 3; LEOPARD Syndrome; Cardiofaciocutaneous syndrome; Cardiofaciocutaneous Syndrome; Cardio-facio-cutaneous syndrome; Noonan Syndrome to Cardiofaciocutaneous syndrome, OMIM:115150; LEOPARD syndrome 3, OMIM:613707; Noonan syndrome 7, OMIM:613706
Growth failure in early childhood v3.13 ANKRD11 Arina Puzriakova Phenotypes for gene: ANKRD11 were changed from KBG; KBG syndrome, 148050 to KBG syndrome, OMIM:148050
Growth failure in early childhood v3.12 ACAN Arina Puzriakova Phenotypes for gene: ACAN were changed from Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (AD), 165800; Spondyloepimetaphyseal dysplasia, aggrecan type (AR), 612813; short stature, accelerated bone maturation, Spondyloepiphyseal dysplasia, early onset osteoarthritis; ?Spondyloepiphyseal dysplasia, Kimberley type (AD), 608361 to Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans, OMIM:165800 (AD); ?Spondyloepiphyseal dysplasia, Kimberley type, OMIM:608361 (AD); Spondyloepimetaphyseal dysplasia, aggrecan type, OMIM:612813 (AR)
Fetal anomalies v3.146 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from RAPADILINO SYNDROME; ROTHMUND-THOMSON SYNDROME; BALLER-GEROLD SYNDROME to Baller-Gerold syndrome, OMIM:218600; RAPADILINO syndrome, OMIM:266280; Rothmund-Thomson syndrome, type 2, OMIM:268400
Non-syndromic familial congenital anorectal malformations v1.9 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Baller-Gerold syndrome 218600; Rothmund-Thomson syndrome 268400 to Baller-Gerold syndrome, OMIM:218600; Rothmund-Thomson syndrome, type 2, OMIM:268400
Cutaneous photosensitivity with a likely genetic cause v3.5 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund-Thomson syndrome, 268400 to Rothmund-Thomson syndrome, type 2, OMIM:268400
Primary immunodeficiency or monogenic inflammatory bowel disease v4.196 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Combined immunodeficiency; Rothmund-Thomson syndrome, 268400 to Rothmund-Thomson syndrome, type 2, OMIM:268400; Combined immunodeficiency
Bilateral congenital or childhood onset cataracts v4.9 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund-Thomson syndrome, 268400; RAPADILINO syndrome, 266280; Baller-Gerold syndrome, 218600; Rothmund-Thomson syndrome to Rothmund-Thomson syndrome, type 2, OMIM:268400
Pigmentary skin disorders v3.11 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund-Thompson syndrome; RTS2; RAPADILINO SYNDROME, ROTHMUND-THOMSON SYNDROME, TYPE 2 to Baller-Gerold syndrome, OMIM:218600; Rothmund-Thomson syndrome, type 2, OMIM:268400
Childhood solid tumours cancer susceptibility v1.27 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund Thomson Syndrome to Rothmund-Thomson syndrome, type 2, OMIM:268400
Sarcoma cancer susceptibility v1.25 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund-Thomson, Beller-Gerold and RAPADALINO syndromes; Osteosarcoma to Rothmund-Thomson syndrome, type 2, OMIM:268400; Osteosarcoma
Childhood solid tumours v4.16 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Rothmund Thomson Syndrome; 268400 to Rothmund-Thomson syndrome, type 2, OMIM:268400
Skeletal dysplasia v4.54 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from RAPILINO syndrome 266280; Rothmund-Thomson syndrome 268400; Baller-Gerold syndrome 218600 to Baller-Gerold syndrome, OMIM:218600; RAPADILINO syndrome, OMIM:266280; Rothmund-Thomson syndrome, type 2, OMIM:268400
Limb disorders v4.18 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Baller-Gerold syndrome 218600; RAPILINO syndrome 266280; RAPILINO syndrome, 266280; Rothmund-Thomson syndrome, 268400; Rothmund-Thomson syndrome 268400; Baller-Gerold syndrome, 218600 to Baller-Gerold syndrome, OMIM:218600; RAPADILINO syndrome, OMIM:266280; Rothmund-Thomson syndrome, type 2, OMIM:268400
Radial dysplasia v1.24 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Baller-Gerold syndrome, 218600; RAPILINO syndrome, 266280; Rothmund-Thomson syndrome, 268400 to Baller-Gerold syndrome, OMIM:218600; RAPADILINO syndrome, OMIM:266280; Rothmund-Thomson syndrome, type 2, OMIM:268400
Growth failure in early childhood v3.11 RECQL4 Arina Puzriakova Publications for gene: RECQL4 were set to PMID: 38021400
Growth failure in early childhood v3.10 RECQL4 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: RECQL4.
Tag Q1_24_NHS_review tag was added to gene: RECQL4.
Growth failure in early childhood v3.10 RECQL4 Arina Puzriakova Classified gene: RECQL4 as Amber List (moderate evidence)
Growth failure in early childhood v3.10 RECQL4 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Melissa Connolly. RECQL4 is associated with multiple phenotypes, one of which is Rothmund-Thomson syndrome which can present with short stature. Review of case reports in the literature did not clearly indicate the level of severity, although 'small size' for height and weight is often mentioned. Patients have been followed up specifically for short stature, indicating that this panel is a plausible route for referral.

This, considered alongside the Green rating that has been allocated to the other Rothmund-Thomson syndrome gene (ANAPC1) as highlighted by Melissa Connolly, supports the promotion of RECQL4 to Green status at the next GMS panel update.
Growth failure in early childhood v3.10 RECQL4 Arina Puzriakova Gene: recql4 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v3.9 RECQL4 Arina Puzriakova Phenotypes for gene: RECQL4 were changed from Short stature; frontal bossing; prognathism; juvenile cataracts to Rothmund-Thomson syndrome, type 2, OMIM:268400
Growth failure in early childhood v3.8 MSTO1 Arina Puzriakova Tag Q1_24_NHS_review tag was added to gene: MSTO1.
Ichthyosis and erythrokeratoderma v3.25 ABHD5 Arina Puzriakova changed review comment from: Comment on list classification: New gene added to this panel by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Chanarin-Dorfman, caused by biallelic variants in the ABHD5 gene, is a neutral lipid storage disorder. The phenotype is variable with multiple organ involvement; however, one of the most the most prominent of features is non-bullous congenital ichthyosiform erythroderma. As ichthyosis is a cardinal feature of this condition, a Green rating on this panel is warranted.; to: Comment on list classification: New gene added to this panel by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Chanarin-Dorfman, caused by biallelic variants in the ABHD5 gene, is a neutral lipid storage disorder. The phenotype is variable with multiple organ involvement; however, the most prominent feature is non-bullous congenital ichthyosiform erythroderma. As ichthyosis is a cardinal feature of this condition, a Green rating on this panel is warranted.
Ichthyosis and erythrokeratoderma v3.25 ABHD5 Arina Puzriakova Classified gene: ABHD5 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v3.25 ABHD5 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Tom Cullup (GOSH). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Chanarin-Dorfman, caused by biallelic variants in the ABHD5 gene, is a neutral lipid storage disorder. The phenotype is variable with multiple organ involvement; however, one of the most the most prominent of features is non-bullous congenital ichthyosiform erythroderma. As ichthyosis is a cardinal feature of this condition, a Green rating on this panel is warranted.
Ichthyosis and erythrokeratoderma v3.25 ABHD5 Arina Puzriakova Gene: abhd5 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v3.24 ABHD5 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: ABHD5.
Tag Q1_24_NHS_review tag was added to gene: ABHD5.
Ichthyosis and erythrokeratoderma v3.24 ABHD5 Arina Puzriakova Publications for gene: ABHD5 were set to PubMed: 11590543
Intellectual disability - microarray and sequencing v5.505 ABHD5 Arina Puzriakova Phenotypes for gene: ABHD5 were changed from Chanarin-Dorfman syndrome, 275630; CHANARIN-DORFMAN SYNDROME (CDS) to Chanarin-Dorfman syndrome, OMIM:275630
Palmoplantar keratodermas v3.25 ABHD5 Arina Puzriakova Phenotypes for gene: ABHD5 were changed from Neutral lipid storage disease to Chanarin-Dorfman syndrome, OMIM:275630
Ichthyosis and erythrokeratoderma v3.23 ABHD5 Arina Puzriakova Phenotypes for gene: ABHD5 were changed from Chanarin-Dorfman syndrome to Chanarin-Dorfman syndrome, OMIM:275630
Pulmonary fibrosis familial v1.7 ZCCHC8 Arina Puzriakova Publications for gene: ZCCHC8 were set to 31488579
Malformations of cortical development v4.25 COL3A1 Eleanor Williams gene: COL3A1 was added
gene: COL3A1 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: COL3A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL3A1 were set to 19455184; 25205403; 28742248; 28258187
Phenotypes for gene: COL3A1 were set to Polymicrogyria with or without vascular-type EDS, OMIM:618343; polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, MONDO:0032688
Review for gene: COL3A1 was set to GREEN
Added comment: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance.

Several cases reported:

PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant.

PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria
Sources: Literature
Malformations of cortical development v4.25 COL3A1 Eleanor Williams gene: COL3A1 was added
gene: COL3A1 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: COL3A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COL3A1 were set to 19455184; 25205403; 28742248; 28258187
Phenotypes for gene: COL3A1 were set to Polymicrogyria with or without vascular-type EDS, OMIM:618343; polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, MONDO:0032688
Review for gene: COL3A1 was set to GREEN
Added comment: Associated with Polymicrogyria with or without vascular-type EDS in OMIM (OMIM:618343) with a autosomal recessive mode of inheritance.

Several cases reported:

PMID: 19455184 Plancke et al 2009 - report an 11 year old female with consangiuneous parents, who had vascular EDS. The phenotype also included diffuse cortical dysplasia. A homozygous nucleotide duplication (c.479dupT) in COL3A1 resulting in a premature termination codon (p.Lys161GlnfsX45) was identified. Both parents were heterozygous for this variant.

PMID: 25205403 Jørgensen et al 2015 - report 2 siblings who are compound heterozygous for COL3A1 sequence variants. One sibling died suddenly due to extensive aortic dissection at age 15. The younger sibling was cerebral cortical dysplasia with thickened frontoparietal cortices bilaterally, small gyri and findings consistent with pachy micropolygyria
Sources: Literature
Vascular skin disorders v1.63 STAMBP Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: STAMBP.
Vascular skin disorders v1.63 STAMBP Arina Puzriakova Publications for gene: STAMBP were set to 23542699
Vascular skin disorders v1.62 STAMBP Arina Puzriakova Classified gene: STAMBP as Amber List (moderate evidence)
Vascular skin disorders v1.62 STAMBP Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Multiple unrelated cases reported in the literature of biallelic variants in the STAMBP gene as the cause of microcephaly-capillary malformation syndrome (PMID: 21271646; 21548128; 21815250; 23542699; 25692795; 27531570; 29907875). Generalised capillary malformations on the skin are a cardinal feature of this condition and therefore inclusion of STAMBP on the panel is warranted.
Vascular skin disorders v1.62 STAMBP Arina Puzriakova Gene: stambp has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.504 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from MICROCEPHALY CAPILLARY MALFORMATION (MIC-CAP) SYNDROME to Microcephaly-capillary malformation syndrome, OMIM:614261
Early onset or syndromic epilepsy v4.183 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from Microcephaly-capillary malformation syndrome 614261 to Microcephaly-capillary malformation syndrome, OMIM:614261
Clefting v4.108 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME; MICCAP to Microcephaly-capillary malformation syndrome, OMIM:614261
Fetal anomalies v3.145 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from MICROCEPHALYÐCAPILLARY MALFORMATION (MIC-CAP) SYNDROME to Microcephaly-capillary malformation syndrome, OMIM:614261
Severe microcephaly v4.66 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from Microcephaly-capillary malformation syndrome 614261 to Microcephaly-capillary malformation syndrome, OMIM:614261
Vascular skin disorders v1.61 STAMBP Arina Puzriakova Phenotypes for gene: STAMBP were changed from Microcephaly-capillary malformation syndrome, MIM# 614261 to Microcephaly-capillary malformation syndrome, OMIM:614261
Vascular skin disorders v1.60 PIK3R2 Arina Puzriakova Publications for gene: PIK3R2 were set to 22729224; 23745720; 28502725
Vascular skin disorders v1.59 PIK3R2 Arina Puzriakova commented on gene: PIK3R2
Vascular skin disorders v1.59 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1, OMIM:603387 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Intellectual disability - microarray and sequencing v5.503 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Early onset or syndromic epilepsy v4.182 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 603387 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Clefting v4.107 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1; MPPH1 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Fetal anomalies v3.144 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Limb disorders v4.17 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 603387; Polydactyly to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Malformations of cortical development v4.24 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 603387 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Segmental overgrowth disorders - Deep sequencing v3.17 PIK3R2 Arina Puzriakova Phenotypes for gene: PIK3R2 were changed from Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, 603387; MPPH1; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, 603387; Macrocephaly and Overgrowth Syndromes; Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome 1 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, OMIM:603387
Vascular skin disorders v1.58 FOXC2 Arina Puzriakova Classified gene: FOXC2 as Green List (high evidence)
Vascular skin disorders v1.58 FOXC2 Arina Puzriakova Added comment: Comment on list classification: Inclusion of FOXC2 should be reviewed by the GMS specialist team due to conflicting reviews.

Lymphedema-distichiasis syndrome caused by heterozygous variants in this gene does not seem to fit the panel scope and is more appropriate for R136 Primary lymphoedema.
Vascular skin disorders v1.58 FOXC2 Arina Puzriakova Gene: foxc2 has been classified as Green List (High Evidence).
Vascular skin disorders v1.57 FOXC2 Arina Puzriakova Tag Q1_24_demote_red tag was added to gene: FOXC2.
Tag Q1_24_expert_review tag was added to gene: FOXC2.
Vascular skin disorders v1.57 FLT4 Arina Puzriakova Classified gene: FLT4 as Green List (high evidence)
Vascular skin disorders v1.57 FLT4 Arina Puzriakova Added comment: Comment on list classification: Inclusion of FLT4 should be reviewed by the GMS specialist team due to conflicting reviews.

Primary lymphoedema caused by heterozygous variants in this gene does not fit the panel scope and is more appropriate for R136 Primary lymphoedema. Since 2002, there has only been one report of a somatic variant causing skin capillary haemangiomas (PMID:11807987). There has been no evidence of germline variants causing a similar phenotype.
Vascular skin disorders v1.57 FLT4 Arina Puzriakova Gene: flt4 has been classified as Green List (High Evidence).
Vascular skin disorders v1.56 FLT4 Arina Puzriakova Tag somatic tag was added to gene: FLT4.
Tag Q1_24_demote_red tag was added to gene: FLT4.
Tag Q1_24_expert_review tag was added to gene: FLT4.
Pulmonary fibrosis familial v1.6 ZCCHC8 Matthew Edwards reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31488579, 38375433; Phenotypes: Pulmonary fibrosis (PF), telomere related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Growth failure in early childhood v3.8 RECQL4 Melissa Connolly changed review comment from: ANAPC1 was added to the R147.1 panel for Rothmund-Thomson syndrome but RECQL4 gene, which is a more common cause of the this disorder was not. From gene reviews this gene causes 60% of RTS cases vs. ANAPC1 causing 10%. To complete the screening for RTS in short stature patients, this gene should be added to the panel
Sources: Literature; to: ANAPC1 was added to the R147.1 panel for Rothmund-Thomson syndrome but RECQL4, which is a more common cause of the this disorder was not. From gene reviews this gene causes 60% of RTS cases vs. ANAPC1 causing 10%. To complete the screening for RTS in short stature patients, this gene should be added to the panel
Sources: Literature
Growth failure in early childhood v3.8 RECQL4 Melissa Connolly gene: RECQL4 was added
gene: RECQL4 was added to Growth failure in early childhood. Sources: Literature
Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RECQL4 were set to PMID: 38021400
Phenotypes for gene: RECQL4 were set to Short stature; frontal bossing; prognathism; juvenile cataracts
Penetrance for gene: RECQL4 were set to Complete
Review for gene: RECQL4 was set to GREEN
Added comment: ANAPC1 was added to the R147.1 panel for Rothmund-Thomson syndrome but RECQL4 gene, which is a more common cause of the this disorder was not. From gene reviews this gene causes 60% of RTS cases vs. ANAPC1 causing 10%. To complete the screening for RTS in short stature patients, this gene should be added to the panel
Sources: Literature
CAKUT v1.175 ROBO1 Arina Puzriakova Phenotypes for gene: ROBO1 were changed from unilateral kidney agenesis; bilateral kidney agenesis; vesicoureteral junction obstruction; vesicoureteral reflux; posterior urethral valve; genital malformation; increased kidney echogenicity to Neurooculorenal syndrome, OMIM:620305
CAKUT v1.174 ROBO1 Arina Puzriakova Classified gene: ROBO1 as Green List (high evidence)
CAKUT v1.174 ROBO1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Laura Claus (UMC). Rating Green as there is enough evidence to support the gene-disease association. Included on the R27 Paediatric disorders GMS panel via inclusion on the R29 Intellectual disability panel.

Biallelic variants in the ROBO1 gene are associated with neurooculorenal syndrome (OMIM:620305). Clinical manifestations are generally highly variable and involve several organ systems which may be include a syndromic form of congenital anomalies of the kidney and urinary tract (CAKUT) (PMID: 35227688)
CAKUT v1.174 ROBO1 Arina Puzriakova Gene: robo1 has been classified as Green List (High Evidence).
Fetal anomalies v3.143 ROBO1 Arina Puzriakova Publications for gene: ROBO1 were set to 28592524; 28485101; 30712880; 29194579; 35227688
Fetal anomalies v3.143 ROBO1 Arina Puzriakova Publications for gene: ROBO1 were set to 28592524; 28485101; 30712880
Fetal anomalies v3.142 ROBO1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'monoallelic' to 'both mono- and biallelic' at the next GMS panel update.

Biallelic variants in the ROBO1 gene are associated with neurooculorenal syndrome (OMIM:620305). Clinical manifestations are generally highly variable and involve several organ systems. However, some cases do present in utero with renal agenesis and structural brain abnormalities (PMID: 29194579; 35227688) indicating that the phenotype is relevant to this panel.
Fetal anomalies v3.142 ROBO1 Arina Puzriakova Mode of inheritance for gene: ROBO1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v3.141 ROBO1 Arina Puzriakova Phenotypes for gene: ROBO1 were changed from tetralogy of Fallot and septal defects to Tetralogy of Fallot and septal defects; Neurooculorenal syndrome, OMIM:620305
Fetal anomalies v3.140 ROBO1 Arina Puzriakova Tag Q1_24_MOI tag was added to gene: ROBO1.
Intellectual disability - microarray and sequencing v5.502 ROBO1 Arina Puzriakova Tag watchlist_moi tag was added to gene: ROBO1.
Albinism or congenital nystagmus v3.5 ROBO1 Arina Puzriakova Added comment: Comment on phenotypes: This gene is now associated with a relevant phenotype in OMIM (?Nystagmus 8, congenital, autosomal recessive, OMIM:257400). OMIM have only listed the publications already considered (PMID: 35348658) and therefore there is no new evidence to warrant further review.
Albinism or congenital nystagmus v3.5 ROBO1 Arina Puzriakova Phenotypes for gene: ROBO1 were changed from nystagmus, congenital, autosomal recessive, MONDO:0009762 to ?Nystagmus 8, congenital, autosomal recessive, OMIM:257400
Pituitary hormone deficiency v3.11 ROBO1 Arina Puzriakova Tag watchlist tag was added to gene: ROBO1.
Pituitary hormone deficiency v3.11 ROBO1 Arina Puzriakova Publications for gene: ROBO1 were set to 28402530
Pituitary hormone deficiency v3.10 ROBO1 Arina Puzriakova changed review comment from: Comment on phenotypes: This gene is now associated with relevant phenotype in OMIM (Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303). OMIM have listed the all of the publications (PMID: 28402530; 31448886; 33270637) already previously considered by the GMS expert group and therefore no new evidence to support promotion from amber to green.; to: Comment on phenotypes: This gene is now associated with relevant phenotype in OMIM (Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303). OMIM have listed the all of the publications (PMID: 28402530; 31448886; 33270637) already previously considered by the GMS expert group and therefore there is no new evidence to support promotion from amber to green.
Pituitary hormone deficiency v3.10 ROBO1 Arina Puzriakova changed review comment from: Comment on phenotypes: This gene is now associated with relevant phenotype in OMIM (Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303); to: Comment on phenotypes: This gene is now associated with relevant phenotype in OMIM (Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303). OMIM have listed the all of the publications (PMID: 28402530; 31448886; 33270637) already previously considered by the GMS expert group and therefore no new evidence to support promotion from amber to green.
Pituitary hormone deficiency v3.10 ROBO1 Arina Puzriakova Added comment: Comment on phenotypes: This gene is now associated with relevant phenotype in OMIM (Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303)
Pituitary hormone deficiency v3.10 ROBO1 Arina Puzriakova Phenotypes for gene: ROBO1 were changed from pituitary stalk interruption syndrome, MONDO:0019828 to Pituitary hormone deficiency, combined or isolated, 8, OMIM:620303
Intellectual disability - microarray and sequencing v5.502 CLEC16A Sarah Leigh edited their review of gene: CLEC16A: Added comment: Heterozygous CLEC16A variants have been identified as a genetic risk factor for several autoimmune disorders and for Parkinson disease (PMID: 37175930). PMID: 36538041 reports the neurological effect of homozygous terminating CLEC16A variants in two families. In family 1, the first child died at 5 months, he had progressive microcephaly, failure to thrive and cranial CT showed brain atrophy, dilatation of both central and peripheral liquor spaces, hypoplasia of the corpus callosum (no genetic testing was done), the third pregnancy was terminated (17 weeks of gestation) after prenatal ultrasound showed ventriculomegaly, agenesis of corpus callosum (no genetic testing was done), the fourth pregnancy was also terminated (22 weeks of gestation) as the prenatal ultrasound showed agenesis of corpus callosum. This fetus was homozygous for NM_001243403.1(CLEC16A):c.2062 + 5G > A, RT-PRC showed that this variant resulted in the deletion of exon 19 and a frame shift. Both parents and an unaffected sibling were heterozygous for this variant. In family 2, a single affected child was homozygous for NM_001243403.1(CLEC16A):c.-4_12del, p.Met1fs*. This child had progressive microcephaly, failure to thrive, severe global developmental delay, global brain atrophy and died at 6 years. There is no genetic data from the parents or unaffected siblings in Family 2. PMID: 37175930, also presents zebrafish experiments, where mutagenesis of
clec16a by CRISPR–Cas9 resulted in accumulated acidic/phagolysosome compartments, in neurons
and microglia, and dysregulated mitophagy. This was rescued by wild type CLEC16A, but not by the C-terminal truncated variant. The authors conclude that dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration.; Changed rating: GREEN; Changed publications to: 36538041; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.502 CLEC16A Sarah Leigh Classified gene: CLEC16A as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.502 CLEC16A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Intellectual disability - microarray and sequencing v5.502 CLEC16A Sarah Leigh Gene: clec16a has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.501 CLEC16A Sarah Leigh Publications for gene: CLEC16A were set to 36538041
Intellectual disability - microarray and sequencing v5.500 CLEC16A Sarah Leigh Publications for gene: CLEC16A were set to PMID: 36538041
Intellectual disability - microarray and sequencing v5.500 CLEC16A Sarah Leigh Classified gene: CLEC16A as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.500 CLEC16A Sarah Leigh Gene: clec16a has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v4.23 FHL1 Sarah Leigh reviewed gene: FHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh edited their review of gene: ZFHX3: Added comment: Personal communication from Nour Elkhateeb (Clinical Fellow in Genomics, Genomics England): we have data about 12 individuals with nonsense/frameshift/exon deletions in ZFHX3. Five of the variants are located in exon 9/10 or exon 9, which has been shown to harbour the highest density of pathogenic variants (PMID: 38412861). Eleven of these cases presented with developmental delay / intellectual disability and a range of other features, including dysmorphology, seizures and failure to thrive.; Changed publications to: 38412861
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.32 SMCHD1 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: SMCHD1.
Tag Q1_24_MOI tag was added to gene: SMCHD1.
Tag Q1_24_NHS_review tag was added to gene: SMCHD1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.32 SMCHD1 Sarah Leigh Phenotypes for gene: SMCHD1 were changed from Fascioscapulohumeral muscular dystrophy 2, digenic 158901; fascioscapulohumeral muscular dystrophy to Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM:158901; facioscapulohumeral muscular dystrophy 2, MONDO:0008031
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.31 SMCHD1 Sarah Leigh Publications for gene: SMCHD1 were set to
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 SMCHD1 Sarah Leigh Deleted their comment
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 SMCHD1 Sarah Leigh changed review comment from: In line with Ian Berry's (Leeds Genetics Laboratory) review, the mode of inheritance for SMCHD1 should be updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. At least 10 SMCHD1 variants in unrelated cases have been associated with Fascioscapulohumeral muscular dystrophy 2, digenic (OMIM:158901)(PMID: 23143600; 24075187;31600781).; to: In line with the recommendations from Ian Berry (Leeds Genetics Laboratory), it is recommended that the mode of inheritance for this gene should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. At least 10 SMCHD1 variants in unrelated cases have been associated with Fascioscapulohumeral muscular dystrophy 2, digenic (OMIM:158901)(PMID: 23143600; 24075187;31600781).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 SMCHD1 Sarah Leigh edited their review of gene: SMCHD1: Added comment: In line with Ian Berry's (Leeds Genetics Laboratory) review, the mode of inheritance for SMCHD1 should be updated to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. At least 10 SMCHD1 variants in unrelated cases have been associated with Fascioscapulohumeral muscular dystrophy 2, digenic (OMIM:158901)(PMID: 23143600; 24075187;31600781).; Changed publications to: 23143600, 24075187, 31600781
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 SMCHD1 Sarah Leigh edited their review of gene: SMCHD1: Added comment: In line with the recommendations from Ian Berry (Leeds Genetics Laboratory), it is recommended that the mode of inheritance for this gene should be changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. At least five SMCHD1 variants in unrelated cases have been associated with Fascioscapulohumeral muscular dystrophy 2, digenic, (OMIM:158901)(PMID: ).; Changed rating: GREEN; Changed publications to: 23143600; Changed phenotypes to: Fascioscapulohumeral muscular dystrophy 2, digenic, OMIM:158901, facioscapulohumeral muscular dystrophy 2, MONDO:0008031; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v3.83 SPG7 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: SPG7.
Tag Q1_24_NHS_review tag was added to gene: SPG7.
Hereditary neuropathy or pain disorder v3.83 SPG7 Sarah Leigh edited their review of gene: SPG7: Added comment: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; Changed rating: GREEN; Changed publications to: 30098094, 35637455, 35096021, 35243150, 22964162
Ataxia and cerebellar anomalies - narrow panel v4.58 ZFHX3 Dmitrijs Rots reviewed gene: ZFHX3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v4.58 ZFHX3 Sarah Leigh reviewed gene: ZFHX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZFHX3.
Tag Q1_24_NHS_review tag was added to gene: ZFHX3.
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v4.58 ZFHX3 Sarah Leigh Tag STR tag was added to gene: ZFHX3.
Ataxia and cerebellar anomalies - narrow panel v4.58 ZFHX3 Sarah Leigh Phenotypes for gene: ZFHX3 were changed from syndromic intellectual disability to Spinocerebellar ataxia 4, OMIM:600223; spinocerebellar ataxia type 4, MONDO:0010847
Ataxia and cerebellar anomalies - narrow panel v4.57 ZFHX3 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.499
Ataxia and cerebellar anomalies - narrow panel v4.57 ZFHX3 Sarah Leigh gene: ZFHX3 was added
gene: ZFHX3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: ZFHX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZFHX3 were set to 38412861; 38035881; 37292950
Phenotypes for gene: ZFHX3 were set to syndromic intellectual disability
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh Classified gene: ZFHX3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.499 ZFHX3 Sarah Leigh Gene: zfhx3 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.103 ATP5E Sarah Leigh Tag new-gene-name was removed from gene: ATP5E.
Tag Q4_23_promote_green was removed from gene: ATP5E.
Tag Q4_23_NHS_review was removed from gene: ATP5E.
Tag watchlist tag was added to gene: ATP5E.
Tag Q1_24_promote_green tag was added to gene: ATP5E.
Tag Q1_24_NHS_review tag was added to gene: ATP5E.
Possible mitochondrial disorder - nuclear genes v3.103 ATP5E Sarah Leigh changed review comment from: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; to: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant. In addition, PMID: 34954817 reports significantly reduced ATPase amounts associated with the ATP5F1E variants.
Intellectual disability - microarray and sequencing v5.498 ZFHX3 Sarah Leigh gene: ZFHX3 was added
gene: ZFHX3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZFHX3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZFHX3 were set to 38412861; 38035881; 37292950
Phenotypes for gene: ZFHX3 were set to syndromic intellectual disability
Hereditary neuropathy or pain disorder v3.83 XK Alexander Rossor commented on gene: XK: Should be included in R78 as now inlcudes many other complex phenotype genes that can present with neuropathy
Hereditary neuropathy or pain disorder v3.83 TYMP Alexander Rossor edited their review of gene: TYMP: Added comment: Can present with neuropathy and should be included in R78 panel; Changed publications to: 21933806
Hereditary neuropathy or pain disorder v3.83 SURF1 Alexander Rossor edited their review of gene: SURF1: Added comment: Should be included as R78 now includes complex phenotype genes; Changed publications to: 27475922, 12026244, 24027061
Hereditary neuropathy or pain disorder v3.83 SPTBN4 Alexander Rossor commented on gene: SPTBN4
Hereditary neuropathy or pain disorder v3.83 SLC25A19 Alexander Rossor edited their review of gene: SLC25A19: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Acute encephalopathic episodes and paralysis following febrile illness with almost complete recovery. Absent sensory-motor action potential during illness. Bilateral striatal necrosis on MRI. Additional chronic progressive axonal neuropathy
Hereditary neuropathy or pain disorder v3.83 SCARB2 Alexander Rossor edited their review of gene: SCARB2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 21670406, 19597094
Hereditary neuropathy or pain disorder v3.83 SACS Alexander Rossor edited their review of gene: SACS: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 30460542
Hereditary neuropathy or pain disorder v3.83 POLR3A Alexander Rossor commented on gene: POLR3A: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 PNPLA6 Alexander Rossor commented on gene: PNPLA6: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 PMM2 Alexander Rossor edited their review of gene: PMM2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Neonatal onset, leukodystrophy, abnormal serum glycoproteins, mental retardation, hypotonia, ataxia, retinitis pigmentosa, seizures, slowly progressive neuropathy with SNCV, severe infections, hepatic insufficiency and cardiomyopathy.
Hereditary neuropathy or pain disorder v3.83 PLP1 Alexander Rossor edited their review of gene: PLP1: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 12601703
Hereditary neuropathy or pain disorder v3.83 PEX7 Alexander Rossor edited their review of gene: PEX7: Added comment: Should be included in R78 as can present with neuropathy and other complex disease are now include in R78; Changed publications to: 11493716
Hereditary neuropathy or pain disorder v3.83 PEX10 Alexander Rossor edited their review of gene: PEX10: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 27230853, 20695019
Hereditary neuropathy or pain disorder v3.83 PDYN Alexander Rossor commented on gene: PDYN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 NAGA Alexander Rossor commented on gene: NAGA: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 MTTP Alexander Rossor commented on gene: MTTP: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 MMACHC Alexander Rossor edited their review of gene: MMACHC: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Onset infancy to adulthood, thrombotic thrombocytopenia with encephalopathy, myelopathy, renal and pulmonary complications (can be life threatening), retinitis pigmentosa, axonal motor neuropathy. Treated with high dose vitamin B12.
Hereditary neuropathy or pain disorder v3.83 LYST Alexander Rossor commented on gene: LYST: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 IARS2 Alexander Rossor edited their review of gene: IARS2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 25130867, 28328135, 30041933, 30419932
Hereditary neuropathy or pain disorder v3.83 GBA2 Alexander Rossor commented on gene: GBA2: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 BCKDHB Alexander Rossor edited their review of gene: BCKDHB: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 18855118, 11180212; Changed phenotypes to: Maple Syrup Urine Disease, Metabolic encephalopathy, elevated branched chain amino acids in urine, acute axonal neuropathy
Hereditary neuropathy or pain disorder v3.83 B4GALNT1 Alexander Rossor commented on gene: B4GALNT1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 APOA1 Alexander Rossor commented on gene: APOA1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 AP1S1 Alexander Rossor Deleted their comment
Hereditary neuropathy or pain disorder v3.83 AP1S1 Alexander Rossor commented on gene: AP1S1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 AGXT Alexander Rossor edited their review of gene: AGXT: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 4701948, 25363903
Hereditary neuropathy or pain disorder v3.83 AGTPBP1 Alexander Rossor commented on gene: AGTPBP1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 ABHD12 Alexander Rossor edited their review of gene: ABHD12: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 29571850, 20797687
Hereditary neuropathy or pain disorder v3.83 GAN Alexander Rossor commented on gene: GAN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 FXN Alexander Rossor edited their review of gene: FXN: Added comment: FA can present with a sensory neuropathy and should be included in the R78 panel. A missense may prompt testing for an expansion in the other allele.; Changed publications to: 20339857
Hereditary neuropathy or pain disorder v3.83 GALC Alexander Rossor edited their review of gene: GALC: Added comment: Can present with peripheral neuropathy and should be included in R78 panel; Changed publications to: 26840509; Changed phenotypes to: Krabbe. Spastic paraplegia, developmental delay, optic atrophy, adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy
Intellectual disability - microarray and sequencing v5.497 SOX9 Tracy Lester reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Skeletal dysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v4.24 SNF8 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are two unrelated cases reported with optic atrophy and hence this gene should be rated amber with Current evidence.; to: Comment on list classification: There are two unrelated cases reported with optic atrophy and hence this gene should be rated amber with current evidence.
Optic neuropathy v4.24 SNF8 Achchuthan Shanmugasundram Classified gene: SNF8 as Amber List (moderate evidence)
Optic neuropathy v4.24 SNF8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are two unrelated cases reported with optic atrophy and hence this gene should be rated amber with Current evidence.
Optic neuropathy v4.24 SNF8 Achchuthan Shanmugasundram Gene: snf8 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.23 SNF8 Achchuthan Shanmugasundram gene: SNF8 was added
gene: SNF8 was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; optic atrophy, MONDO:0003608
Review for gene: SNF8 was set to AMBER
Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8.

The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Three of the patients (from two families) with the milder phenotype also have optic atrophy.

Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Classified gene: SNF8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two unrelated patients reported with seizures and hence this gene should be rated amber with current evidence.
Early onset or syndromic epilepsy v4.181 SNF8 Achchuthan Shanmugasundram Gene: snf8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.180 SNF8 Achchuthan Shanmugasundram gene: SNF8 was added
gene: SNF8 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: SNF8 was set to AMBER
Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8.

The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.

Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.134 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ia; Glycogen storage disease Ia, 232200; Glycogen storage disease type 1a, von Gierke (Glycogen storage disorders); Glycogen storage disease Ia; fasting intolerance with enlarged liver, renal tubular disease to Glycogen storage disease Ia, OMIM:232200
Mitochondrial disorders v4.167 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease Ia to Glycogen storage disease Ia, OMIM:232200
Possible mitochondrial disorder - nuclear genes v3.103 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease Ia, 232200 to Glycogen storage disease Ia, OMIM:232200
Undiagnosed metabolic disorders v1.615 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease type 1a, von Gierke (Glycogen storage disorders); fasting intolerance with enlarged liver, renal tubular disease; Glycogen storage disease Ia, 232200; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ia to Glycogen storage disease Ia, OMIM:232200
Glycogen storage disease v2.4 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from Glycogen storage disease Ia 232200 to Glycogen storage disease Ia, OMIM:232200
Ketotic hypoglycaemia v1.9 G6PC Arina Puzriakova Phenotypes for gene: G6PC were changed from fasting intolerance with enlarged liver, renal tubular disease; Glycogen storage disease Ia, 232200; Glycogen Storage Disease Type I; Glycogen Storage Disorders- Liver; Glycogen Storage Disease; Glycogen Storage Disease Ia to Glycogen storage disease Ia, OMIM:232200
Mitochondrial disorder with complex V deficiency v2.16 ATPAF1 Arina Puzriakova Classified gene: ATPAF1 as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v2.16 ATPAF1 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex V deficiency v2.16 ATPAF1 Arina Puzriakova Gene: atpaf1 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.102 ATPAF1 Arina Puzriakova Classified gene: ATPAF1 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.102 ATPAF1 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.102 ATPAF1 Arina Puzriakova Gene: atpaf1 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex IV deficiency v3.19 COA4 Arina Puzriakova Classified gene: COA4 as Red List (low evidence)
Mitochondrial disorder with complex IV deficiency v3.19 COA4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex IV deficiency v3.19 COA4 Arina Puzriakova Gene: coa4 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.101 COA4 Arina Puzriakova Classified gene: COA4 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.101 COA4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.101 COA4 Arina Puzriakova Gene: coa4 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex IV deficiency v3.18 COX17 Arina Puzriakova Classified gene: COX17 as Red List (low evidence)
Mitochondrial disorder with complex IV deficiency v3.18 COX17 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex IV deficiency v3.18 COX17 Arina Puzriakova Gene: cox17 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.100 COX17 Arina Puzriakova Classified gene: COX17 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.100 COX17 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.100 COX17 Arina Puzriakova Gene: cox17 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex IV deficiency v3.17 COX18 Arina Puzriakova Classified gene: COX18 as Red List (low evidence)
Mitochondrial disorder with complex IV deficiency v3.17 COX18 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex IV deficiency v3.17 COX18 Arina Puzriakova Gene: cox18 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.99 COX18 Arina Puzriakova Classified gene: COX18 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.99 COX18 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.99 COX18 Arina Puzriakova Gene: cox18 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex IV deficiency v3.16 COX19 Arina Puzriakova Classified gene: COX19 as Red List (low evidence)
Mitochondrial disorder with complex IV deficiency v3.16 COX19 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex IV deficiency v3.16 COX19 Arina Puzriakova Gene: cox19 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.98 COX19 Arina Puzriakova Classified gene: COX19 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.98 COX19 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.98 COX19 Arina Puzriakova Gene: cox19 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex IV deficiency v3.15 COX6B2 Arina Puzriakova Classified gene: COX6B2 as Red List (low evidence)
Mitochondrial disorder with complex IV deficiency v3.15 COX6B2 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex IV deficiency v3.15 COX6B2 Arina Puzriakova Gene: cox6b2 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.97 COX6B2 Arina Puzriakova Classified gene: COX6B2 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.97 COX6B2 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.97 COX6B2 Arina Puzriakova Gene: cox6b2 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex I deficiency v3.8 NDUFAF7 Arina Puzriakova Classified gene: NDUFAF7 as Red List (low evidence)
Mitochondrial disorder with complex I deficiency v3.8 NDUFAF7 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex I deficiency v3.8 NDUFAF7 Arina Puzriakova Gene: ndufaf7 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.96 NDUFAF7 Arina Puzriakova Classified gene: NDUFAF7 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.96 NDUFAF7 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.96 NDUFAF7 Arina Puzriakova Gene: ndufaf7 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.95 SDHAF3 Arina Puzriakova Classified gene: SDHAF3 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.95 SDHAF3 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.95 SDHAF3 Arina Puzriakova Gene: sdhaf3 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex II deficiency v2.10 SDHAF3 Arina Puzriakova Classified gene: SDHAF3 as Red List (low evidence)
Mitochondrial disorder with complex II deficiency v2.10 SDHAF3 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex II deficiency v2.10 SDHAF3 Arina Puzriakova Gene: sdhaf3 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.94 SDHAF4 Arina Puzriakova Classified gene: SDHAF4 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.94 SDHAF4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Possible mitochondrial disorder - nuclear genes v3.94 SDHAF4 Arina Puzriakova Gene: sdhaf4 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex II deficiency v2.9 SDHAF4 Arina Puzriakova Classified gene: SDHAF4 as Red List (low evidence)
Mitochondrial disorder with complex II deficiency v2.9 SDHAF4 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with human disease.
Mitochondrial disorder with complex II deficiency v2.9 SDHAF4 Arina Puzriakova Gene: sdhaf4 has been classified as Red List (Low Evidence).
Mitochondrial disorder with complex V deficiency v2.15 ATP5J2 Arina Puzriakova Classified gene: ATP5J2 as Red List (low evidence)
Mitochondrial disorder with complex V deficiency v2.15 ATP5J2 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with a human disease.
Mitochondrial disorder with complex V deficiency v2.15 ATP5J2 Arina Puzriakova Gene: atp5j2 has been classified as Red List (Low Evidence).
Possible mitochondrial disorder - nuclear genes v3.93 ATP5J2 Arina Puzriakova Classified gene: ATP5J2 as Red List (low evidence)
Possible mitochondrial disorder - nuclear genes v3.93 ATP5J2 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with a human disease.
Possible mitochondrial disorder - nuclear genes v3.93 ATP5J2 Arina Puzriakova Gene: atp5j2 has been classified as Red List (Low Evidence).
Mitochondrial disorders v4.166 ATP5J2 Arina Puzriakova Classified gene: ATP5J2 as Red List (low evidence)
Mitochondrial disorders v4.166 ATP5J2 Arina Puzriakova Added comment: Comment on list classification: Demoting from Amber to Red as this gene has not been associated with a human disease.
Mitochondrial disorders v4.166 ATP5J2 Arina Puzriakova Gene: atp5j2 has been classified as Red List (Low Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.133 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4, 612004 to Thrombocytopenia 4, OMIM:612004
Possible mitochondrial disorder - nuclear genes v3.92 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4, 612004 to Thrombocytopenia 4, OMIM:612004
Possible mitochondrial disorder - nuclear genes v3.91 CYCS Arina Puzriakova Publications for gene: CYCS were set to
Cytopenia - NOT Fanconi anaemia v3.27 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4, 612004; Thrombocytopenia to Thrombocytopenia 4, OMIM:612004
Bleeding and platelet disorders v3.8 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from 612004 Thrombocytopenia 4 to Thrombocytopenia 4, OMIM:612004
Cytopenias and congenital anaemias v1.118 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4, 612004 to Thrombocytopenia 4, OMIM:612004
Inherited bleeding disorders v1.176 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4 to Thrombocytopenia 4, OMIM:612004
Mitochondrial disorders v4.165 CYCS Arina Puzriakova Phenotypes for gene: CYCS were changed from Thrombocytopenia 4, 612004 to Thrombocytopenia 4, OMIM:612004
Possible mitochondrial disorder - nuclear genes v3.90 CYCS Arina Puzriakova Classified gene: CYCS as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.90 CYCS Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to support a gene-disease association and given that in vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain, this gene can be promoted to Green status at the next GMS panel update.
Possible mitochondrial disorder - nuclear genes v3.90 CYCS Arina Puzriakova Gene: cycs has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.89 CYCS Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: CYCS.
Possible mitochondrial disorder - nuclear genes v3.89 CYCS Arina Puzriakova commented on gene: CYCS
Mitochondrial disorders v4.164 CYCS Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: CYCS.
Mitochondrial disorders v4.164 CYCS Arina Puzriakova Classified gene: CYCS as Amber List (moderate evidence)
Mitochondrial disorders v4.164 CYCS Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases to support a gene-disease association and given that in vitro studies of patient variants have shown functional defects in the mitochondrial respiratory chain, this gene can be promoted to Green status at the next GMS panel update.
Mitochondrial disorders v4.164 CYCS Arina Puzriakova Gene: cycs has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.163 SPATA5 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: SPATA5.
Mitochondrial disorders v4.163 SPATA5 Arina Puzriakova Publications for gene: SPATA5 were set to 27246907; 29343804; 26299366; 28293831
Mitochondrial disorders v4.162 SPATA5 Arina Puzriakova Classified gene: SPATA5 as Amber List (moderate evidence)
Mitochondrial disorders v4.162 SPATA5 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases to promote this gene to Green at the next GMS panel update. Patients display a phenotype that resembles a mitochondrial disorder and functional studies on patient-derived cells have demonstrated an impact on mitochondrial function, further supporting inclusion of SPATA5 on this panel.
Mitochondrial disorders v4.162 SPATA5 Arina Puzriakova Gene: spata5 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.161 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Intellectual disability - microarray and sequencing v5.497 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome, 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Early onset or syndromic epilepsy v4.179 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Monogenic hearing loss v4.26 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from Epilepsy, hearing loss, and mental retardation syndrome 616577 to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Fetal anomalies v3.140 SPATA5 Arina Puzriakova Phenotypes for gene: SPATA5 were changed from EPILEPSY, HEARING LOSS, AND MENTAL RETARDATION SYNDROME to Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities, OMIM:616577
Childhood onset dystonia, chorea or related movement disorder v3.74 PRNP Arina Puzriakova changed review comment from: Comment on list classification: Given that the age of onset associated with the multiple phenotypes related to this gene, inclusion on this panel should be reviewed by the GMS specialist group.; to: Comment on list classification: Given that the age of onset associated with the multiple phenotypes related to this gene is almost always in adulthood and poses risk of incidental findings, inclusion of PRNP on this panel should be reviewed by the GMS specialist group.
Childhood onset dystonia, chorea or related movement disorder v3.74 PRNP Arina Puzriakova Classified gene: PRNP as Green List (high evidence)
Childhood onset dystonia, chorea or related movement disorder v3.74 PRNP Arina Puzriakova Added comment: Comment on list classification: Given that the age of onset associated with the multiple phenotypes related to this gene, inclusion on this panel should be reviewed by the GMS specialist group.
Childhood onset dystonia, chorea or related movement disorder v3.74 PRNP Arina Puzriakova Gene: prnp has been classified as Green List (High Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.73 PRNP Arina Puzriakova Phenotypes for gene: PRNP were changed from Creutzfeldt-Jakob disease 123400; Huntington disease-like 1 603218; Cerebral amyloid angiopathy, PRNP-related 137440; Gerstmann-Straussler disease 137440 to Cerebral amyloid angiopathy, PRNP-related, OMIM:137440; Huntington disease-like 1, OMIM:603218; Gerstmann-Straussler disease, OMIM:137440; Creutzfeldt-Jakob disease, OMIM:123400
Childhood onset dystonia, chorea or related movement disorder v3.72 PRNP Arina Puzriakova Publications for gene: PRNP were set to
Childhood onset dystonia, chorea or related movement disorder v3.71 PRNP Arina Puzriakova Tag Q1_24_demote_red tag was added to gene: PRNP.
Tag Q1_24_expert_review tag was added to gene: PRNP.
Childhood onset dystonia, chorea or related movement disorder v3.71 PRNP Arina Puzriakova reviewed gene: PRNP: Rating: ; Mode of pathogenicity: None; Publications: 16831973; Phenotypes: ; Mode of inheritance: None
Sarcoma susceptibility v1.81 TP53 Arina Puzriakova Phenotypes for gene: TP53 were changed from Li-Fraumeni syndrome, OMIM:151623; Sarcoma, MONDO:0005089 to Li-Fraumeni syndrome, OMIM:151623; Solitary Fibrous Tumour; Sarcoma, MONDO:0005089
Sarcoma susceptibility v1.80 TP53 Arina Puzriakova Publications for gene: TP53 were set to 27050224; 28338660
Sarcoma susceptibility v1.79 TERT Arina Puzriakova Publications for gene: TERT were set to PMID: 31529158
Sarcoma susceptibility v1.78 TERT Arina Puzriakova Classified gene: TERT as Red List (low evidence)
Sarcoma susceptibility v1.78 TERT Arina Puzriakova Added comment: Comment on list classification: Although there is evidence to support that TERT promoter variants affect prognosis, they are not the driving alteration in SFT. Furthermore, this cancer panel is intended for germline susceptibility findings rather than somatic variants as described in the case of TERT.

Therefore, assigning a Red rating to the TERT gene on this panel.
Sarcoma susceptibility v1.78 TERT Arina Puzriakova Gene: tert has been classified as Red List (Low Evidence).
Sarcoma susceptibility v1.77 TERT Arina Puzriakova Tag promoter tag was added to gene: TERT.
Tag somatic tag was added to gene: TERT.
Sarcoma susceptibility v1.77 TERT Arina Puzriakova reviewed gene: TERT: Rating: ; Mode of pathogenicity: None; Publications: 24726063, 27562490, 29985536, 31529158, 31321477, 38392213, 38357190; Phenotypes: Solitary Fibrous Tumours; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.496 SNF8 Achchuthan Shanmugasundram Classified gene: SNF8 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.496 SNF8 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases with intellectual disability and hence this gene can be promoted to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.496 SNF8 Achchuthan Shanmugasundram Gene: snf8 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.495 SNF8 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: SNF8.
Intellectual disability - microarray and sequencing v5.495 SNF8 Achchuthan Shanmugasundram changed review comment from: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.
Sources: Literature; to: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8.

The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.

Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.495 SNF8 Achchuthan Shanmugasundram gene: SNF8 was added
gene: SNF8 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Review for gene: SNF8 was set to GREEN
Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.195 EZR Arina Puzriakova Classified gene: EZR as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.195 EZR Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Not yet associated with any phenotype in OMIM or G2P. Rating Red as only a single case has been reported to date (PMID: 37301410). Patient had B-cell deficiency with progressive hypogammaglobulinemia. Additional cases required prior to promoting this gene.

A homozygous variant in EZR was also found in two siblings with a profound intellectual disability (PMID: 25504542) but no immunological manifestations were reported.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.195 EZR Arina Puzriakova Gene: ezr has been classified as Red List (Low Evidence).
Vascular skin disorders v1.56 CCBE1 Arina Puzriakova commented on gene: CCBE1
Vascular skin disorders v1.56 CCBE1 Arina Puzriakova Tag Q1_24_demote_red tag was added to gene: CCBE1.
Tag Q1_24_expert_review tag was added to gene: CCBE1.
Intellectual disability - microarray and sequencing v5.494 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam lymphangiectasia-lymphedema syndrome, 235510; HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME (HLLS) to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
Primary lymphoedema v3.10 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam lymphangiectasia-lymphedema syndrome, 235510; Hennekam Lymphangiectasia-Lymphedema Syndrome to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.179 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam-lymphangiectasia-lymphedema syndrome 1 235510 to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
Fetal anomalies v3.139 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510
Primary immunodeficiency or monogenic inflammatory bowel disease v4.194 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam lymphangiectasia-lymphedema syndrome 1, 235510; Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features; Combined immunodeficiencies with associated or syndromic features to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510; Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features; Combined immunodeficiencies with associated or syndromic features
Fetal hydrops v1.64 CCBE1 Arina Puzriakova Phenotypes for gene: CCBE1 were changed from Hennekam lymphangiectasia-lymphedema syndrome 1, 235510; generalised lymphatic dysplasia; fetal hydrops to Hennekam lymphangiectasia-lymphedema syndrome 1, OMIM:235510; generalised lymphatic dysplasia; fetal hydrops
Vascular skin disorders v1.56 ALAS2 Arina Puzriakova Classified gene: ALAS2 as Green List (high evidence)
Vascular skin disorders v1.56 ALAS2 Arina Puzriakova Added comment: Comment on list classification: Inclusion of ALAS2 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

Gain-of-function variants in the ALAS2 gene cause erythropoietic protoporphyria which is associated with acute phototoxic skin reactions following sunlight exposure. Although the origin of cutaneous manifestations is not directly vascular, this panel may provide a differential diagnosis. The FECH gene which also causes erythropoietic protoporphyria is also included on the panel.

Additionally, previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.
Vascular skin disorders v1.56 ALAS2 Arina Puzriakova Gene: alas2 has been classified as Green List (High Evidence).
Mitochondrial disorders v4.160 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Anemia, sideroblastic, 1 300751; Protoporphyria, erythropoietic, X-linked 300752 to Anemia, sideroblastic, 1, OMIM:300751; Protoporphyria, erythropoietic, X-linked, OMIM:300752
Likely inborn error of metabolism - targeted testing not possible v4.132 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Erythropoietic protoporphyria, mild variant; X-linked sideroblastic anaemia (XLSA) (Porphyrias with acute painful photosensitivity); X-linked dominant protoporphyria (Porphyrias with acute painful photosensitivity) to Anemia, sideroblastic, 1, OMIM:300751; Protoporphyria, erythropoietic, X-linked, OMIM:300752
Undiagnosed metabolic disorders v1.614 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from X-linked dominant protoporphyria (Porphyrias with acute painful photosensitivity); X-linked sideroblastic anaemia (XLSA) (Porphyrias with acute painful photosensitivity); Erythropoietic protoporphyria, mild variant to Anemia, sideroblastic, 1, OMIM:300751; Protoporphyria, erythropoietic, X-linked, OMIM:300752
Iron metabolism disorders - NOT common HFE mutations v2.5 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Protoporphyria, erythropoietic, X-linked OMIM:300752; Anemia, sideroblastic, 1 OMIM:300751; X-linked erythropoietic protoporphyria MONDO:0010420; X-linked sideroblastic anemia 1 MONDO:0020721 to Anemia, sideroblastic, 1, OMIM:300751
Rare anaemia v3.8 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Anemia, sideroblastic, 1, 300751; Anemia, sideroblastic, 1 300751; 300751 Sideroblastic anaemia 1; 300751 Anemia, sideroblastic, 1 to Anemia, sideroblastic, 1, OMIM:300751
Cytopenias and congenital anaemias v1.117 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Anemia, sideroblastic, 1 300751 to Anemia, sideroblastic, 1, OMIM:300751
Cutaneous photosensitivity with a likely genetic cause v3.4 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Protoporphyria, erythropoietic, X-linked, 300752; Anemia, sideroblastic, X-linked, 300751 to Protoporphyria, erythropoietic, X-linked, OMIM:300752
Non-acute porphyrias v1.24 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Protoporphyria, erythropoietic, X-linked OMIM:300752; X-linked erythropoietic protoporphyria MONDO:0010420; Anemia, sideroblastic, X-linked OMIM:300751; X-linked sideroblastic anemia 1 MONDO:0020721 to Protoporphyria, erythropoietic, X-linked, OMIM:300752
Erythropoietic protoporphyria, mild variant v1.3 ALAS2 Arina Puzriakova Phenotypes for gene: ALAS2 were changed from Anemia, sideroblastic, X-linked, 300751; Protoporphyria, erythropoietic, X-linked, 300752 to Protoporphyria, erythropoietic, X-linked, OMIM:300752
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicating that this panel may be applicable in some cases and represents a differential diagnosis.

Additionally, previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.; to: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura and petechiae, indicating that this panel may be applicable in some cases and represents a differential diagnosis.

Additionally, previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicating that this panel may be applicable in some cases and represents a differential diagnosis.

Previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.; to: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicating that this panel may be applicable in some cases and represents a differential diagnosis.

Additionally, previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicates that this panel may be applicable in some cases and represents a differential diagnosis.

Previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.; to: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicating that this panel may be applicable in some cases and represents a differential diagnosis.

Previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova Classified gene: ADAMTS13 as Green List (high evidence)
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova Added comment: Comment on list classification: Inclusion of ADAMTS13 was reassessed in light of the Red review by Zornitza Stark (Australian Genomics).

ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura which is predominantly characterised by haematological abnormalities. These defects can results in secondary dermatological features such as purpura, petechiae and vasculitis, indicates that this panel may be applicable in some cases and represents a differential diagnosis.

Previous discussions with the clinical specialist team indicated that this gene should be on the panel and therefore maintaining the current Green rating.
Vascular skin disorders v1.55 ADAMTS13 Arina Puzriakova Gene: adamts13 has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v3.26 TUBA4A Achchuthan Shanmugasundram Phenotypes for gene: TUBA4A were changed from Thrombocytopenia to autosomal dominant macrothrombocytopenia, MONDO:0015372
Cytopenia - NOT Fanconi anaemia v3.25 TUBA4A Achchuthan Shanmugasundram Classified gene: TUBA4A as Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v3.25 TUBA4A Achchuthan Shanmugasundram Gene: tuba4a has been classified as Red List (Low Evidence).
Cytopenia - NOT Fanconi anaemia v3.24 TUBA4A Achchuthan Shanmugasundram reviewed gene: TUBA4A: Rating: RED; Mode of pathogenicity: None; Publications: 30760556; Phenotypes: autosomal dominant macrothrombocytopenia, MONDO:0015372; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.193 PTCRA Boaz Palterer gene: PTCRA was added
gene: PTCRA was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCRA were set to 38422122
Phenotypes for gene: PTCRA were set to Autoimmunity; elevated TCRgamma/delta T cells; lymphopenia; low TREC
Penetrance for gene: PTCRA were set to Incomplete
Review for gene: PTCRA was set to GREEN
Added comment: Materna et al. identified 10 subjects from 7 kindreds with biallelic LOF PTCRA variants, moreover, the authors identified common hypomorphic alleles significantly associated with autoimmunity. Extensive in vivo, in vitro, and mouse functional validation and epidemiologic data.
Sources: Literature
Retinal disorders v4.81 SLC37A3 Siying Lin reviewed gene: SLC37A3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 35486108; Phenotypes: Retinitis pigmentosa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v4.25 RIPOR2 Dmitrijs Rots reviewed gene: RIPOR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32631815; Phenotypes: Adult-onset hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurological segmental overgrowth v2.9 MAX James Poulter gene: MAX was added
gene: MAX was added to Neurological segmental overgrowth. Sources: Literature
Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAX were set to PMID:38141607
Phenotypes for gene: MAX were set to Macrocephaly; Polydactyly; delayed ophthalmic development; autism
Penetrance for gene: MAX were set to Complete
Review for gene: MAX was set to GREEN
Added comment: Recurrent de novo variant (p.Arg60Gln) identified in 3 unrelated individuals. Pathogenicity supported by functional analysis.
Sources: Literature
Intellectual disability - microarray and sequencing v5.493 DYNC2H1 Arina Puzriakova commented on gene: DYNC2H1: - PMID: 22589734 (2012) - A 29 Mb deletion encompassing DYNC2H1 was found in one patient with syndromic hirschsprung disease which included moderate mental retardation, mild hydrocephalus, microcephaly, cardiomyopathy and congenital hypotonia. Other candidate genes in this region include CNTN5 and CARD17. Skeletal findings that are typical for DYNC2H1 are not reported.

Comment on publications: PMID: 22589734 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.493 DYNC2H1 Arina Puzriakova Publications for gene: DYNC2H1 were set to
Neurological ciliopathies v3.18 EXOC3L2 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: EXOC3L2.
Neurological ciliopathies v3.18 EXOC3L2 Sarah Leigh Classified gene: EXOC3L2 as Amber List (moderate evidence)
Neurological ciliopathies v3.18 EXOC3L2 Sarah Leigh Added comment: Comment on list classification: There is sufficient evidence for this gene to be green on this panel.
Neurological ciliopathies v3.18 EXOC3L2 Sarah Leigh Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v3.17 EXOC3L2 Sarah Leigh Publications for gene: EXOC3L2 were set to 28749478; 27894351; 30327448
Neurological ciliopathies v3.16 EXOC3L2 Sarah Leigh reviewed gene: EXOC3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Neurological ciliopathies v3.16 EXOC3L2 Sarah Leigh Publications for gene: EXOC3L2 were set to 28749478; 27894351
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Classified gene: PCLO as Red List (low evidence)
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Added comment: Comment on list classification: There is not enough evidence for this gene to be Amber on this panel.
Early onset or syndromic epilepsy v4.178 PCLO Sarah Leigh Gene: pclo has been classified as Red List (Low Evidence).
Leber hereditary optic neuropathy v2.9 DNAJC30 Arina Puzriakova Tag curated_removed tag was added to gene: DNAJC30.
Early onset or syndromic epilepsy v4.177 ZNFX1 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.492
Early onset or syndromic epilepsy v4.177 ZNFX1 Sarah Leigh gene: ZNFX1 was added
gene: ZNFX1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q1_24_promote_green, Q1_24_NHS_review tags were added to gene: ZNFX1.
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33876776; 33872655
Phenotypes for gene: ZNFX1 were set to Immunodeficiency 91 and hyperinflammation, OMIM:619644; immunodeficiency 91 and hyperinflammation, MONDO:0030491
Intellectual disability - microarray and sequencing v5.492 ZNFX1 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZNFX1.
Tag Q1_24_NHS_review tag was added to gene: ZNFX1.
Intellectual disability - microarray and sequencing v5.492 ZNFX1 Sarah Leigh Classified gene: ZNFX1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.492 ZNFX1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be green on this panel.
Intellectual disability - microarray and sequencing v5.492 ZNFX1 Sarah Leigh Gene: znfx1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.491 ZNFX1 Sarah Leigh edited their review of gene: ZNFX1: Added comment: ZNFX1 variants are associated with Immunodeficiency 91 and hyperinflammation (OMIM:619644). Neurological involvement has been observed in at least 11 patients with OMIM:619644 (PMID:33876776;33872655). Of these, four had seizures, three had developmental regression, and one had developmental delay. The incidence of neurological involvement could be higher, but the mortality of affected children is high; in PMID:33872655 11/15 cases were deceased, with seven of these not surviving to 3 months of age.; Changed rating: GREEN
Intellectual disability - microarray and sequencing v5.491 ZNFX1 Sarah Leigh gene: ZNFX1 was added
gene: ZNFX1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: ZNFX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNFX1 were set to 33876776; 33872655
Phenotypes for gene: ZNFX1 were set to Immunodeficiency 91 and hyperinflammation, OMIM:619644; immunodeficiency 91 and hyperinflammation, MONDO:0030491
Review for gene: ZNFX1 was set to AMBER
Added comment: Sources: Literature
Intellectual disability - microarray and sequencing v5.490 SRPX2 Arina Puzriakova Phenotypes for gene: SRPX2 were changed from Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3; ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX) to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643
Early onset or syndromic epilepsy v4.176 SRPX2 Arina Puzriakova Phenotypes for gene: SRPX2 were changed from ?Rolandic epilepsy, mental retardation, and speech dyspraxia 300643 to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643
Intellectual disability - microarray and sequencing v5.489 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Gene2Phenotype confirmed gene with ID HPO to Schimke immunoosseous dysplasia, OMIM:242900
Intellectual disability - microarray and sequencing v5.488 SMARCAL1 Arina Puzriakova Publications for gene: SMARCAL1 were set to
Intellectual disability - microarray and sequencing v5.487 SMARCAL1 Arina Puzriakova edited their review of gene: SMARCAL1: Changed phenotypes to: Schimke immunoosseous dysplasia, OMIM:242900
Intellectual disability - microarray and sequencing v5.487 SMARCAL1 Arina Puzriakova reviewed gene: SMARCAL1: Rating: ; Mode of pathogenicity: None; Publications: 28796785, 20301550; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v4.193 SMARCAL1 Arina Puzriakova Added comment: Comment on phenotypes: Previous (overwritten) phenotypes: Schimke disease;Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure;Combined immunodeficiencies with associated or syndromic features
Primary immunodeficiency or monogenic inflammatory bowel disease v4.193 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900; Schimke disease; Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure; Combined immunodeficiencies with associated or syndromic features to Schimke immunoosseous dysplasia, OMIM:242900
Proteinuric renal disease v4.7 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia #242900 to Schimke immunoosseous dysplasia, OMIM:242900
Fetal anomalies v3.138 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from SCHIMKE IMMUNOOSSEOUS DYSPLASIA to Schimke immunoosseous dysplasia, OMIM:242900
Unexplained young onset end-stage renal disease v3.39 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900 to Schimke immunoosseous dysplasia, OMIM:242900
Cytopenia - NOT Fanconi anaemia v3.24 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia, 242900 to Schimke immunoosseous dysplasia, OMIM:242900
Skeletal dysplasia v4.53 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900; Schimke immunoosseous dysplasia 242900 to Schimke immunoosseous dysplasia, OMIM:242900
Unexplained kidney failure in young people v1.118 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900 to Schimke immunoosseous dysplasia, OMIM:242900
Cerebral vascular malformations v3.11 SMARCAL1 Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900 to Schimke immunoosseous dysplasia, OMIM:242900
Intellectual disability - microarray and sequencing v5.487 ZFX Sarah Leigh changed review comment from: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.; to: To date, germline variants in ZFX have not been associated with a phenotype in OMIM or Gen2Phen.
A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.
Intellectual disability - microarray and sequencing v5.487 ZFX Sarah Leigh Phenotypes for gene: ZFX were changed from to X-linked neurodevelopmental disorder with recurrent facial gestalt
Intellectual disability - microarray and sequencing v5.486 ZFX Sarah Leigh Publications for gene: ZFX were set to 26350204; 26740508
Intellectual disability - microarray and sequencing v5.486 ZFX Sarah Leigh Classified gene: ZFX as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.486 ZFX Sarah Leigh Added comment: Comment on list classification: There is sufficient evidence for this gene to be green on this panel.
Intellectual disability - microarray and sequencing v5.486 ZFX Sarah Leigh Gene: zfx has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.485 ZFX Sarah Leigh Tag Q1_24_promote_green tag was added to gene: ZFX.
Tag Q1_24_NHS_review tag was added to gene: ZFX.
Intellectual disability - microarray and sequencing v5.485 ZFX Sarah Leigh reviewed gene: ZFX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38325380; Phenotypes: X-linked neurodevelopmental disorder with recurrent facial gestalt; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Leber hereditary optic neuropathy v2.9 DNAJC30 Sarah Leigh commented on gene: DNAJC30: DNAJC30 has been demoted to Grey on this panel, because in the October 2022 test directory, the single gene test for DNAJC30 was removed from the Leber hereditary optic neuropathy (R42) clinical indication and was moved to the Optic neuropathy (R41) panel (this change was visible in the April 2023 data release of PanelApp).
Intellectual disability - microarray and sequencing v5.485 AFF2 Arina Puzriakova Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type, 309548; FRAXE Syndrome; FRAGILE X-E MENTAL RETARDATION SYNDROME (FRAXE) to Intellectual developmental disorder, X-linked 109, OMIM:309548; Fragile XE syndrome (FRAXE)
Intellectual disability - microarray and sequencing v5.484 PPP2R2B Arina Puzriakova Publications for gene: PPP2R2B were set to
Intellectual disability - microarray and sequencing v5.483 PPP2R2B Arina Puzriakova edited their review of gene: PPP2R2B: Added comment: - PMID: 25356899 (2014) - missense variant (c.413G>C, p.Arg138Pro) in the PPP2R2B gene identified in a 7-year-old boy with moderate ID, intractable seizures and autistic features. Otherwise limited information provided.

Comment on publications: PMID: 25356899 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; Changed publications to: 25356899; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.483 NXF5 Arina Puzriakova Classified gene: NXF5 as Red List (low evidence)
Intellectual disability - microarray and sequencing v5.483 NXF5 Arina Puzriakova Added comment: Comment on list classification: Maintaining Red rating as evidence linking this gene to ID is not definitive since patient variants have involved multiple genes and no cases of SNVs in the NXF5 gene have been reported.
Intellectual disability - microarray and sequencing v5.483 NXF5 Arina Puzriakova Gene: nxf5 has been classified as Red List (Low Evidence).
Intellectual disability - microarray and sequencing v5.482 NXF5 Arina Puzriakova Added comment: Comment on publications: PMID: 23675524 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.482 NXF5 Arina Puzriakova Publications for gene: NXF5 were set to 11566096; 26350204; 23675524; 22030050; 20096387
Intellectual disability - microarray and sequencing v5.481 NXF5 Arina Puzriakova Publications for gene: NXF5 were set to 11566096; 26350204; 23675524; 22030050
Intellectual disability - microarray and sequencing v5.480 NXF5 Arina Puzriakova reviewed gene: NXF5: Rating: ; Mode of pathogenicity: None; Publications: 11566096, 20096387, 22030050, 23675524; Phenotypes: ; Mode of inheritance: None
Cytopenia - NOT Fanconi anaemia v3.23 TUBA8 Achchuthan Shanmugasundram edited their review of gene: TUBA8: Changed publications to: 34704371
Cytopenia - NOT Fanconi anaemia v3.23 TUBA8 Achchuthan Shanmugasundram commented on gene: TUBA8: Six unrelated individuals were identified with TUBA8 missense variants in a large cohort of blood donors with mild thrombocytopenia and these individuals were generally asymptomatic and one had menorrhagia. There is also some functional data available.
Cytopenia - NOT Fanconi anaemia v3.23 TUBA8 Achchuthan Shanmugasundram Classified gene: TUBA8 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v3.23 TUBA8 Achchuthan Shanmugasundram Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v3.22 TUBA8 Achchuthan Shanmugasundram Phenotypes for gene: TUBA8 were changed from Macrothrombocytopenia, isolated, 2, autosomal dominant to Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840
Cytopenia - NOT Fanconi anaemia v3.21 TUBA8 Achchuthan Shanmugasundram reviewed gene: TUBA8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Macrothrombocytopenia, isolated, 2, autosomal dominant, OMIM:619840; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v3.137 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation 611291 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Severe microcephaly v4.65 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation 611291 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Primary immunodeficiency or monogenic inflammatory bowel disease v4.192 NHEJ1 Arina Puzriakova Added comment: Comment on phenotypes: Previous (overwritten) phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation;Severe combined immunodeficiency with microcephaly, growth retardation and sensitivity to ionizing radiation, 611291;T-B- SCID;T-B+ SCID;Combined immunodeficiency;Cernunnos/XLF deficiency;Nl NK, radiation sensitive, microcephaly;Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency or monogenic inflammatory bowel disease v4.192 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation; Severe combined immunodeficiency with microcephaly, growth retardation and sensitivity to ionizing radiation, 611291; T-B- SCID; T-B+ SCID; Combined immunodeficiency; Cernunnos/XLF deficiency; Nl NK, radiation sensitive, microcephaly; Immunodeficiencies affecting cellular and humoral immunity to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Intellectual disability - microarray and sequencing v5.480 NHEJ1 Arina Puzriakova Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, OMIM:611291
Intellectual disability - microarray and sequencing v5.479 KIRREL3 Arina Puzriakova Added comment: Comment on publications: New publication added - PMID:25902260. This paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques

Provides review of cases in literature and functional studies demonstrating brain expressed proteins that interact with the KIRREL3 using yeast two-hybrid screening supporting a link to neurological and cognitive disorders. They also show KIRREL3 localisation to the Golgi complex and synaptic secretary vesicles.
Intellectual disability - microarray and sequencing v5.479 KIRREL3 Arina Puzriakova Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Monogenic diabetes v2.57 SMPD4 Achchuthan Shanmugasundram Classified gene: SMPD4 as Amber List (moderate evidence)
Monogenic diabetes v2.57 SMPD4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are five individuals from three unrelated families with biallelic loss-of-function SMPD4 variants. They developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly. In addition, review of past reports showed 27% of patients had insulin-dependent diabetes.

This gene can therefore be promoted to green rating in the next GMS review.
Monogenic diabetes v2.57 SMPD4 Achchuthan Shanmugasundram Gene: smpd4 has been classified as Amber List (Moderate Evidence).
Monogenic diabetes v2.56 SMPD4 Achchuthan Shanmugasundram Phenotypes for gene: SMPD4 were changed from NDD, microcephaly and diabetes to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies, OMIM:618622; type 1 diabetes mellitus, MONDO:0005147
Monogenic diabetes v2.55 SMPD4 Achchuthan Shanmugasundram Publications for gene: SMPD4 were set to PMID: 36732302
Monogenic diabetes v2.54 SMPD4 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: SMPD4.
Monogenic diabetes v2.54 SMPD4 Achchuthan Shanmugasundram edited their review of gene: SMPD4: Changed publications to: 36732302
Monogenic diabetes v2.54 SMPD4 Achchuthan Shanmugasundram reviewed gene: SMPD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies, OMIM:618622, type 1 diabetes mellitus, MONDO:0005147; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.478 KIF26B Arina Puzriakova Phenotypes for gene: KIF26B were changed from to Progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis
Intellectual disability - microarray and sequencing v5.477 INTS1 Arina Puzriakova Phenotypes for gene: INTS1 were changed from Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:618571
Intellectual disability - microarray and sequencing v5.476 INTS1 Arina Puzriakova Publications for gene: INTS1 were set to 28542170; 30622326; 17544522
Optic neuropathy v4.22 INTS8 Arina Puzriakova Phenotypes for gene: INTS8 were changed from Optic atrophy to ?Neurodevelopmental disorder with cerebellar hypoplasia and spasticity, OMIM:618572
Intellectual disability - microarray and sequencing v5.475 INTS8 Arina Puzriakova Phenotypes for gene: INTS8 were changed from to ?Neurodevelopmental disorder with cerebellar hypoplasia and spasticity, OMIM:618572
Hereditary neuropathy or pain disorder v3.83 SPG7 Williams Kirsty reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: sensory neuropathy, motor neuropathy, lower-limb neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.474 EFNB1 Arina Puzriakova Classified gene: EFNB1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.474 EFNB1 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber as a literature search did reveal evidence to suggest that some individuals may develop intellectual deficits. However, in most affected cases this was a mild presentation and there are more prominent and recognisable features observed in the general group of EFNB1-related cases which are more likely to inform diagnostic testing (e.g. craniosynostosis and clefting).
Intellectual disability - microarray and sequencing v5.474 EFNB1 Arina Puzriakova Gene: efnb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.473 EFNB1 Arina Puzriakova Added comment: Comment on publications: PMID: 25679214 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.473 EFNB1 Arina Puzriakova Publications for gene: EFNB1 were set to 23335590
Intellectual disability - microarray and sequencing v5.472 EFNB1 Arina Puzriakova reviewed gene: EFNB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23335590, 25679214, 27650623, 31088393, 24520368; Phenotypes: Craniofrontonasal dysplasia, OMIM:304110; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v4.175 SLC5A6 Sarah Leigh Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219
Early onset or syndromic epilepsy v4.174 SLC5A6 Sarah Leigh Classified gene: SLC5A6 as Red List (low evidence)
Early onset or syndromic epilepsy v4.174 SLC5A6 Sarah Leigh Gene: slc5a6 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v4.173 SLC5A6 Sarah Leigh edited their review of gene: SLC5A6: Added comment: There is insufficient evidence of epilepsy associated with SLC5A6 variants (PMID: 35013551; 38036278; 38012394; 37391029; 31754459) for this gene to be rated as Amber on the Early onset or syndromic epilepsy, therefore it have been demoted to Red.; Changed rating: RED
Early onset or syndromic epilepsy v4.173 SLC5A6 Sarah Leigh Tag watchlist was removed from gene: SLC5A6.
Tag for-review was removed from gene: SLC5A6.
Tag to_be_confirmed_NHSE was removed from gene: SLC5A6.
Severe microcephaly v4.64 AKT3 Sarah Leigh reviewed gene: AKT3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.64 AKT3 Sarah Leigh Classified gene: AKT3 as Amber List (moderate evidence)
Severe microcephaly v4.64 AKT3 Sarah Leigh Gene: akt3 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.21 DNAJC30 Sarah Leigh Tag gene-checked was removed from gene: DNAJC30.
Leber hereditary optic neuropathy v2.9 DNAJC30 Sarah Leigh Publications for gene: DNAJC30 were set to 33465056; 35091433
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Classified gene: ANK2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.173 ANK2 Achchuthan Shanmugasundram Gene: ank2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: ANK2.
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram changed review comment from: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2, of which seven patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature; to: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2 and with a complex neurodevelopmental disorder comprising intellectual disability, autism spectrum disorder and early-onset epilepsy. Seven of 12 patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature
Early onset or syndromic epilepsy v4.172 ANK2 Achchuthan Shanmugasundram gene: ANK2 was added
gene: ANK2 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 37195288
Phenotypes for gene: ANK2 were set to neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Review for gene: ANK2 was set to GREEN
Added comment: PMID:37195288 reported 12 individuals with heterozygous de novo LoF variants in ANK2, of which seven patients had early-onset epilepsy, with an onset of epilepsy before the age of 2 years. 4 patients had neonatal onset epilepsy. 1 patient had bilateral tonic-clinic seizures at 3 years of age. Another patient had focal epilepsy with focal motor seizures.
Sources: Literature
Retinal disorders v4.81 MT-TL1 Achchuthan Shanmugasundram Classified gene: MT-TL1 as Amber List (moderate evidence)
Retinal disorders v4.81 MT-TL1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Retinal disorders v4.81 MT-TL1 Achchuthan Shanmugasundram Gene: mt-tl1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.80 MT-TL1 Achchuthan Shanmugasundram Phenotypes for gene: MT-TL1 were changed from Retinitis pigmentosa to Retinal dystrophy, HP:0000556; Macular dystrophy, HP:0007754
Retinal disorders v4.79 MT-TL1 Achchuthan Shanmugasundram Publications for gene: MT-TL1 were set to
Retinal disorders v4.78 MT-TL1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: MT-TL1.
Tag Q1_24_NHS_review tag was added to gene: MT-TL1.
Retinal disorders v4.78 MT-TL1 Achchuthan Shanmugasundram reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18332310, 23806424; Phenotypes: Retinal dystrophy, HP:0000556, Macular dystrophy, HP:0007754; Mode of inheritance: MITOCHONDRIAL
Retinal disorders v4.78 TTC21B Achchuthan Shanmugasundram Classified gene: TTC21B as Amber List (moderate evidence)
Retinal disorders v4.78 TTC21B Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Siying Lin, an additional case has been seen with the inherited retinal disease service at Moorfields Eye Hospital and was reported with a homozygous variant in 100k genome project.

As there are three cases reported with retinal dystrophy, this gene can be promoted to green rating in the next GMS review.
Retinal disorders v4.78 TTC21B Achchuthan Shanmugasundram Gene: ttc21b has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.77 TTC21B Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: TTC21B.
Tag Q1_24_NHS_review tag was added to gene: TTC21B.
Retinal disorders v4.77 TTC21B Achchuthan Shanmugasundram edited their review of gene: TTC21B: Changed rating: GREEN
Retinal disorders v4.77 JAG1 Achchuthan Shanmugasundram Classified gene: JAG1 as Amber List (moderate evidence)
Retinal disorders v4.77 JAG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Retinal disorders v4.77 JAG1 Achchuthan Shanmugasundram Gene: jag1 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.76 JAG1 Achchuthan Shanmugasundram Phenotypes for gene: JAG1 were changed from Alagille syndrome 1, OMIM:118450 to Alagille syndrome 1, OMIM:118450; exudative vitreoretinopathy, MONDO:0019516
Retinal disorders v4.75 JAG1 Achchuthan Shanmugasundram Publications for gene: JAG1 were set to
Retinal disorders v4.74 JAG1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: JAG1.
Tag Q1_24_NHS_review tag was added to gene: JAG1.
Retinal disorders v4.74 JAG1 Achchuthan Shanmugasundram reviewed gene: JAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31273345, 34185059; Phenotypes: Alagille syndrome 1, OMIM:118450, exudative vitreoretinopathy, MONDO:0019516; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v4.16 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from Craniofrontonasal syndrome, 304110 to Craniofrontonasal dysplasia, OMIM:304110
Skeletal dysplasia v4.52 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from Craniofrontonasal dysplasia 304110 to Craniofrontonasal dysplasia, OMIM:304110
Fetal anomalies v3.136 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from CRANIOFRONTONASAL SYNDROME to Craniofrontonasal dysplasia, OMIM:304110
Clefting v4.106 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from CRANIOFRONTONASAL SYNDROME; CFNS to Craniofrontonasal dysplasia, OMIM:304110
Rare syndromic craniosynostosis or isolated multisuture synostosis v4.178 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from 304110; Craniofrontonasal syndrome 304110 to Craniofrontonasal dysplasia, OMIM:304110
Intellectual disability - microarray and sequencing v5.472 EFNB1 Arina Puzriakova Phenotypes for gene: EFNB1 were changed from Gene2Phenotype confirmed gene with ID HPO to Craniofrontonasal dysplasia, OMIM:304110
Intellectual disability - microarray and sequencing v5.471 EFNB1 Arina Puzriakova Publications for gene: EFNB1 were set to
Intellectual disability - microarray and sequencing v5.470 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly, 613091 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Skeletal ciliopathies v3.21 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly; Thoracic and Cranioectodermal Dysplasia (Skeletal Ciliopathy) 15 Gene Panel; Jeune syndrome; Short-rib thoracic dysplasia 3 with or without polydactyly, 613091 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Renal ciliopathies v3.4 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly; Thoracic and Cranioectodermal Dysplasia (Skeletal Ciliopathy) 15 Gene Panel; Jeune syndrome; Short-rib thoracic dysplasia 3 with or without polydactyly, 613091 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Rare multisystem ciliopathy disorders v1.169 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly, 613091; Thoracic and Cranioectodermal Dysplasia (Skeletal Ciliopathy) 15 Gene Panel; Jeune syndrome; Short-rib thoracic dysplasia 3 with or without polydactyly to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Clefting v4.105 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from SHORT-RIB THORACIC DYSPLASIA 3 WITH OR WITHOUT POLYDACTYLY; SRTD3 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Unexplained young onset end-stage renal disease v3.38 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Thoracic and Cranioectodermal Dysplasia (Skeletal Ciliopathy) 15 Gene Panel; Short-rib thoracic dysplasia 3 with or without polydactyly, 613091; Short-rib thoracic dysplasia 3 with or without polydactyly; Jeune syndrome to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Skeletal dysplasia v4.51 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short rib polydactyly syndrome (SRPS) type 3 with or without polydactyly, 613091; Short rib polydactyly syndrome (SRPS) type 1/3 (Saldino-Noonan/Verma-Naumoff); Asphyxiating thoracic dystrophy 3, 613091Short rib-polydactyly syndrome, type III, 263510Short rib-polydactyly syndrome, type IIB, 615087 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Primary ciliary disorders v1.41 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from ciliopathies to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Ductal plate malformation v1.28 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly (613091) to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Limb disorders v4.15 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Short-rib thoracic dysplasia 3 with or without polydactyly 613091; Polydactyly to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Thoracic dystrophies v1.19 DYNC2H1 Arina Puzriakova Phenotypes for gene: DYNC2H1 were changed from Asphyxiating thoracic dystrophy 3, 613091Short rib-polydactyly syndrome, type III, 263510Short rib-polydactyly syndrome, type IIB, 615087 to Short-rib thoracic dysplasia 3 with or without polydactyly, OMIM:613091
Intellectual disability - microarray and sequencing v5.469 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome, OMIM:160120 to Episodic ataxia/myokymia syndrome, OMIM:160120
Intellectual disability - microarray and sequencing v5.469 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome, 160120 to Episodic ataxia/myokymia syndrome, OMIM:160120
Intellectual disability - microarray and sequencing v5.468 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 27730449; 30055040; 34778950
Intellectual disability - microarray and sequencing v5.468 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 27730449
Intellectual disability - microarray and sequencing v5.467 KCNA1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.466 KCNA1 Achchuthan Shanmugasundram Classified gene: KCNA1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.466 KCNA1 Achchuthan Shanmugasundram Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.465 KCNA1 Achchuthan Shanmugasundram reviewed gene: KCNA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of these variants with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of the three variants from PMID:30055040 with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of these variants with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Classified gene: KCNA1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic KCNA1 variants with epilepsy/ epileptic encephalopathy and hence this gene can be promoted to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.171 KCNA1 Achchuthan Shanmugasundram Gene: kcna1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.170 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771; 24578548; 31586945; 32316562; 34778950
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram edited their review of gene: KCNA1: Changed publications to: 30055040, 31586945, 32316562, 34778950
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram changed review comment from: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).; to: PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:34778950 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE) and a de novo variant in the voltage sensor (p.Ala261Ter) identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).
Early onset or syndromic epilepsy v4.169 KCNA1 Achchuthan Shanmugasundram Phenotypes for gene: KCNA1 were changed from Episodic ataxia/myokymia syndrome 160120 to Episodic ataxia/ myokymia syndrome, OMIM:160120; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.168 KCNA1 Achchuthan Shanmugasundram Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771; 24578548
Early onset or syndromic epilepsy v4.167 KCNA1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.166 KCNA1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA1.
Tag Q1_24_NHS_review tag was added to gene: KCNA1.
Early onset or syndromic epilepsy v4.166 KCNA1 Achchuthan Shanmugasundram reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31586945, 32316562, 34778950; Phenotypes: epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v3.79 TAF4 Achchuthan Shanmugasundram Tag curated_removed was removed from gene: TAF4.
DDG2P v3.79 PBX1 Achchuthan Shanmugasundram Tag curated_removed was removed from gene: PBX1.
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: SAMD7.
Tag Q1_24_NHS_review tag was added to gene: SAMD7.
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: As the evidence for this gene-disease association has been very recent, biallelic variants in SMAD7 has not yet been associated with retinal phenotypes either in OMIM or in Gene2Phenotype.; to: Comment on phenotypes: As the evidence for this gene-disease association has been very recent, biallelic variants in SAMD7 have not yet been associated with retinal phenotypes either in OMIM or in Gene2Phenotype.
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Siying Lin, there are six unrelated families identified with biallelic SMAD7 variants. Of these patients from four families had macular dystrophy with cone dysfunction, while patients from two families had macular dystrophy without cone dysfunction. Hence, this gene should be promoted to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Siying Lin, there are six unrelated families identified with biallelic SAMD7 variants. Of these, patients from four families had macular dystrophy with cone dysfunction, while patients from two other families had macular dystrophy without cone dysfunction. Hence, this gene should be promoted to green rating in the next GMS review.
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram Classified gene: SAMD7 as Amber List (moderate evidence)
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Siying Lin, there are six unrelated families identified with biallelic SMAD7 variants. Of these patients from four families had macular dystrophy with cone dysfunction, while patients from two families had macular dystrophy without cone dysfunction. Hence, this gene should be promoted to green rating in the next GMS review.
Retinal disorders v4.74 SAMD7 Achchuthan Shanmugasundram Gene: samd7 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.73 SAMD7 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: As the evidence for this gene-disease association has been very recent, biallelic variants in SMAD7 has not yet been associated with retinal phenotypes either in OMIM or in Gene2Phenotype.
Retinal disorders v4.73 SAMD7 Achchuthan Shanmugasundram Phenotypes for gene: SAMD7 were changed from Macular dystrophy; cone dystrophy to macular dystrophy, retinal, MONDO:0031166; Congenital stationary cone dysfunction, HP:0030637
Retinal disorders v4.72 SAMD7 Achchuthan Shanmugasundram Publications for gene: SAMD7 were set to PMID: 38272031
Retinal disorders v4.71 SAMD7 Achchuthan Shanmugasundram reviewed gene: SAMD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38272031; Phenotypes: macular dystrophy, retinal, MONDO:0031166, Congenital stationary cone dysfunction, HP:0030637; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.465 CTNND2 Arina Puzriakova commented on gene: CTNND2
Intellectual disability - microarray and sequencing v5.465 CTNND2 Arina Puzriakova Phenotypes for gene: CTNND2 were changed from to CTNND2-related neurodevelopmental disorder
Intellectual disability - microarray and sequencing v5.464 CTNND2 Arina Puzriakova Mode of inheritance for gene: CTNND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.463 CLIC2 Arina Puzriakova Tag disputed tag was added to gene: CLIC2.
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Tag Q1_22_NHS_review tag was added to gene: RNASEH2C.
Tag Q1_24_promote_green tag was added to gene: RNASEH2C.
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Tag Q1_24_promote_green tag was added to gene: RNASEH2B.
Tag Q1_24_NHS_review tag was added to gene: RNASEH2B.
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Deleted their comment
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh Tag Q1_24_promote_green tag was added to gene: RNASEH2A.
Tag Q1_24_NHS_review tag was added to gene: RNASEH2A.
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2C Sarah Leigh edited their review of gene: RNASEH2C: Added comment: Saikat Santra (Birmingham Children's Hospital)(23 Jan 2024), has suggested that this gene should be green on this panel - R98.; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2B Sarah Leigh edited their review of gene: RNASEH2B: Added comment: Saikat Santra (Birmingham Children's Hospital)(23 Jan 2024), has suggested that this gene should be green on this panel - R98.; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.131 RNASEH2A Sarah Leigh edited their review of gene: RNASEH2A: Added comment: Saikat Santra (Birmingham Children's Hospital)(23 Jan 2024), has suggested that this gene should be green on this panel - R98.; Changed rating: GREEN
Palmoplantar keratodermas v3.24 PEX7 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: PEX7.
Palmoplantar keratodermas v3.24 PEX7 Sarah Leigh reviewed gene: PEX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.24 MVK Sarah Leigh reviewed gene: MVK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.24 MVK Sarah Leigh Tag Q1_24_demote_red tag was added to gene: MVK.
Tag Q1_24_expert_review tag was added to gene: MVK.
Palmoplantar keratodermas v3.24 CLDN1 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: CLDN1.
Tag Q1_24_expert_review tag was added to gene: CLDN1.
Palmoplantar keratodermas v3.24 CLDN1 Sarah Leigh reviewed gene: CLDN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.24 CASP14 Sarah Leigh edited their review of gene: CASP14: Changed rating: RED
Palmoplantar keratodermas v3.24 CASP14 Sarah Leigh reviewed gene: CASP14: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.24 CASP14 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: CASP14.
Tag Q1_24_expert_review tag was added to gene: CASP14.
Intellectual disability - microarray and sequencing v5.463 CLIC2 Arina Puzriakova Phenotypes for gene: CLIC2 were changed from Intellectual developmental disorder, X-linked syndromic 32 , OMIM:300886 to Intellectual developmental disorder, X-linked syndromic 32, OMIM:300886
Hydrocephalus v4.4 CLIC2 Arina Puzriakova Phenotypes for gene: CLIC2 were changed from ?Mental retardation, X-linked, syndromic 32, OMIM:300886 to Intellectual developmental disorder, X-linked syndromic 32, OMIM:300886
Intellectual disability - microarray and sequencing v5.462 CLIC2 Arina Puzriakova Phenotypes for gene: CLIC2 were changed from Mental retardation, X-linked, syndromic 32, 300886 to Intellectual developmental disorder, X-linked syndromic 32 , OMIM:300886
Intellectual disability - microarray and sequencing v5.461 ARHGEF6 Arina Puzriakova changed review comment from: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMID: 22511880 (2012) was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques; to: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMIDs: 22511880 (2012) and 26177020 (2015) were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.461 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020; 22511880
Intellectual disability - microarray and sequencing v5.461 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088; 26177020
Intellectual disability - microarray and sequencing v5.460 ARHGEF6 Arina Puzriakova commented on gene: ARHGEF6: PMID: 22511880 (2012) - a variant in the ARHGEF6 gene (p.I444N) was identified in a male patient with autism. However, this individual harboured variants in other genes (UBE3B) that were likely to explain their phenotype so conclusions about the consequence of the ARHGEF6 variant cannot be made in this case.

Comment on publications: PMID: 22511880 (2012) was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.460 ARHGEF6 Arina Puzriakova Publications for gene: ARHGEF6 were set to 21989057; 20861843; 17304053; 11017088
Intellectual disability - microarray and sequencing v5.459 ARHGEF6 Arina Puzriakova Phenotypes for gene: ARHGEF6 were changed from Mental retardation, X-linked 46, 300436; Mental Retardation, X-linked; MENTAL RETARDATION X-LINKED TYPE 46 to Intellectual developmental disorder, X-linked 46, OMIM:300436
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram changed review comment from: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature; to: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures. Microcephaly was severe in five children from four families.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Severe microcephaly v4.63 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Red List (low evidence)
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Severe microcephaly v4.62 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Red List (Low Evidence).
Severe microcephaly v4.61 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Early onset or syndromic epilepsy v4.166 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.165 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
Intellectual disability - microarray and sequencing v5.458 CAMSAP1 Achchuthan Shanmugasundram Classified gene: CAMSAP1 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.458 CAMSAP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.458 CAMSAP1 Achchuthan Shanmugasundram Gene: camsap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.457 CAMSAP1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: CAMSAP1.
Severe microcephaly v4.61 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Early onset or syndromic epilepsy v4.165 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Intellectual disability - microarray and sequencing v5.457 CAMSAP1 Achchuthan Shanmugasundram gene: CAMSAP1 was added
gene: CAMSAP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CAMSAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMSAP1 were set to 36283405
Phenotypes for gene: CAMSAP1 were set to Cortical dysplasia, complex, with other brain malformations 12, OMIM:620316
Review for gene: CAMSAP1 was set to GREEN
Added comment: Seven children from five unrelated families were identified with either homozygous or compound heterozygous CAMSAP1 variants and were reported with a severe neurodevelopmental disorder apparent from infancy. Clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, lissencephaly, agenesis or severe hypogenesis of the corpus callosum, severe or profound global developmental delay, cortical visual impairment, and seizures.

This gene has been associated with relevant phenotypes in both OMIM (MIM #620316) and in Gene2Phenotype (with 'moderate' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: ZNF335.
Tag Q1_24_expert_review tag was added to gene: ZNF335.
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Other than the one case that was reported by Chicago lab with ZNF335 heterozygous variant (c.2515_2518dupGCCA/ p.Thr840Serfs) and with microcephaly, encephalopathy and developmental delay, all other cases reported in the literature and ClinVar had biallelic variants in ZNF335. Hence, the MOI should be updated to "BIALLELIC, autosomal or pseudoautosomal" in the next GMS review.
Severe microcephaly v4.60 ZNF335 Achchuthan Shanmugasundram Mode of inheritance for gene: ZNF335 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v4.59 ZNF335 Achchuthan Shanmugasundram edited their review of gene: ZNF335: Changed rating: GREEN
Severe microcephaly v4.59 ZNF335 Achchuthan Shanmugasundram reviewed gene: ZNF335: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.456 BAZ2B Achchuthan Shanmugasundram Classified gene: BAZ2B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.456 BAZ2B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.456 BAZ2B Achchuthan Shanmugasundram Gene: baz2b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.455 BAZ2B Achchuthan Shanmugasundram Phenotypes for gene: BAZ2B were changed from developmental delay, intellectual disability and autism spectrum disorder to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to 31999386; 37872713
Intellectual disability - microarray and sequencing v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to 31999386; 37872713
Intellectual disability - microarray and sequencing v5.454 BAZ2B Achchuthan Shanmugasundram Publications for gene: BAZ2B were set to PMID: 31999386
Intellectual disability - microarray and sequencing v5.453 BAZ2B Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: BAZ2B.
Intellectual disability - microarray and sequencing v5.453 BAZ2B Achchuthan Shanmugasundram reviewed gene: BAZ2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 37872713; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.71 JAG1 Siying Lin changed review comment from: Well-demarcated peripheral chorioretinal atrophic changes appear to be a not infrequent finding in patiets with Alagille syndrome, and have also been seen in within our inherited retinal dystrophy clinical cohort.; to: Well-demarcated peripheral chorioretinal atrophic changes appear to be a not infrequent finding in patiets with Alagille syndrome, and these retinal findings have also been seen in at least 2 unrelated patients with Alagille syndrome within our inherited retinal dystrophy clinical cohort
Retinal disorders v4.71 JAG1 Siying Lin reviewed gene: JAG1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 34185059; Phenotypes: Retinal dystrophy, peripheral chorioretial atrophy, Alagille syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v4.71 TTC21B Siying Lin reviewed gene: TTC21B: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: Retinal dystrophy, renal failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.71 MT-TL1 Siying Lin reviewed gene: MT-TL1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 18332310, 23806424; Phenotypes: retinal dystrophy, macular dystrophy, chorioretinal atrophy, MELAS; Mode of inheritance: MITOCHONDRIAL
Retinal disorders v4.71 ATXN7_CAG Siying Lin STR: ATXN7_CAG was added
STR: ATXN7_CAG was added to Retinal disorders. Sources: Literature
Mode of inheritance for STR: ATXN7_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: ATXN7_CAG were set to PMID: 27632585,
Phenotypes for STR: ATXN7_CAG were set to Maculopaty; Cone-Rod Dystrophy
Review for STR: ATXN7_CAG was set to GREEN
Added comment: PMID: 27632585 (father of proband), this ARVO abstract ( https://iovs.arvojournals.org/article.aspx?articleid=2768575) and cases from our clinical cohort, demonstrate that affected individuals can present with a seemingly isolated maculopathy or cone-rod dystrophy that precedes the onset of neurological symptoms
Sources: Literature
Retinal disorders v4.71 SAMD7 Siying Lin gene: SAMD7 was added
gene: SAMD7 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SAMD7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SAMD7 were set to PMID: 38272031
Phenotypes for gene: SAMD7 were set to Macular dystrophy; cone dystrophy
Penetrance for gene: SAMD7 were set to unknown
Mode of pathogenicity for gene: SAMD7 was set to Other
Review for gene: SAMD7 was set to GREEN
Added comment: 5 different variants identified in homozygosity in 6 families from varying ethnicities (Pakistani, African, Yemenite Jewish, Berber/Morocccan) segregating with disease. All affected individuals presented with macular dystrophy, a few had additional cone system involvement. Immunofluorescence studies show SAMD7 localisation to inner and outer nuclear layers of the human retina.
Sources: Literature
Early onset or syndromic epilepsy v4.164 KCNA1 Tracy Lester Deleted their comment
Early onset or syndromic epilepsy v4.164 KCNA1 Tracy Lester edited their review of gene: KCNA1: Added comment: There have been several recent reports that show de novo missense variants in specific regions of this gene are associated with epileptic encephalopathy, supported by functional studies, and gene now meets criteria to be green for this phenotype; Changed rating: GREEN; Changed publications to: 24578548, 3055040, 34778950; Changed phenotypes to: epilep
Intellectual disability - microarray and sequencing v5.453 KCNA1 Tracy Lester reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30055040, 34778950; Phenotypes: epileptic encephalopathy, ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 SMCHD1 Ian Berry reviewed gene: SMCHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other; Current diagnostic: yes
Leber hereditary optic neuropathy v2.8 DNAJC30 Sarah Leigh Tag gene-checked was removed from gene: DNAJC30.
Leber hereditary optic neuropathy v2.8 DNAJC30 Sarah Leigh commented on gene: DNAJC30
Optic neuropathy v4.21 DNAJC30 Sarah Leigh commented on gene: DNAJC30
Optic neuropathy v4.21 DNAJC30 Sarah Leigh Phenotypes for gene: DNAJC30 were changed from Leber hereditary optic neuropathy, MONDO:0010788 to Leber-like hereditary optic neuropathy, autosomal recessive 1, MONDO:0958183; Leber-like hereditary optic neuropathy, autosomal recessive 1, OMIM:619382
Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated cases reported now with biallelic LCP2 variants. Hence, this gene should be rated green in the next GMS review.; to: Comment on list classification: There are three unrelated cases reported with biallelic LCP2 variants and functional data available in support of the disease association. Hence, this gene should be rated green in the next GMS review.
Optic neuropathy v4.20 DNAJC30 Sarah Leigh Publications for gene: DNAJC30 were set to 33465056; 35091433
Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram Classified gene: LCP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported now with biallelic LCP2 variants. Hence, this gene should be rated green in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.191 LCP2 Achchuthan Shanmugasundram Gene: lcp2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.190 LCP2 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LCP2.
Tag Q1_24_NHS_review tag was added to gene: LCP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.190 LCP2 Achchuthan Shanmugasundram Phenotypes for gene: LCP2 were changed from SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation to ?Immunodeficiency 81, OMIM:619374
Primary immunodeficiency or monogenic inflammatory bowel disease v4.189 LCP2 Achchuthan Shanmugasundram Publications for gene: LCP2 were set to 33231617
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 LCP2 Achchuthan Shanmugasundram reviewed gene: LCP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33231617, 36474126, 37211057; Phenotypes: ?Immunodeficiency 81, OMIM:619374; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v4.104 LRRC32 Achchuthan Shanmugasundram Classified gene: LRRC32 as Amber List (moderate evidence)
Clefting v4.104 LRRC32 Achchuthan Shanmugasundram Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Clefting v4.103 LRRC32 Achchuthan Shanmugasundram gene: LRRC32 was added
gene: LRRC32 was added to Clefting. Sources: Literature
founder-effect tags were added to gene: LRRC32.
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112; 35656379
Phenotypes for gene: LRRC32 were set to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
Review for gene: LRRC32 was set to AMBER
Added comment: PMID:30976112 reported two unrelated families with global developmental delay, cleft palate, and proliferative retinopathy and they were identified with the same homozygous LRRC32 variant c.1630C>T/ p.Arg544Ter. This variant was suggested to be founder variant, as indicated by haplotype analysis.

PMID:35656379 reported a different homozygous LRRC32 variant (c.1354 G > A/ p.Glu452Lys) in a 15-year-old male with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy.

This gene has already been associated with relevant phenotypes in OMIM (MIM #619074), but not yet in Gene2Phenotype.
Sources: Literature
Retinal disorders v4.71 CNGA1 Arina Puzriakova Publications for gene: CNGA1 were set to
Structural eye disease v3.74 CNGA1 Arina Puzriakova Phenotypes for gene: CNGA1 were changed from Retinitis pigmentosa 49, 613756; Eye Disorders to Retinitis pigmentosa 49, OMIM:613756
Glaucoma (developmental) v1.45 CNGA1 Arina Puzriakova Mode of inheritance for gene: CNGA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Glaucoma (developmental) v1.44 CNGA1 Arina Puzriakova Phenotypes for gene: CNGA1 were changed from Eye Disorders to Retinitis pigmentosa 49, OMIM:613756
Retinal disorders v4.70 CNGA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update - could not find any evidence to suggest that heterozygous variants can lead to disease. Family members of patients that are heterozygous carriers are unaffected.
Retinal disorders v4.70 CNGA1 Arina Puzriakova Mode of inheritance for gene: CNGA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v4.69 CNGA1 Arina Puzriakova Tag Q1_24_MOI tag was added to gene: CNGA1.
Retinal disorders v4.69 CNGA1 Arina Puzriakova Phenotypes for gene: CNGA1 were changed from Retinitis pigmentosa 49, RP49 (AR); Eye Disorders; Retinitis pigmentosa; Retinitis Pigmentosa, Recessive; Retinitis pigmentosa 49, 613756 to Retinitis pigmentosa 49, OMIM:613756
Retinal disorders v4.68 LRRC32 Achchuthan Shanmugasundram Classified gene: LRRC32 as Amber List (moderate evidence)
Retinal disorders v4.68 LRRC32 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two different homozygous LRRC32 variants reported (c.1630C>T/ p.Arg544Ter & c.1354 G>A/ p.Glu452Lys) in three unrelated families, of which p.Arg544Ter variant reported in two families was suggested to be a founder variant as indicated by haplotype analysis. Hence, this gene should be rated amber with current evidence.
Retinal disorders v4.68 LRRC32 Achchuthan Shanmugasundram Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.67 LRRC32 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has already been associated with relevant phenotypes in OMIM (MIM #619074), but not yet in Gene2Phenotype.
Retinal disorders v4.67 LRRC32 Achchuthan Shanmugasundram Phenotypes for gene: LRRC32 were changed from Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074 to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
Retinal disorders v4.66 LRRC32 Achchuthan Shanmugasundram Phenotypes for gene: LRRC32 were changed from Cleft palate, proliferative retinopathy, and developmental delay to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
Retinal disorders v4.65 LRRC32 Achchuthan Shanmugasundram Publications for gene: LRRC32 were set to PMID: 30976112; PMID: 35656379
Retinal disorders v4.64 LRRC32 Achchuthan Shanmugasundram reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.64 LRRC32 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: LRRC32.
Intellectual disability - microarray and sequencing v5.453 LRRC32 Achchuthan Shanmugasundram Classified gene: LRRC32 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.453 LRRC32 Achchuthan Shanmugasundram Gene: lrrc32 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.452 LRRC32 Achchuthan Shanmugasundram Publications for gene: LRRC32 were set to 30976112
Intellectual disability - microarray and sequencing v5.451 LRRC32 Achchuthan Shanmugasundram reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976112, 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.64 MT-ATP6 Andrew Webster reviewed gene: MT-ATP6: Rating: GREEN; Mode of pathogenicity: Other; Publications: PubMed: 8095070, 33600551, 8476414; Phenotypes: retinal dystrophy, macular dystrophy, retinitis pigmentosa, neuropathy, ataxia.; Mode of inheritance: MITOCHONDRIAL
Likely inborn error of metabolism - targeted testing not possible v4.131 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Likely inborn error of metabolism - targeted testing not possible v4.131 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.89 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Possible mitochondrial disorder - nuclear genes v3.89 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital muscular dystrophy v4.23 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Congenital muscular dystrophy v4.23 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.56 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Ataxia and cerebellar anomalies - narrow panel v4.56 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v4.30 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Hereditary ataxia with onset in adulthood v4.30 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v4.29 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Mitochondrial disorders v4.159 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Mitochondrial disorders v4.159 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mitochondrial disorders v4.158 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Growth failure in early childhood v3.8 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Growth failure in early childhood v3.8 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Growth failure in early childhood v3.7 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Fetal anomalies v3.135 MSTO1 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal.
Fetal anomalies v3.135 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v3.134 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Possible mitochondrial disorder - nuclear genes v3.88 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Likely inborn error of metabolism - targeted testing not possible v4.130 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Ataxia and cerebellar anomalies - narrow panel v4.55 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Hereditary ataxia with onset in adulthood v4.29 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to
Mitochondrial disorders v4.158 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28554942; 28544275; 29339779
Growth failure in early childhood v3.7 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 29339779; 28544275; 31604776; 31130378; 28554942
Likely inborn error of metabolism - targeted testing not possible v4.130 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28554942; 28544275
Fetal anomalies v3.134 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 29339779; 28544275; 31604776; 31130378; 28554942
Possible mitochondrial disorder - nuclear genes v3.88 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28554942; 28544275; 29339779
Congenital muscular dystrophy v4.22 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28544275; 28554942; 31130378; 29339779; 37431817
Ataxia and cerebellar anomalies - narrow panel v4.55 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28554942; 28544275; 31604776; 31463572; 31130378; 30684668; 29339779
Retinal disorders v4.64 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 29339779; 28544275; 31604776; 31130378; 28554942
Congenital muscular dystrophy v4.21 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 28544275; 28554942; 31130378; 29339779
Congenital muscular dystrophy v4.20 MSTO1 Sarah Leigh Tag Q1_24_MOI tag was added to gene: MSTO1.
Severe Paediatric Disorders v1.182 MSTO1 Sarah Leigh Publications for gene: MSTO1 were set to 30847515
Severe Paediatric Disorders v1.181 MSTO1 Sarah Leigh Mode of inheritance for gene: MSTO1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v4.28 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.157 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v3.6 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v3.133 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Possible mitochondrial disorder - nuclear genes v3.87 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.129 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v4.20 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.54 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe Paediatric Disorders v1.180 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.63 MSTO1 Sarah Leigh changed review comment from: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.; to: Gal et al (2017) reported a family with autosomal dominant mitochondrial myopathy and ataxia caused by a monoallelic MSTO1 variant (PMID: 28554942). Subsequently, the variant involved (rs762798018) has been reclassified as a variant of unknown significance, this is because Gal et al (2023)(PMID:37431817) have retracted their claim that there is a direct link between the variant and the patients' myopathy and ataxia phenotypes.
There are no further reports of monoallelic Myopathy, mitochondrial, and ataxia (OMIM:617675).
Retinal disorders v4.63 MSTO1 Sarah Leigh reviewed gene: MSTO1: Rating: ; Mode of pathogenicity: None; Publications: 28554942, 37431817; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.451 ACBD6 Jana Jezkova reviewed gene: ACBD6: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37951597; Phenotypes: HP:0001263, HP:0001249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v3.10 ADA2 Sarah Leigh Publications for gene: ADA2 were set to 3471198, 25528372
Undiagnosed metabolic disorders v1.613 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Likely inborn error of metabolism - targeted testing not possible v4.129 SLC6A19 Tracy Lester reviewed gene: SLC6A19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh edited their review of gene: PTEN: Added comment: Based on the review from Zornitza Stark, this gene has been demoted to amber on this panel.; Changed rating: AMBER
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh Classified gene: PTEN as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.42 PTEN Sarah Leigh Gene: pten has been classified as Amber List (Moderate Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.41 PTEN Sarah Leigh Publications for gene: PTEN were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 HSPA1L Zornitza Stark reviewed gene: HSPA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease, MONDO:0005265, HSPA1L-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v4.36 VWA1 Eleanor Williams Classified gene: VWA1 as Amber List (moderate evidence)
Congenital myopathy v4.36 VWA1 Eleanor Williams Added comment: Comment on list classification: Promoting to amber, with a recommendation for consideration for a green rating following expert review as to whether the phenotype fits the scope of the congenital myopathy panel.
Congenital myopathy v4.36 VWA1 Eleanor Williams Gene: vwa1 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v4.35 VWA1 Eleanor Williams gene: VWA1 was added
gene: VWA1 was added to Congenital myopathy. Sources: Literature
Q1_24_promote_green, Q1_24_expert_review tags were added to gene: VWA1.
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to 33459760
Phenotypes for gene: VWA1 were set to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Added comment: In PMID: 33459760 Deschauer et al 2021 report 15 affected individuals from six families of German, Arabic, and Roma descent with biallelic loss of function variants in VWA1 and a neuromuscular phenotype. In 3 of the families the onset of symptoms was in childhood (ages 2-18yr in F3, ages 2-3yr in F4, and at school age in F5). Muscle biopsies of 3 individuals (F1-II.2, F2-II.1, and F5-II.1) revealed myopathic changes. A 10-bp tandem repeat is duplicated in one variant (p.Gly25Argfs*74]) and deleted in another variant (p.Gly21Alafs*12]). The duplication was found in 3 German families, homozygous in one and compound heterozygous in the other two.

PMID: 33559681 Pagnamenta et al 2021 report 17 individuals from 15 families with an autosomal-recessive, hereditary motor neuropathy and rare biallelic variants in VWA1. The p.(G25Rfs*74) 10-bp repeat expansion was observed in 14/15 families and was homozygous in 10/15. The authors state that the mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations.

Given the young age of onset in some patients and myopathy seen in biopsys this gene may be a candidate for green rating on this panel, subject to expert review.
Sources: Literature
Hereditary neuropathy or pain disorder v3.83 VWA1 Eleanor Williams Phenotypes for gene: VWA1 were changed from Neuropathy, hereditary motor, with myopathic features OMIM:619216; neuropathy, hereditary motor, with myopathic features MONDO:0030977 to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Cystic kidney disease v4.24 OFD1 Nour Elkhateeb changed review comment from: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455.; to: OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected females. PMID: 10910455.
Cystic kidney disease v4.24 OFD1 Nour Elkhateeb reviewed gene: OFD1: Rating: ; Mode of pathogenicity: None; Publications: PMID: 10910455; Phenotypes: renal cysts; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.188 SIRT1 Achchuthan Shanmugasundram Phenotypes for gene: SIRT1 were changed from Type 1 diabetes; autoimmune disease to autoimmune disease, MONDO:0007179
Primary immunodeficiency or monogenic inflammatory bowel disease v4.187 SIRT1 Achchuthan Shanmugasundram Publications for gene: SIRT1 were set to PMID: 23473037
Primary immunodeficiency or monogenic inflammatory bowel disease v4.186 SIRT1 Achchuthan Shanmugasundram Classified gene: SIRT1 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.186 SIRT1 Achchuthan Shanmugasundram Gene: sirt1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SIRT1 Achchuthan Shanmugasundram reviewed gene: SIRT1: Rating: RED; Mode of pathogenicity: None; Publications: 23473037; Phenotypes: autoimmune disease, MONDO:0007179; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SCGN Achchuthan Shanmugasundram Classified gene: SCGN as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.185 SCGN Achchuthan Shanmugasundram Gene: scgn has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.184 SCGN Achchuthan Shanmugasundram Phenotypes for gene: SCGN were changed from ?early-onset ulcerative colitis to ulcerative colitis, MONDO:0005101
Primary immunodeficiency or monogenic inflammatory bowel disease v4.183 SCGN Achchuthan Shanmugasundram Publications for gene: SCGN were set to PMID: 31663849
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 SCGN Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 SCGN Achchuthan Shanmugasundram reviewed gene: SCGN: Rating: AMBER; Mode of pathogenicity: None; Publications: 31663849; Phenotypes: ulcerative colitis, MONDO:0005101; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v4.46 ATXN2_CAG Jemeen Sreedharan reviewed STR: ATXN2_CAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 20740007, 21479228, 21537950, 21562247; Phenotypes: amyotrophic lateral sclerosis, spinocerebellar ataxia 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Classified gene: HSPA1L as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (seven unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 HSPA1L Achchuthan Shanmugasundram Gene: hspa1l has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.181 HSPA1L Achchuthan Shanmugasundram Phenotypes for gene: HSPA1L were changed from Inflammatory bowel disease to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v4.180 HSPA1L Achchuthan Shanmugasundram Publications for gene: HSPA1L were set to PMID: 28126021
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 HSPA1L Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HSPA1L.
Tag Q1_24_NHS_review tag was added to gene: HSPA1L.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 HSPA1L Achchuthan Shanmugasundram reviewed gene: HSPA1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 28126021; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.179 CARD8 Achchuthan Shanmugasundram Publications for gene: CARD8 were set to 29408806
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Classified gene: CARD8 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are two unrelated cases with heterozygous variants and Inflammatory bowel disease (Crohn disease). Hence, this gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.178 CARD8 Achchuthan Shanmugasundram Gene: card8 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.177 CARD8 Achchuthan Shanmugasundram Phenotypes for gene: CARD8 were changed from ?Inflammatory bowel disease (Crohn disease) 30 to ?Inflammatory bowel disease (Crohn disease) 30, OMIM:619079
Primary immunodeficiency or monogenic inflammatory bowel disease v4.176 CARD8 Achchuthan Shanmugasundram Publications for gene: CARD8 were set to PMID: 29408806
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 CARD8 Achchuthan Shanmugasundram reviewed gene: CARD8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Inflammatory bowel disease (Crohn disease) 30, OMIM:619079; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Classified gene: ANKZF1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: AS there is sufficient evidence for the association of monoallelic variants with infantile-onset inflammatory bowel disease, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.175 ANKZF1 Achchuthan Shanmugasundram Gene: ankzf1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_moi' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Tag watchlist_moi tag was added to gene: ANKZF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation.

The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 ANKZF1 Achchuthan Shanmugasundram Mode of inheritance for gene: ANKZF1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.173 ANKZF1 Achchuthan Shanmugasundram Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589
Primary immunodeficiency or monogenic inflammatory bowel disease v4.172 ANKZF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.172 ANKZF1 Achchuthan Shanmugasundram Phenotypes for gene: ANKZF1 were changed from Inflammatory bowel disease to inflammatory bowel disease, MONDO:0005265
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 ANKZF1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: ANKZF1.
Tag Q1_24_NHS_review tag was added to gene: ANKZF1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 ANKZF1 Achchuthan Shanmugasundram reviewed gene: ANKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302725, 36857589; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available (three unrelated cases and functional studies) for the association of this gene with disabling pansclerotic morphea of childhood (MIM #620443) and hence this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Classified gene: STAT4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.171 STAT4 Achchuthan Shanmugasundram Gene: stat4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: STAT4.
Tag Q1_24_NHS_review tag was added to gene: STAT4.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram changed review comment from: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that the variants caused a gain-of-function effect.; to: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that STAT4 variants caused a gain-of-function effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.170 STAT4 Achchuthan Shanmugasundram Mode of inheritance for gene: STAT4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.169 STAT4 Achchuthan Shanmugasundram Added comment: Comment on mode of pathogenicity: As reported in PMID:37256972, functional studies demonstrated that the variants caused a gain-of-function effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.169 STAT4 Achchuthan Shanmugasundram Mode of pathogenicity for gene: STAT4 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
Primary immunodeficiency or monogenic inflammatory bowel disease v4.168 STAT4 Achchuthan Shanmugasundram Publications for gene: STAT4 were set to 29029192
Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 STAT4 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIMs #612253 & #620443), but not in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 STAT4 Achchuthan Shanmugasundram Phenotypes for gene: STAT4 were changed from Paracoccidioidomycosis; Impaired IFN-γ Immunity; {Systemic lupus erythematosus, susceptibility to, 11}, 612253 to Disabling pansclerotic morphea of childhood, OMIM:620443; {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 STAT4 Achchuthan Shanmugasundram reviewed gene: STAT4: 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: 37256972; Phenotypes: Disabling pansclerotic morphea of childhood, OMIM:620443, {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.9 KCNQ1 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: KCNQ1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: LACC1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LACC1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Classified gene: LACC1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there is sufficient evidence available for the association of this gene with juvenile arthritis and hence with this panel. So, this gene should be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.166 LACC1 Achchuthan Shanmugasundram Gene: lacc1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.165 LACC1 Achchuthan Shanmugasundram Publications for gene: LACC1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.164 LACC1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #618795), but not yet in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.164 LACC1 Achchuthan Shanmugasundram Phenotypes for gene: LACC1 were changed from Juvenile arthritis to Juvenile arthritis, OMIM:618795
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LACC1 Achchuthan Shanmugasundram reviewed gene: LACC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25220867, 27881174, 29717096, 30872671; Phenotypes: Juvenile arthritis, OMIM:618795; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pituitary hormone deficiency v3.9 KCNQ1 Achchuthan Shanmugasundram Publications for gene: KCNQ1 were set to 29097701
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Classified gene: KCNQ1 as Amber List (moderate evidence)
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously identified variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.8 KCNQ1 Achchuthan Shanmugasundram Gene: kcnq1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram commented on gene: KCNQ1: As reviewed by Suzanne Page, PMID:36077086 reports two unrelated cases with KCNQ1 variants in addition to the cases previously reported in PMID: 29097701 with pituitary hormone deficiency and maternally inherited gingival fibromatosis. The single individual reported in PMID:36077086 with p.Pro369Leu variant had growth hormone deficiency and postnatal growth retardation in addition to coarse facial features and early-onset gingival overgrowth. However, three members of the other family with p.Val185Met variant had only coarse facial features and early-onset gingival overgrowth.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36077086; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Deleted their review
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously reported variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously identified variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the NHSE.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 that this gene has insufficient evidence for promotion to green rating.

There is an additional case reported with a previously reported variant (p.Pro369Leu) and growth hormone deficiency. Hence, I am tagging this gene for expert review by the NHSE to assess whether this evidence is sufficient for promotion to green rating.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the GLHs.; to: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the NHSE.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Classified gene: KCNQ1 as Amber List (moderate evidence)
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene was previously demoted from green to amber after being discussed and agreed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019 to have insufficient evidence for promotion to green rating. Hence, I am tagging this gene for expert review by the GLHs.
Pituitary hormone deficiency v3.7 KCNQ1 Achchuthan Shanmugasundram Gene: kcnq1 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v3.6 KCNQ1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNQ1.
Tag Q1_24_expert_review tag was added to gene: KCNQ1.
Pituitary hormone deficiency v3.6 KCNQ1 Achchuthan Shanmugasundram Mode of inheritance for gene: KCNQ1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pituitary hormone deficiency v3.5 KCNQ1 Achchuthan Shanmugasundram reviewed gene: KCNQ1: 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: 36077086; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh reviewed gene: SLC26A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh Classified gene: SLC26A1 as Red List (low evidence)
Nephrocalcinosis or nephrolithiasis v4.13 SLC26A1 Sarah Leigh Gene: slc26a1 has been classified as Red List (Low Evidence).
Nephrocalcinosis or nephrolithiasis v4.12 SLC26A1 Sarah Leigh Publications for gene: SLC26A1 were set to 27210743; 20160351; 30383413; 27125215; 24250268
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Tag Q1_24_expert_review tag was added to gene: RASGRP2.
Osteopetrosis v1.34 RASGRP2 Sarah Leigh reviewed gene: RASGRP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: RASGRP2.
Osteopetrosis v1.34 RASGRP2 Sarah Leigh Publications for gene: RASGRP2 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 SIRT1 Hannah Knight gene: SIRT1 was added
gene: SIRT1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIRT1 were set to PMID: 23473037
Phenotypes for gene: SIRT1 were set to Type 1 diabetes; autoimmune disease
Review for gene: SIRT1 was set to RED
Added comment: In PMID: 36634696 (2023) as one of the genes associated with monogenic IBD.
Just one previous report of it causing disease?
PMID: 23473037 (2013) - five individuals in one family found to have a missense SIRT1 variant (p.L107P). Four presented with type 1 diabetes, and one with ulcerative colitis
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 SCGN Hannah Knight gene: SCGN was added
gene: SCGN was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: SCGN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCGN were set to PMID: 31663849
Phenotypes for gene: SCGN were set to ?early-onset ulcerative colitis
Review for gene: SCGN was set to RED
Added comment: Not linked to a phenotype in OMIM.
PMID: 31663849 (2019) reported three siblings with early onset UC, all with a homozygous missense variant in SCGN (p.Arg77His). Parents were both heterozygous. Some functional work done
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LACC1 Hannah Knight gene: LACC1 was added
gene: LACC1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LACC1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LACC1 were set to Juvenile arthritis
Review for gene: LACC1 was set to GREEN
Added comment: PMID: 25220867 (2015) - in 13 patients and unaffected members of 5 consanguineous Saudi Arabian families with systemic juvenile idiopathic arthritis, a homozygous missense variant in LACC1 was identified (p.C284R). This segregated fully with disease, and haplotype analysis was consistent with a common founder for the 5 families. Systemic features were present including organomegaly, fevers and rashes
PMID: 27881174 (2016) - 2 Lebanese sisters with juvenile arthritis found to have a homozygous 1bp deletion in LACC1 (c.827delC). Present in heterozygosity in their unaffected consanguineous parents, but was not found in 2 unaffected sibs or in the ExAC database
PMID: 29717096 (2018) identified three different families with homozygous LACC1 variants (p.M1I, p.R414X, p.Ile330del)
PMID: 30872671 (2019) - three affected siblings with a homozygous variant (p.Cys43TyrfsTer6)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 HSPA1L Hannah Knight gene: HSPA1L was added
gene: HSPA1L was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: HSPA1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPA1L were set to PMID: 28126021
Phenotypes for gene: HSPA1L were set to Inflammatory bowel disease
Review for gene: HSPA1L was set to AMBER
Added comment: PMID: 28126021 (2017) identified a heterozygous de novo variant (c.830C > T; p.Ser277Leu) in HSPA1L in a patient with IBD + some in vitro testing which supported pathogenicity
Then identified five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients from their IBD cohort
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 CARD8 Hannah Knight gene: CARD8 was added
gene: CARD8 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: CARD8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CARD8 were set to PMID: 29408806
Phenotypes for gene: CARD8 were set to ?Inflammatory bowel disease (Crohn disease) 30
Review for gene: CARD8 was set to AMBER
Added comment: On OMIM as ?association.
PMID: 29408806 (2018) identified a heterozygous missense CARD8 variant (V44I) in a boy, his mother, and his maternal aunt with Crohn disease. Not found in the proband's unaffected father. Functional analysis suggested a dominant-negative effect.

PMID: 37724393 (2023) identified a CARD8 VUS in a paediatric patient with IBD and arthritis. Can't see full paper however
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 ANKZF1 Hannah Knight gene: ANKZF1 was added
gene: ANKZF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ANKZF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589
Phenotypes for gene: ANKZF1 were set to Inflammatory bowel disease
Review for gene: ANKZF1 was set to AMBER
Added comment: PMID: 28302725 (2017) identified two infantile-onset IBD patients with biallelic ANKZF1 variants + some functional work:
One homozygous for R585Q - although this variant is very common in gnomAD
One compound heterozygous for E152K and V32_Q87del
Also two patients with one heterozygous variants

PMID: 36857589 (2023) also identified a de novo variant (p.Leu415Val) in a young patient with IBD
Sources: Literature
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Deleted their comment
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh commented on gene: MADD: Apnoea is a feature of DEEAH syndrome (OMIM:619004) and Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia (OMIM:619005), both of which are caused by biallelic MADD variants (PMID: 32761064).
Possible mitochondrial disorder - nuclear genes v3.87 BTD Mohamed Nassr commented on gene: BTD
Intellectual disability - microarray and sequencing v5.451 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
Early onset or syndromic epilepsy v4.164 MADD Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562
Intellectual disability - microarray and sequencing v5.450 DHX37 Sarah Leigh changed review comment from: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.; to: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variants have not been associated with intellectual disability.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh edited their review of gene: EFEMP1: Added comment: Monoallelic EFEMP1 variants have been associated with Doyne honeycomb degeneration of retina (OMIM:126600). PMIDs 31792352; 32006683; 33807164 report four recessive EFEMP1 variants in three cases with a pronounced connective tissue disorder. PMID: 31792352 also describes a Efemp1 knockout mouse model, with a phenotype that matches the human cases.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: EFEMP1.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Classified gene: EFEMP1 as Amber List (moderate evidence)
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ehlers Danlos syndrome with a likely monogenic cause v3.11 EFEMP1 Sarah Leigh Gene: efemp1 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndrome with a likely monogenic cause v3.10 EFEMP1 Sarah Leigh Publications for gene: EFEMP1 were set to 32006683; 31792352
Growth failure in early childhood v3.6 MSTO1 Suzanne Page changed review comment from: The associated claims regarding the presence of MSTO1 mutation c.22 G > A (p.Val8Met) in the investigated patients and the direct link between this mutation and patients' myopathy and ataxia phenotypes are retracted.; to: The mode of inheritance for this disorder should be changed to Biallelic. The only reported case of autosomal dominant inheritance (PMID 37431817) has been redacted. "The associated claims regarding the presence of MSTO1 mutation c.22 G > A (p.Val8Met) in the investigated patients and the direct link between this mutation and patients' myopathy and ataxia phenotypes are retracted."
Growth failure in early childhood v3.6 MSTO1 Suzanne Page reviewed gene: MSTO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37431817; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Pituitary hormone deficiency v3.5 KCNQ1 Suzanne Page changed review comment from: Bauer et al 2022 PMID: 36077086 - Identified a single individual with the KCNQ1 variant P369L and three family members with the V185M variant. All had gingival overgrowth. Tommiska et al 2017 (PMID: 29097701) have already identified 3 families affected with pituitary hormone deficiency and maternally inherited gingival fibromatosis. Bauer et al showed that all 3 variants impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component.; to: Bauer et al 2022 PMID: 36077086 - Identified a single individual with the KCNQ1 variant P369L and three family members with the V185M variant. All had gingival overgrowth. Tommiska et al 2017 (PMID: 29097701) have already identified 3 families affected with pituitary hormone deficiency and maternally inherited gingival fibromatosis. Bauer et al showed that all 3 variants impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. They suggest that the impaired Ca2+ sensitivity of the KCNQ1 mutant channels R116L, V185M and P369L is causally related to their gain-of-function when forming heteromers with KCNE2.
Pituitary hormone deficiency v3.5 KCNQ1 Suzanne Page reviewed gene: KCNQ1: 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: 36077086; Phenotypes: Gingival overgrowth, with or without postnatal growth retardation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.163 SLC5A6 Helen Lord edited their review of gene: SLC5A6: Added comment: PMID 35013551 Holling et al, 2022 - reporting 5 individuals from 3 families with motor neuropathies. Hom variant c.1285A>G p.(Ser429Gly) in 3 aff siblings and a simplex patient; and a third family where proband had a mat inherited c.280C>T p.(Arg94*) and a pat inherited c.485A>G p.(Tyr162Cys). in silico tools suggest missense variants affect function. No mention of epilepsy in any of these individuals.

PMID 38036278 Hsieh et al 2023 - Family with compound het SLC5A6 missense variants reported. No mention of epilepsy in affected individuals.

PMID 38012394 Utsuno et al 2024 - 3 sibs from a Japanese family with periventricular brain cysts and motor developmental delay - all compund het for SLC5A6 missense variants - no mention of epilepsy/seizure in any of these sibs.

PMID 37391029 Montomoli et al 2023 - 3 members of the same family - Patient 2 had a generalised tonic-clonic seizre and EEG showed sharp waves in left centro-temporal region. No mention of seizures at follow up at 24 years of age, and no mention prior to this seizure but lots of other clinical features. All affecteds had a hom fs SLC5A6 variant, parents het. Table summarising cases showed epilepsy in 2/13 case - patient 2 in this paper and the Byrne et al paper.

PMID 31754459 Byrne et al - see review 31/01/2021.

No new evidence to support a stronger link with SLC5A6 and an epilepsy phenotype.; Changed publications to: 35013551, 38036278, 38012394, 37391029, 31754459, 27904971
Early onset or syndromic epilepsy v4.163 CACNB4 Helen Lord edited their review of gene: CACNB4: Added comment: PMID 35813387 - Naseer et al, 2022: WES i one family and targeted sequencing of SCN1A and CACNB4 in 25 sporadic epilepsy patients. 3 different unrelated patients found to have the c.78_79insG variant in CACNB4. Do mention that tecently het CACNB4 mutations are not linked with epilepsy [Heyne et al 2019] and that het mutated animal model did not show any tyoe of deformities [Coba et al, 2012].

Also PMID32176688 - see previous occurence where identifed homozygously.; Changed rating: AMBER; Changed publications to: 35813387
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 STAT4 Hannah Knight reviewed gene: STAT4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37256972; Phenotypes: Disabling pansclerotic morphea of childhood; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from None to None
Intellectual disability - microarray and sequencing v5.450 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from Other to None
Intellectual disability - microarray and sequencing v5.449 ABCC9 Tracy Lester edited their review of gene: ABCC9: Added comment: This gene is currently green for monoallelic inheritance but the associated review relates to cases with biallelic inheritance. The MOI for this gene should be amended to biallelic only. Monoallelic variants are associated with Cantu syndrome which is not primarily an ID disorder or DCM.; Changed rating: GREEN
Intellectual disability - microarray and sequencing v5.449 DHX37 Sarah Leigh Tag Q1_24_MOI tag was added to gene: DHX37.
Tag Q1_24_NHS_review tag was added to gene: DHX37.
Intellectual disability - microarray and sequencing v5.449 DHX37 Sarah Leigh Added comment: Comment on mode of inheritance: The mode of inheritance for DHX37 on the Intellectual disability panel should be biallelic as monoallelic variant have not been associated with intellectual disability.
Intellectual disability - microarray and sequencing v5.449 DHX37 Sarah Leigh Mode of inheritance for gene: DHX37 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.448 DHX37 Sarah Leigh edited their review of gene: DHX37: Added comment: Biallelic DHX37 variants have been associated with Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies (OMIM:618731). Five DHX37 variants have been reported in three unrelated cases of OMIM:618731. Zebra fish models, support the role of DHX37 variants in aberrant behaviors (PMID: 24027265); Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.448 ABCC9 Sarah Leigh Added comment: Comment on mode of pathogenicity: Loss of function variants do cause the phenotype of Intellectual disability and myopathy syndrome (OMIM:619719) , which is relevant to this panel.
Intellectual disability - microarray and sequencing v5.448 ABCC9 Sarah Leigh Mode of pathogenicity for gene: ABCC9 was changed from to Other
Intellectual disability - microarray and sequencing v5.447 DHX37 Sarah Leigh Publications for gene: DHX37 were set to 26539891; 31256877
Intellectual disability - microarray and sequencing v5.446 ABCC9 Sarah Leigh Tag watchlist_moi was removed from gene: ABCC9.
Tag Q1_24_MOI tag was added to gene: ABCC9.
Tag Q1_24_NHS_review tag was added to gene: ABCC9.
Intellectual disability - microarray and sequencing v5.446 ABCC9 Sarah Leigh Phenotypes for gene: ABCC9 were changed from Cardiomyopathy, dilated, 10, 608569; Atrial fibrillation, familial, 12, 614050; Hypertrichotic osteochondrodysplasia, 239850; CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA to Intellectual disability and myopathy syndrome, OMIM:619719; intellectual disability and myopathy syndrome, MONDO:0859224
Intellectual disability - microarray and sequencing v5.445 ABCC9 Sarah Leigh changed review comment from: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872).; to: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872). Heterozygous parents of the cases, did not show a consistent phenotype, although intrauterine death was reported in two families (PMID: 38217872). In family 4 the fetus was homozygous for c.1858C>T, p.(Arg620Ter) and in family 8 the parents were both heterozygous for c.2140_2141del, p.(Leu714SerfsTer7), but analysis of the fetus was not possible.
Intellectual disability - microarray and sequencing v5.445 ABCC9 Sarah Leigh reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: 38217872; Phenotypes: Intellectual disability and myopathy syndrome, OMIM:619719, intellectual disability and myopathy syndrome, MONDO:0859224; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.445 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858; 38217872
Intellectual disability - microarray and sequencing v5.444 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858
Intellectual disability - microarray and sequencing v5.443 ABCC9 Sarah Leigh Publications for gene: ABCC9 were set to
Early onset or syndromic epilepsy v4.163 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Intellectual disability - microarray and sequencing v5.442 MADD Sarah Leigh edited their review of gene: MADD: Added comment: Comments from Karen Stals (Royal Devon and Exeter Hospital), 4 Dec 2023: Apnoea a presenting feature in 13/14 patients with MADD-related disorder with biallelic MADD variants in Schneeberger et al 2020 PMID: 32761064. Identified biallelic variants in this gene in a patient with a consistent phenotype.; Changed rating: GREEN; Changed publications to: 32761064
Paediatric or syndromic cardiomyopathy v3.43 CASZ1 Ludmila Volozonoka gene: CASZ1 was added
gene: CASZ1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 36293425; 31268246; 28099117; 27693370; 37509718
Phenotypes for gene: CASZ1 were set to Pediatric Dilated Cardiomyopathy; Pediatric LVNC
Review for gene: CASZ1 was set to GREEN
Added comment: Loss of Function variants described in patients with pediatric dilated cardiomyopathy, pediatric LVNC (36293425; 31268246). Our laboratory identified the LOF variant in a pediatric patient with LVNC.

The limited implication in congenital ventricular septal defect (27693370) - authors identified a missense variant.

Review article on CASZ1 (37509718).
Sources: Literature
Left Ventricular Noncompaction Cardiomyopathy v1.4 CASZ1 Ludmila Volozonoka gene: CASZ1 was added
gene: CASZ1 was added to Left Ventricular Noncompaction Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 36293425; 31268246; 28099117; 27693370; 37509718
Phenotypes for gene: CASZ1 were set to Pediatric Cardiomyopathy; Pediatric LVNC
Review for gene: CASZ1 was set to GREEN
Added comment: Loss of Function variants described in patients with pediatric dilated cardiomyopathy, pediatric LVNC (36293425; 31268246), as well as in adults (28099117).
The limited implication in congenital ventricular septal defect (27693370) - authors identified a missense variant.
Review article on CASZ1 (37509718).
Our laboratory identified LOF variant in a pediatric patient with LVNC.
Sources: Literature
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Classified gene: UBAP1L as Amber List (moderate evidence)
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Hannah Knight, there are five unrelated cases with four different UBAP1L variants reported with either Rod-cone dystrophy, cone-rod dystrophy or retinitis pigmentosa. Hence, this gene should be promoted to green rating in the next GMS review.
Retinal disorders v4.63 UBAP1L Achchuthan Shanmugasundram Gene: ubap1l has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.62 UBAP1L Achchuthan Shanmugasundram Phenotypes for gene: UBAP1L were changed from Retinitis pigmentosa to Rod-cone dystrophy, HP:0000510; cone-rod dystrophy, MONDO:0015993; retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.61 UBAP1L Achchuthan Shanmugasundram Publications for gene: UBAP1L were set to 28041643
Retinal disorders v4.60 UBAP1L Achchuthan Shanmugasundram Mode of inheritance for gene: UBAP1L was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: UBAP1L.
Tag Q1_24_NHS_review tag was added to gene: UBAP1L.
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram edited their review of gene: UBAP1L: Changed phenotypes to: Rod-cone dystrophy, HP:0000510, cone-rod dystrophy, MONDO:0015993, retinitis pigmentosa, MONDO:0019200
Retinal disorders v4.59 UBAP1L Achchuthan Shanmugasundram reviewed gene: UBAP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rod-cone dystrophy, HP:0000510, cone-rod dystrophy, MONDO:0015993; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.59 RAX2 Achchuthan Shanmugasundram Publications for gene: RAX2 were set to
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.; to: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available for the association of biallelic RAX2 variants with retinitis pigmentosa. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Retinal disorders v4.58 RAX2 Achchuthan Shanmugasundram Mode of inheritance for gene: RAX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Retinal disorders v4.57 RAX2 Achchuthan Shanmugasundram Phenotypes for gene: RAX2 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Macular Degeneration; Eye Disorders; Cone-Rod Dystrophy, Dominant; Cone-rod dystrophy 11 to Cone-rod dystrophy 11, OMIM:610381; Retinitis pigmentosa 95, OMIM:620102; ?Macular degeneration, age-related, 6, OMIM:613757
Retinal disorders v4.56 RAX2 Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: RAX2.
Retinal disorders v4.56 RAX2 Achchuthan Shanmugasundram reviewed gene: RAX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30377383, 30607024; Phenotypes: Cone-rod dystrophy 11, OMIM:610381, Retinitis pigmentosa 95, OMIM:620102, ?Macular degeneration, age-related, 6, OMIM:613757; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.442 KIRREL3 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: KIRREL3.
Intellectual disability - microarray and sequencing v5.442 KIRREL3 Sarah Leigh Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947
Intellectual disability - microarray and sequencing v5.441 KIRREL3 Sarah Leigh changed review comment from: At least 15 missense KIRREL3 variants have been reported in 17 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 19012874; 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, lists KIRREL3 variants and demonstrates that the variants maybe either de novo (9/16) or inherited from one of the parents (7/9). (PMID: 37605258). The KIRREL3 variants are either absent from control databases or are present at a very low frequency.; to: At least 12 missense KIRREL3 variants have been reported in 12 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, reviews KIRREL3 variants and demonstrates that the variants maybe either de novo (4/11) or inherited from one of the parents (7/11)(mode of inheritance was unknown for one of the variants). The KIRREL3 variants are either absent from controls or are present at a very low frequency. However, the three variants reported in PMID: 19012874, were shown to be present in publicly databases at a high frequency (see KIRREL3 OMIM entry).
Intellectual disability - microarray and sequencing v5.441 KIRREL3 Sarah Leigh Classified gene: KIRREL3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.441 KIRREL3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability - microarray and sequencing v5.441 KIRREL3 Sarah Leigh Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.440 KIRREL3 Sarah Leigh reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 29271092; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.440 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092; 37605258
Intellectual disability - microarray and sequencing v5.439 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092:37605258
Intellectual disability - microarray and sequencing v5.438 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 37605258
Intellectual disability - microarray and sequencing v5.437 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 33853164; 37605258
Intellectual disability - microarray and sequencing v5.436 KIRREL3 Sarah Leigh Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164
Intellectual disability - microarray and sequencing v5.435 KIRREL3 Sarah Leigh Mode of inheritance for gene: KIRREL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Tag Q1_24_promote_green tag was added to gene: LMNA.
Tag Q1_24_NHS_review tag was added to gene: LMNA.
Pigmentary skin disorders v3.10 LMNA Sarah Leigh edited their review of gene: LMNA: Added comment: LMNA variants have been associated with various conditions, including Hutchinson-Gilford progeria (OMIM:176670) and Mandibuloacral dysplasia (OMIM:248370). Skin mottling has been reported in both of these conditions, and hyper and hypopigmentation is a feature of Mandibuloacral dysplasia (OMIM:248370). Numerous LMNA variants have been reported in these conditions.; Changed rating: GREEN
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Classified gene: LMNA as Amber List (moderate evidence)
Pigmentary skin disorders v3.10 LMNA Sarah Leigh Gene: lmna has been classified as Amber List (Moderate Evidence).
Pigmentary skin disorders v3.9 LMNA Sarah Leigh Added comment: Comment on mode of inheritance: Hutchinson-Gilford progeria, OMIM:176670 is monoallelic, Mandibuloacral dysplasia, OMIM:248370 is biallelic
Pigmentary skin disorders v3.9 LMNA Sarah Leigh Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pigmentary skin disorders v3.8 LMNA Sarah Leigh Phenotypes for gene: LMNA were changed from Hutchinson-Gilford progeria syndrome (HGPS) (MIM 176670); Mandibuloacral dysplasia with type A lipodystrophy (MADA) to Hutchinson-Gilford progeria, OMIM:176670; Hutchinson-Gilford progeria syndrome, MONDO:0008310; Mandibuloacral dysplasia, OMIM:248370; mandibuloacral dysplasia with type A lipodystrophy MONDO:0009557
Pigmentary skin disorders v3.7 LMNA Sarah Leigh Publications for gene: LMNA were set to PMID: 12714972; https://www.ncbi.nlm.nih.gov/books/NBK1121/#; 12075506; 17848409
Retinal disorders v4.56 UBAP1L Hannah Knight reviewed gene: UBAP1L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38293907, PMID: 28041643; Phenotypes: Rod-cone dystrophy, cone-rod dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 LCP2 Hannah Knight reviewed gene: LCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 37211057, PMID: 36474126; Phenotypes: ?Immunodeficiency 81; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v3.24 PHYH Sarah Leigh Phenotypes for gene: PHYH were changed from Refsum disease to Refsum disease, OMIM:266500
Palmoplantar keratodermas v3.23 PHYH Sarah Leigh reviewed gene: PHYH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Palmoplantar keratodermas v3.23 PHYH Sarah Leigh Tag Q1_24_demote_red tag was added to gene: PHYH.
Tag Q1_24_expert_review tag was added to gene: PHYH.
Palmoplantar keratodermas v3.23 SLC27A4 Sarah Leigh Tag Q1_24_expert_review tag was added to gene: SLC27A4.
Palmoplantar keratodermas v3.23 SLC27A4 Sarah Leigh Phenotypes for gene: SLC27A4 were changed from Ichthyosis prematurity syndrome to Ichthyosis prematurity syndrome, OMIM:608649
Palmoplantar keratodermas v3.22 SLC27A4 Sarah Leigh Tag Q1_24_demote_red tag was added to gene: SLC27A4.
Palmoplantar keratodermas v3.22 SLC27A4 Sarah Leigh reviewed gene: SLC27A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Classified gene: POPDC3 as Amber List (moderate evidence)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.30 POPDC3 Sarah Leigh Gene: popdc3 has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh Tag watchlist was removed from gene: POPDC3.
Tag Q1_24_promote_green tag was added to gene: POPDC3.
Tag Q1_24_NHS_review tag was added to gene: POPDC3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh reviewed gene: POPDC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.29 POPDC3 Sarah Leigh Phenotypes for gene: POPDC3 were changed from Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848 to Muscular dystrophy, limb-girdle, autosomal recessive 26, OMIM:618848; muscular dystrophy, limb-girdle, autosomal recessive 26, MONDO:0030014
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v4.28 POPDC3 Sarah Leigh Publications for gene: POPDC3 were set to 31610034
Likely inborn error of metabolism - targeted testing not possible v4.129 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 27604308
Undiagnosed metabolic disorders v1.613 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 27604308
Congenital disorders of glycosylation v4.18 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to 18455129; 18452889; 26864433; 27148795
Intellectual disability - microarray and sequencing v5.434 TUSC3 Arina Puzriakova Publications for gene: TUSC3 were set to
Likely inborn error of metabolism - targeted testing not possible v4.128 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from TUSC3-CDG (Disorders of protein N-glycosylation); Mental retardation, autosomal recessive 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Fetal anomalies v3.133 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Undiagnosed metabolic disorders v1.612 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from TUSC3-CDG (Disorders of protein N-glycosylation); Mental retardation, autosomal recessive 7 to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Congenital disorders of glycosylation v4.17 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7 611093; TUSC3-CDG (Disorders of protein N-glycosylation) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Intellectual disability - microarray and sequencing v5.433 TUSC3 Arina Puzriakova Phenotypes for gene: TUSC3 were changed from Mental retardation, autosomal recessive 7, 611093; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 7 (MRT7) to Intellectual developmental disorder, autosomal recessive 7, OMIM:611093
Intellectual disability - microarray and sequencing v5.432 CC2D1A Arina Puzriakova Publications for gene: CC2D1A were set to
Retinal disorders v4.56 LRRC32 Hannah Knight gene: LRRC32 was added
gene: LRRC32 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to PMID: 30976112; PMID: 35656379
Phenotypes for gene: LRRC32 were set to Cleft palate, proliferative retinopathy, and developmental delay
Review for gene: LRRC32 was set to AMBER
Added comment: PMID: 30976112 - homozygous founder variant (p.R544X) identified in two consanguineous families of Palestinian descent - sister and brother, and an unrelated boy. All with cleft palate, proliferative retinopathy, and developmental delay. Segregated with disease in both families.
PMID: 35656379 - rare homozygous missense in a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy
Sources: Literature
Intellectual disability - microarray and sequencing v5.431 CC2D1A Arina Puzriakova Phenotypes for gene: CC2D1A were changed from Mental retardation, autosomal recessive 3, 608443; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 (MRT3) to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443
Fetal anomalies v3.132 CC2D1A Arina Puzriakova Phenotypes for gene: CC2D1A were changed from MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 3 to Intellectual developmental disorder, autosomal recessive 3, OMIM:608443
White matter disorders and cerebral calcification - narrow panel v3.31 RARS Arina Puzriakova Publications for gene: RARS were set to 24777941; 27564080
Intellectual disability - microarray and sequencing v5.430 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941; 30500859
Intellectual disability - microarray and sequencing v5.429 LRRC32 Hannah Knight reviewed gene: LRRC32: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 35656379; Phenotypes: Cleft palate, proliferative retinopathy, and developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.179 RARS Arina Puzriakova Publications for gene: RARS were set to 24777941; 27564080
Early onset or syndromic epilepsy v4.163 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Inherited white matter disorders v1.178 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
White matter disorders and cerebral calcification - narrow panel v3.30 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Leukodystrophy, hypomyelinating, 9 616140 to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Intellectual disability - microarray and sequencing v5.429 RARS Arina Puzriakova Phenotypes for gene: RARS were changed from Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties to Leukodystrophy, hypomyelinating, 9, OMIM:616140
Intellectual disability - microarray and sequencing v5.428 ASPM Arina Puzriakova Publications for gene: ASPM were set to
Severe microcephaly v4.59 ASPM Arina Puzriakova Publications for gene: ASPM were set to
Malformations of cortical development v4.23 ASPM Arina Puzriakova Publications for gene: ASPM were set to 12355089
Fetal anomalies v3.131 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from PRIMARY AUTOSOMAL RECESSIVE MICROCEPHALY to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Intellectual disability - microarray and sequencing v5.427 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive, 608716; PRIMARY AUTOSOMAL RECESSIVE MICROCEPHALY to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Severe microcephaly v4.58 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive; MCPH; primary microcephaly; Primary Microcephaly, Recessive; Autosomal recessive primary microcephaly (MCPH) ; Microcephaly 5, primary, autosomal recessive, 608716; Microcephaly 5, Primary, Autosomal Recessive to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Malformations of cortical development v4.22 ASPM Arina Puzriakova Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive 608716 to Microcephaly 5, primary, autosomal recessive, OMIM:608716
Intellectual disability - microarray and sequencing v5.426 RARS Arina Puzriakova Publications for gene: RARS were set to 31814314; 28905880; 24777941
Malformations of cortical development v4.21 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Early onset or syndromic epilepsy v4.162 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to 21834044; 20890278; 20729831; 28377545
Severe microcephaly v4.57 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Intellectual disability - microarray and sequencing v5.425 WDR62 Arina Puzriakova Publications for gene: WDR62 were set to
Intellectual disability - microarray and sequencing v5.424 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly, Cortical Malformations, and Mental Retardation; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; MICROCEPHALY CORTICAL MALFORMATIONS AND MENTAL RETARDATION (MCMMR) to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Early onset or syndromic epilepsy v4.161 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Severe microcephaly v4.56 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from MCPH; primary microcephaly; Primary Microcephaly 2 With or Without Cortical Malformations; Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, 604317; microcephaly cortical malformations and mental retardation (MCMMR), 604317; Microcephaly 2, Primary, Autosomal Recessive, With Or Without Cortical Malformations to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Malformations of cortical development v4.20 WDR62 Arina Puzriakova Phenotypes for gene: WDR62 were changed from Microcephaly 2, primary, autosomal recessive, with or without cortical malformations 604317 to Microcephaly 2, primary, autosomal recessive, with or without cortical malformations, OMIM:604317
Intellectual disability - microarray and sequencing v5.423 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
Severe microcephaly v4.55 MCPH1 Arina Puzriakova Publications for gene: MCPH1 were set to
Intellectual disability - microarray and sequencing v5.422 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from genetic heterogeneity Microcephaly 1, primary, autosomal recessive, 251200; MICROCEPHALY PRIMARY TYPE 1 (MCPH1) to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Severe microcephaly v4.54 MCPH1 Arina Puzriakova Phenotypes for gene: MCPH1 were changed from MCPH; primary microcephaly; Primary Microcephaly, Recessive; Microcephaly 1, primary, autosomal recessive, 251200; Microcephaly 1, Primary, Autosomal Recessive to Microcephaly 1, primary, autosomal recessive, OMIM:251200
Early onset or syndromic epilepsy v4.160 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - seizures can be a reported feature of HSD10 disease (PMID: 12872843; 22132097; 26950678; 27295195; 34765396)
Early onset or syndromic epilepsy v4.159 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v4.19 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - optic nerve atrophy with visual loss can be a reported feature of HSD10 disease (PMIDs: 22132097; 26950678; 27295195)
Optic neuropathy v4.18 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.71 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova changed review comment from: 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 - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490); to: 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 - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 27295195; 31654490)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Classified gene: HSD17B10 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 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 - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Gene: hsd17b10 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.69 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: HSD17B10.
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: None; Publications: 19706438, 22132097, 12696021, 26950678, 27604308, 12872843, 12555940; Phenotypes: HSD10 mitochondrial disease, OMIM:300438; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Optic neuropathy v4.17 HSD17B10 Arina Puzriakova gene: HSD17B10 was added
gene: HSD17B10 was added to Optic neuropathy. Sources: Literature
Q1_24_promote_green tags were added to gene: HSD17B10.
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, OMIM:300438
Review for gene: HSD17B10 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for intellectual development disorder syndromic X-linked type 10. Multiple unrelated individuals (at least 8 variants) with supportive functional studies reported in the literature, including some affected female carriers presenting with mild to moderate developmental delay or intellectual disability.
Phenotype in severely affected males comprises developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation.
Sources: Literature
Early onset or syndromic epilepsy v4.158 HSD17B10 Arina Puzriakova gene: HSD17B10 was added
gene: HSD17B10 was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: HSD17B10.
Mode of inheritance for gene: HSD17B10 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308; 12872843; 12555940
Phenotypes for gene: HSD17B10 were set to HSD10 mitochondrial disease, OMIM:300438
Review for gene: HSD17B10 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for 2-methyl-3-hydroxybutyrylL-coA dehydrogenase deficiency and for intellectual development disorder syndromic X-linked type 10. Multiple unrelated individuals (at least 8 variants) with supportive functional studies reported in the literature, including some affected female carriers presenting with mild to moderate developmental delay or intellectual disability.
Phenotype in severely affected males comprises developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.127 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to 19706438; 22132097; 12696021; 26950678; 27604308
Intellectual disability - microarray and sequencing v5.421 HSD17B10 Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'XL, biallelic in females' to 'XL, monoallelic in females' as female patients harbouring heterozygous variants have been described. Some carrier females shown to have mild to moderate developmental delay or intellectual disability (PMIDs: 12112118; 16148061; 22127393; 34765396)
Intellectual disability - microarray and sequencing v5.421 HSD17B10 Arina Puzriakova Mode of inheritance for gene: HSD17B10 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.420 HSD17B10 Arina Puzriakova Tag Q1_24_MOI tag was added to gene: HSD17B10.
Childhood onset dystonia, chorea or related movement disorder v3.68 HSD17B10 Arina Puzriakova Mode of inheritance for gene: HSD17B10 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.420 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Possible mitochondrial disorder - nuclear genes v3.87 HSD17B10 Arina Puzriakova Publications for gene: HSD17B10 were set to
Mitochondrial disorders v4.157 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Intellectual disability - microarray and sequencing v5.419 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from 17-beta-hydroxysteroid dehydrogenase X deficiency, 300438Mental retardation, X-linked syndromic 10, 300220Mental retardation, X-linked 17/31, microduplication, 300705; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE DEFICIENCY (MHBD DEFICIENCY) to HSD10 mitochondrial disease, OMIM:300438
Childhood onset dystonia, chorea or related movement disorder v3.67 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from to HSD10 mitochondrial disease, OMIM:300438
Likely inborn error of metabolism - targeted testing not possible v4.126 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Possible mitochondrial disorder - nuclear genes v3.86 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease, 300438 to HSD10 mitochondrial disease, OMIM:300438
Undiagnosed metabolic disorders v1.611 HSD17B10 Arina Puzriakova Phenotypes for gene: HSD17B10 were changed from HSD10 mitochondrial disease 300438 to HSD10 mitochondrial disease, OMIM:300438
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Classified gene: COL4A3BP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Early onset or syndromic epilepsy v4.157 COL4A3BP Arina Puzriakova Gene: col4a3bp has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova commented on gene: COL4A3BP: Added new-gene-name tag, new approved HGNC gene symbol for COL4A3BP is CERT1
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova Tag new-gene-name tag was added to gene: COL4A3BP.
Early onset or syndromic epilepsy v4.156 COL4A3BP Arina Puzriakova gene: COL4A3BP was added
gene: COL4A3BP was added to Early onset or syndromic epilepsy. Sources: Literature
Q1_24_promote_green tags were added to gene: COL4A3BP.
Mode of inheritance for gene: COL4A3BP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Phenotypes for gene: COL4A3BP were set to Intellectual developmental disorder, autosomal dominant 34, OMIM:616351
Review for gene: COL4A3BP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and in Gene2Phenotype (definitive disease confidence category for CERT1-related INTELLECTUAL DISABILITY)

At least 35 cases have been reported in literature with heterozygous variants. Seizures were observed in at least 19 individuals.
Sources: Literature
Intellectual disability - microarray and sequencing v5.418 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Intellectual disability - microarray and sequencing v5.417 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465; 34688657; 36976648; 37892645
Intellectual disability - microarray and sequencing v5.417 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962; 33347465
Intellectual disability - microarray and sequencing v5.416 COL4A3BP Arina Puzriakova Phenotypes for gene: COL4A3BP were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder, autosomal dominant 34, OMIM:616351
Intellectual disability - microarray and sequencing v5.415 COL4A3BP Arina Puzriakova Publications for gene: COL4A3BP were set to 25533962
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines. ; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign). Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore reviewed gene: PLD1: Rating: RED; Mode of pathogenicity: Other; Publications: PMIDs: 27799408 and 33645542; Phenotypes: Paediatric cardiomyopathy, cardiac valvular defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy or pain disorder v3.82 GAN Tracy Lester reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301315; Phenotypes: neuropathy, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.414 GAN Tracy Lester reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301315; Phenotypes: Intellectual disability, developmental delay, neuropathy, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 AMFR Boaz Palterer gene: AMFR was added
gene: AMFR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: AMFR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AMFR were set to 38277122
Phenotypes for gene: AMFR were set to Severe VZV; Varicella; HLH; Hemophagocytic lymphohistyocytosis
Penetrance for gene: AMFR were set to Incomplete
Review for gene: AMFR was set to RED
Added comment: 1 patient from one kindred with severe disseminated VZV and HLH, incomplete penetrance as mother and siblings are not affected. Extensive functional ex-vivo and in-vitro data.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Classified gene: GSTZ1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:27876694 and reviewed by Saikat Santra, there are three boys and three girls with maleylacetoacetate isomerase deficiency (MAAID), identified by newborn screening with mildly elevated succinylacetone (SA) by mass spectrometry on dried blood spot.

Four of them were identified with homozygous GSTZ1 variants, one with compound heterozygous variants and one with heterozygous variant.

Hence, there is sufficient evidence available for the association of biallelic GSTZ1 variants with MAAID and this gene can be promoted to green rating in the next GMS review.
Likely inborn error of metabolism - targeted testing not possible v4.125 GSTZ1 Achchuthan Shanmugasundram Gene: gstz1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.124 GSTZ1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with maleylacetoacetate isomerase deficiency in OMIM (MIM #617596), but not with any phenotypes in Gene2Phenotype.
Likely inborn error of metabolism - targeted testing not possible v4.124 GSTZ1 Achchuthan Shanmugasundram Phenotypes for gene: GSTZ1 were changed from Biochemical to [Maleylacetoacetate isomerase deficiency], OMIM:617596
Likely inborn error of metabolism - targeted testing not possible v4.123 GSTZ1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: GSTZ1.
Tag Q1_24_NHS_review tag was added to gene: GSTZ1.
Likely inborn error of metabolism - targeted testing not possible v4.123 GSTZ1 Achchuthan Shanmugasundram reviewed gene: GSTZ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: [Maleylacetoacetate isomerase deficiency], OMIM:617596; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Classified gene: KCNA3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:37964487 and reviewed by Gavin Ryan, epilepsy was present in eight of twelve patients for whom detailed clinical information was available. Hence, this gene can be promoted to green rating in this panel in the next GMS review.
Early onset or syndromic epilepsy v4.155 KCNA3 Achchuthan Shanmugasundram Gene: kcna3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.154 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Intellectual disability; Developmental Delay; Epilepsy to Neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027
Early onset or syndromic epilepsy v4.153 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to PMID: 37964487
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA3.
Tag Q1_24_NHS_review tag was added to gene: KCNA3.
Early onset or syndromic epilepsy v4.152 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, epilepsy, MONDO:0005027; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.414 KCNA3 Achchuthan Shanmugasundram Classified gene: KCNA3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.414 KCNA3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reported in PMID:37964487 and reviewed by Gavin Ryan, 12 patients had developmental delays, of which nine patients had mild, moderate or severe intellectual disability. Hence, this gene can be promoted to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.414 KCNA3 Achchuthan Shanmugasundram Gene: kcna3 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.413 KCNA3 Achchuthan Shanmugasundram Phenotypes for gene: KCNA3 were changed from Intellectual disability; Developmental Delay; Epilepsy to Neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.412 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to 37964487
Intellectual disability - microarray and sequencing v5.412 KCNA3 Achchuthan Shanmugasundram Publications for gene: KCNA3 were set to PMID: 37964487
Intellectual disability - microarray and sequencing v5.411 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_NHS_review tag was added to gene: KCNA3.
Intellectual disability - microarray and sequencing v5.411 KCNA3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: KCNA3.
Intellectual disability - microarray and sequencing v5.411 KCNA3 Achchuthan Shanmugasundram reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.82 HMBS Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (three unrelated families) for the association of biallelic HMBS variants with peripheral neuropathy. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Hereditary neuropathy or pain disorder v3.82 HMBS Achchuthan Shanmugasundram Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.81 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from AIP, Abdominal pain, psychosis, depression, seizures, axonal predominantly motor neuropathy; Porphyria, acute intermittent, 176000 to Porphyria, acute intermittent, OMIM:76000; Porphyria, acute intermittent, nonerythroid variant, OMIM:176000; Leukoencephalopathy, HP:0002352; hereditary peripheral neuropathy, MONDO:0020127
Hereditary neuropathy or pain disorder v3.80 HMBS Achchuthan Shanmugasundram edited their review of gene: HMBS: Changed phenotypes to: Porphyria, acute intermittent, OMIM:76000, Porphyria, acute intermittent, nonerythroid variant, OMIM:176000, Leukoencephalopathy, HP:0002352, hereditary peripheral neuropathy, MONDO:0020127
Hereditary neuropathy or pain disorder v3.80 HMBS Achchuthan Shanmugasundram Publications for gene: HMBS were set to
Hereditary neuropathy or pain disorder v3.79 HMBS Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: HMBS.
Hereditary neuropathy or pain disorder v3.79 HMBS Achchuthan Shanmugasundram reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Leukoencephalopathy, HP:0002352, hereditary peripheral neuropathy, MONDO:0020127; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.; to: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.54 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.53 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, HP:0002352; cerebellar ataxia, MONDO:0000437
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram edited their review of gene: HMBS: Changed phenotypes to: Leukoencephalopathy, HP:0002352, cerebellar ataxia, MONDO:0000437
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with spastic paraparesis. Hence, this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.38 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
Ataxia and cerebellar anomalies - narrow panel v4.52 HMBS Achchuthan Shanmugasundram gene: HMBS was added
gene: HMBS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 27558376; 34089223
Phenotypes for gene: HMBS were set to Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064
Review for gene: HMBS was set to GREEN
Added comment: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.38 HMBS Achchuthan Shanmugasundram gene: HMBS was added
gene: HMBS was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 27558376; 34089223
Phenotypes for gene: HMBS were set to Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064
Review for gene: HMBS was set to GREEN
Added comment: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Classified gene: HMBS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with white matter abnormalities. Hence, this gene can be promoted to green rating in the next GMS review.
White matter disorders and cerebral calcification - narrow panel v3.29 HMBS Achchuthan Shanmugasundram Gene: hmbs has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.28 HMBS Achchuthan Shanmugasundram Phenotypes for gene: HMBS were changed from to Leukoencephalopathy, HP:0002352
White matter disorders and cerebral calcification - narrow panel v3.27 HMBS Achchuthan Shanmugasundram Publications for gene: HMBS were set to 27558376, 27271711
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: HMBS.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene has been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene has been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram changed review comment from: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported three patients from two unrelated families with; to: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.
White matter disorders and cerebral calcification - narrow panel v3.26 HMBS Achchuthan Shanmugasundram reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Leukoencephalopathy, HP:0002352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.411 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram changed review comment from: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature; to: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotypes in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Classified gene: LGI3 as Amber List (moderate evidence)
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Arthrogryposis v5.22 LGI3 Achchuthan Shanmugasundram Gene: lgi3 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v5.21 LGI3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LGI3.
Arthrogryposis v5.21 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.

Distal deformities included knee, hip, and ankle contractures (4/14); contractures/deformities of fingers and feet (6/14); and other uncharacterized deformities (4/14). All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability.

Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.411 LGI3 Achchuthan Shanmugasundram Classified gene: LGI3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.411 LGI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (eight unrelated families and mouse model) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.411 LGI3 Achchuthan Shanmugasundram Gene: lgi3 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.410 LGI3 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LGI3.
Intellectual disability - microarray and sequencing v5.410 LGI3 Achchuthan Shanmugasundram gene: LGI3 was added
gene: LGI3 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: LGI3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LGI3 were set to 35948005
Phenotypes for gene: LGI3 were set to Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, OMIM:620007
Review for gene: LGI3 was set to GREEN
Added comment: PMID:35948005 reported sixteen individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. All of them exhibited a potentially clinically recognizable peripheral nerve hyperexcitability syndrome (PNHS) trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. All sixteen patients had global developmental delay and all thirteen tested patients had mild or moderate intellectual disability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons.

This gene has been associated with relevant phenotype in OMIM (MIM #620007), but not yet in Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v4.50 TP53 Sarah Leigh Classified gene: TP53 as Red List (low evidence)
Skeletal dysplasia v4.50 TP53 Sarah Leigh Gene: tp53 has been classified as Red List (Low Evidence).
Skeletal dysplasia v4.49 TP53 Sarah Leigh edited their review of gene: TP53: Added comment: This gene is rated as red, because the variants are somatic, occurring in the tumour.; Changed rating: RED
Skeletal dysplasia v4.49 TP53 Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
This gene is rated as red, because the variants are somatic, occurring in the tumour.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
Skeletal dysplasia v4.49 TP53 Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in
tumorigenesis, giving rise to the dedifferentiated component in DDCS.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.
This gene is rated as red, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Deleted their comment
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Classified gene: IDH2 as Red List (low evidence)
Skeletal dysplasia v4.49 IDH2 Sarah Leigh Gene: idh2 has been classified as Red List (Low Evidence).
Skeletal dysplasia v4.48 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as red, because the variants are somatic, occurring in the tumour.
Early onset or syndromic epilepsy v4.152 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Early onset or syndromic epilepsy. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Intellectual disability - microarray and sequencing v5.409 KCNA3 Gavin Ryan gene: KCNA3 was added
gene: KCNA3 was added to Intellectual disability - microarray and sequencing. Sources: Expert Review
Mode of inheritance for gene: KCNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA3 were set to PMID: 37964487
Phenotypes for gene: KCNA3 were set to Intellectual disability; Developmental Delay; Epilepsy
Penetrance for gene: KCNA3 were set to unknown
Review for gene: KCNA3 was set to GREEN
Added comment: Soldovieri et al identified 14 de novo missense variants in KCNA3 gene. The majority of individuals presented with ID, developmental delay, and epilepsy, amongst other features. Functional studies showed loss-of-function effects for some variants and possible gain-of-function for others. One of these variants has also been identified in NHS GMS WGS patient with consistent features.
Sources: Expert Review
Intellectual disability - microarray and sequencing v5.409 BAZ2B Dmitrijs Rots gene: BAZ2B was added
gene: BAZ2B was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: BAZ2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BAZ2B were set to PMID: 31999386
Phenotypes for gene: BAZ2B were set to developmental delay, intellectual disability and autism spectrum disorder
Review for gene: BAZ2B was set to GREEN
Added comment: BAZ2B gene is intolerant to LoF variants in population (pLI=1) and PMID: 31999386 described that de novo LoF variants are statistically enriched among NDD cases & summarize 10 cases. Enough evidence for the green rating.
Sources: Literature
Cytopenia - NOT Fanconi anaemia v3.21 FCGR3B Dmitrijs Rots reviewed gene: FCGR3B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v4.53 ZNF335 Dmitrijs Rots reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.409 ABCC9 Tracy Lester reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.; to: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram Classified gene: LEF1 as Amber List (moderate evidence)
Ectodermal dysplasia v3.28 LEF1 Achchuthan Shanmugasundram Gene: lef1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Classified gene: LEF1 as Red List (low evidence)
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated families reported with monoallelic variants and a single individual reported with biallelic variants. Hence, this gene should be promoted to green rating in the next GMS review and the MOI should be set as 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Ectodermal dysplasia v3.27 LEF1 Achchuthan Shanmugasundram Gene: lef1 has been classified as Red List (Low Evidence).
Ectodermal dysplasia v3.26 LEF1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Germline variants in this gene have not yet been associated with any phenotypes in OMIM, but monoallelic variants have been associated with LEF1-related ectodermal dysplasia and limb malformation in Gene2Phenotype ('moderate' rating on the DD panel).
Ectodermal dysplasia v3.26 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from ectodermal dysplasia syndrome, MONDO:0019287 to ectodermal dysplasia syndrome, MONDO:0019287
Ectodermal dysplasia v3.25 LEF1 Achchuthan Shanmugasundram Phenotypes for gene: LEF1 were changed from Ectodermal dysplasia, no OMIM# yet to ectodermal dysplasia syndrome, MONDO:0019287
Ectodermal dysplasia v3.24 LEF1 Achchuthan Shanmugasundram Publications for gene: LEF1 were set to 32022899
Ectodermal dysplasia v3.23 LEF1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: LEF1.
Ectodermal dysplasia v3.23 LEF1 Achchuthan Shanmugasundram reviewed gene: LEF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35583550; Phenotypes: ectodermal dysplasia syndrome, MONDO:0019287, limb malformations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Classified gene: STAB1 as Amber List (moderate evidence)
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of STAB1 gene to green rating in the next GMS review.
Iron metabolism disorders - NOT common HFE mutations v2.4 STAB1 Achchuthan Shanmugasundram Gene: stab1 has been classified as Amber List (Moderate Evidence).
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram changed review comment from: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.; to: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram commented on gene: STAB1: PMID:37490907 reported the identification of biallelic variants in STAB10 gene in 10 individuals from 7 families with unexplained hyperferritinaemia without iron overload. All of them were in good health and had no dysmorphologies, psycho-motor development abnormalities, hearing or vision disorders, or other pathologies.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: STAB1.
Iron metabolism disorders - NOT common HFE mutations v2.3 STAB1 Achchuthan Shanmugasundram reviewed gene: STAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37490907; Phenotypes: Genetic hyperferritinemia without iron overload (disorder), SNOMED:766929007; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Classified gene: NOS1AP as Amber List (moderate evidence)
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark and reported in PMID:33523862, there are two unrelated individuals with homozygous NOS1AP variants (c.428G>A/ p.Cys143Tyr & c.345-3T-G) and presenting with nephrotic syndrome, type 22 (MIM# 619155).

Introduction of patient variant (c.428G>A) has resulted in aberrant glomeruli formation in kidney organoids. In addition, homozygous exon 3-deleted mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis.

Hence, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Proteinuric renal disease v4.6 NOS1AP Achchuthan Shanmugasundram Gene: nos1ap has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v4.5 NOS1AP Achchuthan Shanmugasundram Phenotypes for gene: NOS1AP were changed from Nephrotic syndrome, type 22, MIM# 619155 to Nephrotic syndrome, type 22, OMIM:619155
Proteinuric renal disease v4.4 NOS1AP Achchuthan Shanmugasundram Publications for gene: NOS1AP were set to
Proteinuric renal disease v4.3 NOS1AP Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: NOS1AP.
Proteinuric renal disease v4.3 NOS1AP Achchuthan Shanmugasundram reviewed gene: NOS1AP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33523862; Phenotypes: Nephrotic syndrome, type 22, OMIM:619155; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.409 MTSS1L Achchuthan Shanmugasundram edited their review of gene: MTSS1L: Changed phenotypes to: Intellectual developmental disorder with ocular anomalies and distinctive facial features, OMIM:620086
Intellectual disability - microarray and sequencing v5.409 MTSS1L Achchuthan Shanmugasundram changed review comment from: Added new-gene-name tag, new approved HGNC gene symbol for MTSS1L is MTSS2.; to: New approved HGNC gene symbol for MTSS1L is MTSS2.
Intellectual disability - microarray and sequencing v5.409 MTSS1L Achchuthan Shanmugasundram commented on gene: MTSS1L
Cytopenias and congenital anaemias v1.116 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Hypereosinophilic syndrome, idiopathic, resistant to imatinib 607685 to Hypereosinophilic syndrome, idiopathic, resistant to imatinib, OMIM:607685
Inherited predisposition to GIST v1.14 PDGFRA Arina Puzriakova Publications for gene: PDGFRA were set to
Adult solid tumours cancer susceptibility v2.29 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Gastrointestinal stromal tumor to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Childhood solid tumours cancer susceptibility v1.26 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial GIST; Gastrointestinal stromal tumor, somatic 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Sarcoma cancer susceptibility v1.24 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial GIST; Gastrointestinal stromal tumor, somatic 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Childhood solid tumours v4.15 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Familial Gastrointestinal stromal tumour; Gastrointestinal stromal tumor, somatic 606764; Familial GIST; Gastrointestinal stromal tumor, somatic, 606764 to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510; Familial Gastrointestinal stromal tumour; Familial GIST
Adult solid tumours for rare disease v1.40 PDGFRA Arina Puzriakova Phenotypes for gene: PDGFRA were changed from Gastrointestinal stromal tumor to Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, OMIM:175510
Hereditary Erythrocytosis v2.6 PKLR Arina Puzriakova Publications for gene: PKLR were set to 22274579
Hereditary Erythrocytosis v2.5 PKLR Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'monoallelic' only. Limited evidence but historic reports linked heterozygous variants in the PKLR gene to elevation of red cell ATP levels, accompanied by elevated red cell pyruvate kinase activity and mild erythrocytosis. Patients were asymptomatic and no recent cases have been published therefore Red rating is appropriate (PMIDs: 9090535; 4160306; 14300761; 7426754).

Biallelic variants cause pyruvate kinase deficiency which results in nonspherocytic hemolytic anemia rather than erythrocytosis.
Hereditary Erythrocytosis v2.5 PKLR Arina Puzriakova Mode of inheritance for gene: PKLR was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal hydrops v1.63 PKLR Arina Puzriakova Classified gene: PKLR as Green List (high evidence)
Fetal hydrops v1.63 PKLR Arina Puzriakova Added comment: Comment on list classification: Rating Green as non-immune hydrops fetalis reported in multiple cases of Pyruvate kinase deficiency.

Green rating also inline with classification on equivalent GMS panel R21 Fetal anomalies (v3.0).
Fetal hydrops v1.63 PKLR Arina Puzriakova Gene: pklr has been classified as Green List (High Evidence).
Fetal hydrops v1.62 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Pyruvate Kinase deficiency to Pyruvate kinase deficiency, OMIM:266200
Cytopenias and congenital anaemias v1.115 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from PYRUVATE KINASE DEFICIENCY; Enzyme Disorder; Pyruvate kinase deficiency, 266200 to Pyruvate kinase deficiency, OMIM:266200
Rare anaemia v3.7 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Enzyme Disorder; PYRUVATE KINASE DEFICIENCY; Pyruvate kinase deficiency; 266200 PYRUVATE KINASE DEFICIENCY; 266200 Pyruvate kinase deficiency; Pyruvate kinase deficiency, 266200 to Pyruvate kinase deficiency, OMIM:266200
Fetal anomalies v3.130 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Pyruvate kinase deficiency 266200 to Pyruvate kinase deficiency, OMIM:266200
Hereditary Erythrocytosis v2.4 PKLR Arina Puzriakova Phenotypes for gene: PKLR were changed from Familial erythrocytosis to Adenosine triphosphate, elevated, of erythrocytes, OMIM:102900
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: POMP.
Tag Q1_24_expert_review tag was added to gene: POMP.
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova Tag Q1_24_demote_red tag was added to gene: POMP.
Tag Q1_24_expert_review tag was added to gene: POMP.
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Classified gene: POMP as Red List (low evidence)
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to support the gene-disease association but based on previous reviews, POMP is currently classified as Red on this panel due the single 1bp deletion identified in all cases to date residing in the 5'UTR of the POMP gene.

The gene rating is conflicting on the R166 Palmoplantar keratodermas, where POMP is rated Green for the same phenotype. This has been tagged for NHSE expert review, and therefore also tagging the association on this panel so that the two panels can be considered together and the overall classification be aligned.
Ichthyosis and erythrokeratoderma v3.22 POMP Arina Puzriakova Gene: pomp has been classified as Red List (Low Evidence).
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

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Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

PPK is a key feature of KLICK syndrome, and there are sufficient cases to support causation (PMID:20226437 and PMID:27503413). However, the pathogenic variant reported in all cases so far is the same 1bp deletion in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Ichthyosis and erythrokeratoderma v3.21 POMP Arina Puzriakova Publications for gene: POMP were set to 27503413; 20226437
Palmoplantar keratodermas v3.22 POMP Arina Puzriakova Publications for gene: POMP were set to 27503413; 20226437
Ichthyosis and erythrokeratoderma v3.20 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratoderma and erythrokeratodermas v1.31 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratodermas v3.21 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from Keratosis linearis with ichthyosis congenita and sclerosing keratoderma to Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, OMIM:601952
Palmoplantar keratodermas v3.20 POMP Arina Puzriakova Publications for gene: POMP were set to
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Classified gene: POMP as Green List (high evidence)
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Palmoplantar keratodermas v3.19 POMP Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Classified gene: POMP as Green List (high evidence)
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

There is sufficient evidence to support a gene-disease association, however the pathogenic variant reported in all cases so far is in the 5'UTR of the POMP gene (c.-95delC). For this reason, it is currently rated as Red on the R165 Ichthyosis and erythrokeratoderma panel (v3.2).

If it is decided that POMP should remain as Green on this panel, it should probably also be promoted to Green status on R165 (also tagged for expert review).

---
Supporting evidence (reviews copied from R165 panel):

Palmoplantar keratoderma (PPK) is a phenotype of 'Keratosis linearis with ichthyosis congenita and sclerosing keratoderma, 601952 (KLICK syndrome). In 12 patients from 8 unrelated European families (from Spain, Italy, Netherlands, Sweden, Norway) with OMIM:601952, Dahlqvist et al. (2010, PMID: 20226437) identified homozygosity for a 1-bp deletion (-95delC) within a highly conserved 5' region of the POMP gene. Haplotype analysis suggested that the -95delC variant is a recurrent rather than a founder mutation.

PMID:27503413 (Morice-Picard, 2017) report a young patient born from related parents, originally from the SW of France. The patient was presenting at birth with palmar keratoderma, and PPK was still present at the age of 11 years. Molecular analysis identified a homozygous 1-bp deletion in the 5′UTR non-coding region of the POMP gene (c.-95delC)- the same variation as reported in 20226437.
Palmoplantar keratodermas v3.18 POMP Arina Puzriakova Gene: pomp has been classified as Green List (High Evidence).
Ichthyosis and erythrokeratoderma v3.19 POMP Arina Puzriakova Tag non-coding-known-pathogenic tag was added to gene: POMP.
Palmoplantar keratodermas v3.17 POMP Arina Puzriakova Tag promoter tag was added to gene: POMP.
Tag non-coding-known-pathogenic tag was added to gene: POMP.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 POMP Arina Puzriakova Phenotypes for gene: POMP were changed from CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Proteasome-associated autoinflammatory syndrome 2, 618048; combined immunodeficiency with autoinflammation to Proteasome-associated autoinflammatory syndrome 2, OMIM:618048; CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Combined immunodeficiency with autoinflammation
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Classified gene: COQ7 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Gene: coq7 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.78 COQ7 Achchuthan Shanmugasundram Phenotypes for gene: COQ7 were changed from autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9) to Neuronopathy, distal hereditary motor, autosomal recessive 9, OMIM:620402
Hereditary neuropathy or pain disorder v3.77 COQ7 Achchuthan Shanmugasundram Publications for gene: COQ7 were set to PMID: 36758993; 37077559
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: COQ7.
Tag Q1_24_NHS_review tag was added to gene: COQ7.
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram changed review comment from: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:3707755 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.; to: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:37077559 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram edited their review of gene: COQ7: Changed publications to: 36454683, 36758993, 37077559
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36454683, 36758993, 3707755; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 9, OMIM:620402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v4.48 MGP Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available (two unrelated cased and functional studies) for the association of monoallelic MGP variants with spondyloepiphyseal dysplasia, the MOI should be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Skeletal dysplasia v4.48 MGP Achchuthan Shanmugasundram Mode of inheritance for gene: MGP was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v4.47 MGP Achchuthan Shanmugasundram Phenotypes for gene: MGP were changed from Keutel syndrome 245150; Keutel syndrome 245150 to Keutel syndrome, OMIM:245150; spondyloepiphyseal dysplasia, MONDO:0016761
Skeletal dysplasia v4.46 MGP Achchuthan Shanmugasundram Publications for gene: MGP were set to
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram Tag Q1_24_MOI tag was added to gene: MGP.
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram changed review comment from: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.; to: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.

Although phenotype caused by biallelic MGP variants are already reported in both OMIM (MIM #245150) and Gene2Phenotype, phenotype caused by monoallelic variants are not yet reported in either resources.
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram edited their review of gene: MGP: Changed phenotypes to: Keutel syndrome, OMIM:245150, spondyloepiphyseal dysplasia, MONDO:0016761
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram reviewed gene: MGP: Rating: GREEN; Mode of pathogenicity: None; Publications: 37923733; Phenotypes: spondyloepiphyseal dysplasia, MONDO:0016761; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.409 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850 to Hyperprolinemia, type I, OMIM:239500; {Schizophrenia, susceptibility to, OMIM:4}, 600850
Early onset or syndromic epilepsy v4.152 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Likely inborn error of metabolism - targeted testing not possible v4.123 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Undiagnosed metabolic disorders v1.610 PRODH Arina Puzriakova Phenotypes for gene: PRODH were changed from Hyperprolinemia, type I, OMIM; 239500; hyperprolinemia type 1, MONDO:0009400 to Hyperprolinemia, type I, OMIM:239500; hyperprolinemia type 1, MONDO:0009400
Hypogonadotropic hypogonadism v1.41 KISS1R Arina Puzriakova Phenotypes for gene: KISS1R were changed from Hypogonadotropic hypogonadism 8 with or without anosmia, 614837; Precocious puberty, central, 1, (AD), 176400 to Hypogonadotropic hypogonadism 8 with or without anosmia, OMIM:614837; ?Precocious puberty, central, 1, OMIM:176400
Hypogonadotropic hypogonadism (GMS) v3.15 KISS1R Arina Puzriakova Phenotypes for gene: KISS1R were changed from Hypogonadotropic hypogonadism type 8 (OMIM 614837) to Hypogonadotropic hypogonadism 8 with or without anosmia, OMIM:614837
Palmoplantar keratoderma and erythrokeratodermas v1.30 KRT17 Arina Puzriakova Phenotypes for gene: KRT17 were changed from Pachyonychia Congenita, Type 2; Pachyonychia congenita, Jackson-Lawler type, 167210; Steatocystoma multiplex, 184500 to Pachyonychia congenita 2, OMIM:167210; Steatocystoma multiplex, OMIM:184500
Familial hidradenitis suppurativa v1.4 KRT17 Arina Puzriakova Phenotypes for gene: KRT17 were changed from Pachyonychia congenita 2, 167210; pachyonychia congenita with hidradenitis suppurativa to Pachyonychia congenita 2, OMIM:167210; Pachyonychia congenita with hidradenitis suppurativa
Non-syndromic hypotrichosis v1.13 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from hypotrichosis simplex of the scalp; Hypotrichosis 3, 613981; HYPT3 to Hypotrichosis 3, OMIM:613981; HYPT3
Ectodermal dysplasia v3.23 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from Pure hair and nail ectodermal dysplasia (PHNED) Ectodermal dysplasia 7, hair/nail type 614929; hypotrichosis simplex of the scalp; Hypotrichosis 3, 613981; HYPT3 to Woolly hair, autosomal dominant, OMIM:194300 (AD); ?Hypotrichosis 3, OMIM:613981 (AD); ?Ectodermal dysplasia 7, hair/nail type, OMIM:614929 (AR)
Ectodermal dysplasia without a known gene mutation v1.27 KRT74 Arina Puzriakova Phenotypes for gene: KRT74 were changed from Pure hair and nail ectodermal dysplasia (PHNED) Ectodermal dysplasia 7, hair/nail type 614929 to Woolly hair, autosomal dominant, OMIM:194300 (AD); ?Hypotrichosis 3, OMIM:613981 (AD); ?Ectodermal dysplasia 7, hair/nail type, OMIM:614929 (AR)
Ectodermal dysplasia without a known gene mutation v1.26 KRT74 Arina Puzriakova Classified gene: KRT74 as Green List (high evidence)
Ectodermal dysplasia without a known gene mutation v1.26 KRT74 Arina Puzriakova Gene: krt74 has been classified as Green List (High Evidence).
Ectodermal dysplasia without a known gene mutation v1.25 KRT74 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from biallelic to monoallelic inline with MOI on equivalent GMS panel (R163 Ectodermal dysplasia v3.0).

"This gene is Green on the Non-syndromic hypotrichosis panel (version 1.1, code 189) with a monoallelic mode of inheritance for Hypotrichosis. It has a Red rating with a biallelic mode of inheritance on the Ectodermal dysplasia without a known gene mutation panel (version 1.15, code 136), for Ectodermal dysplasia 7 due to one family report (PMID: 24714551). Therefore for the Green status, a monoallelic mode of inheritance is given here."
Ectodermal dysplasia without a known gene mutation v1.25 KRT74 Arina Puzriakova Mode of inheritance for gene: KRT74 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy v1.476 MME Arina Puzriakova changed review comment from: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"; to: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder v3.24).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Ectodermal dysplasia v3.22 KRT74 Arina Puzriakova Tag watchlist_moi tag was added to gene: KRT74.
Hereditary neuropathy v1.476 MME Arina Puzriakova Added comment: Comment on mode of inheritance: Updating from 'biallelic' to 'both mono- and biallelic' inline with MOI on equivalent GMS panel (R78 Hereditary neuropathy or pain disorder).

"Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype"
Hereditary neuropathy v1.476 MME Arina Puzriakova Mode of inheritance for gene: MME was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v3.129 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Megacystis Microcolon Intestinal Hypoperistalsis Syndrome; MMIH to Megacystis-microcolon-intestinal hypoperistalsis syndrome 1, OMIM:249210
Thoracic aortic aneurysm or dissection v1.127 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Aortic aneurysm, familial thoracic 7, 613780; Aortic aneurysm, familial thoracic 7 (613780) to Aortic aneurysm, familial thoracic 7, OMIM:613780
Thoracic aortic aneurysm or dissection (GMS) v3.8 MYLK Arina Puzriakova Phenotypes for gene: MYLK were changed from Aortic aneurysm, familial thoracic 7 (613780); Aortic aneurysm, familial thoracic 7, 613780 to Aortic aneurysm, familial thoracic 7, OMIM:613780
Amyotrophic lateral sclerosis/motor neuron disease v1.69 OPTN Arina Puzriakova Added comment: Comment on publications: PMID: 26566915 - "Here, we report a Chinese family spanning three generations with ALS8 caused by the same VAPB-P56S mutation detected in these cohorts, but which in its initial manifestation displays different features. We also detected a R545Q variant of optineurin (OPTN) in this family and which was previously considered a pathogenic mutation. However, our analysis showed that OPTN-R545Q is benign and that VAPB-P56S accounts for the phenotype."
PMID: 26503823
PMID: 26303227 "We conclude that: (i) OPTN mutations are associated with ALS
(ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS
(iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient
and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration."
PMID: 26203661
PMID: 25943890
PMID: 25859013 - functional evidence
PMID: 25681989
Amyotrophic lateral sclerosis/motor neuron disease v1.69 OPTN Arina Puzriakova Publications for gene: OPTN were set to PMID: 26566915 - "Here, we report a Chinese family spanning three generations with ALS8 caused by the same VAPB-P56S mutation detected in these cohorts, but which in its initial manifestation displays different features. We also detected a R545Q variant of optineurin (OPTN) in this family and which was previously considered a pathogenic mutation. However, our analysis showed that OPTN-R545Q is benign and that VAPB-P56S accounts for the phenotype."; PMID: 26503823; PMID: 26303227 "We conclude that: (i) OPTN mutations are associated with ALS; (ii) optineurin protein is present in a subset of the extramotor inclusions of C9ORF72-ALS; (iii) It is not uncommon for multiple ALS-causing mutations to occur in the same patient; and (iv) studies of optineurin are likely to provide useful dataregarding the pathophysiology of ALS and neurodegeneration."; PMID: 26203661; PMID: 25943890; PMID: 25859013 - functional evidence; PMID: 25681989
Amyotrophic lateral sclerosis/motor neuron disease v1.68 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Amyotrophic Lateral Sclerosis, Recessive; Glaucoma 1, open angle, E, 137760 to Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia, OMIM:613435
Structural eye disease v3.73 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Glaucoma 1, open angle, E, 137760; {Glaucoma, normal tension, susceptibility to} 606657 to Glaucoma 1, open angle, E, OMIM:137760; {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Adult-onset
Glaucoma (developmental) v1.43 OPTN Arina Puzriakova Phenotypes for gene: OPTN were changed from Glaucoma 1, open angle, E 137760; {Glaucoma, normal tension, susceptibility to} 606657 to Glaucoma 1, open angle, E, OMIM:137760; {Glaucoma, normal tension, susceptibility to}, OMIM:606657; Adult-onset
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified to date in Genomics England's Clinical Variant Archive (CVA) dataset are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova changed review comment from: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.; to: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variant (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should also be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.151 PRICKLE1 Arina Puzriakova Publications for gene: PRICKLE1 were set to 18976727; 21276947
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova edited their review of gene: PRICKLE1: Changed publications to: 30564977, 30345727, 21276947, 26727662, 29790814, 31875159, 31035234, 15634728, 15642921, 16376507, 18976727, 20301774
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Tag Q1_24_demote_amber tag was added to gene: PRICKLE1.
Tag Q1_24_expert_review tag was added to gene: PRICKLE1.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Classified gene: PRICKLE1 as Green List (high evidence)
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Added comment: Comment on list classification: Inclusion of this gene on the panel should be reviewed by the NHSE specialist group.

ClinGen have classified PRICKLE1-related AR PME as LIMITED (18 Aug 2020) and AD epilepsy as DISPUTED (01 Sept 2020).

There are reports in the literature of both homozygous (PMID: 30564977; 30345727) and heterozygous cases (PMID: 21276947; 26727662; 29790814; 31875159; 31035234); however, most variants are missense with little further supportive evidence. Founder effect has been suggested for one recurrent homozygous variants (PMID: 15634728; 15642921; 16376507; 18976727) and reports of unaffected carriers should be considered (PMID: 31035234).

GeneReview for PRICKLE1-Related Disorders - PMID: 20301774

ClinVar entries are all VUS/LB/B and all variants identified in Genomics England's Clinical Variant Archive (CVA) dataset to date are UNCLASSIFIED.
Early onset or syndromic epilepsy v4.150 PRICKLE1 Arina Puzriakova Gene: prickle1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Tag disputed tag was added to gene: PRICKLE1.
Hereditary ataxia with onset in adulthood v4.28 PRICKLE1 Arina Puzriakova Classified gene: PRICKLE1 as Red List (low evidence)
Hereditary ataxia with onset in adulthood v4.28 PRICKLE1 Arina Puzriakova Gene: prickle1 has been classified as Red List (Low Evidence).
Adult onset neurodegenerative disorder v4.46 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Early onset or syndromic epilepsy v4.149 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Intellectual disability - microarray and sequencing v5.408 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary ataxia with onset in adulthood v4.27 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904 to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary ataxia v1.332 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Ataxia and cerebellar anomalies - narrow panel v4.51 PRICKLE1 Arina Puzriakova Phenotypes for gene: PRICKLE1 were changed from Progressive Myoclonus Epilepsy with Ataxia to Epilepsy, progressive myoclonic 1B, OMIM:612437
Hereditary neuropathy or pain disorder v3.76 PRX Arina Puzriakova Publications for gene: PRX were set to 11157804; 10848494
Hereditary neuropathy v1.475 PRX Arina Puzriakova Publications for gene: PRX were set to 11157804; 10848494
Intellectual disability - microarray and sequencing v5.407 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine-Sottas disease, 145900; Charcot-Marie-Tooth disease, type 4F, 614895 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Hereditary neuropathy or pain disorder v3.75 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Hereditary neuropathy v1.474 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine Sottas disease, autosomal recessive, 145900; Charcot Marie Tooth disease, type 4F, 614895; Dejerine Sottas disease, autosomal recessive, 145900 to Charcot-Marie-Tooth disease, type 4F, OMIM:614895; Dejerine-Sottas disease, OMIM:145900
Fetal anomalies v3.128 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Dejerine-Sottas disease, OMIM; 145900 to Dejerine-Sottas disease, OMIM:145900
Fetal anomalies v3.127 PRX Arina Puzriakova Phenotypes for gene: PRX were changed from Charcot-Marie-Tooth disease, type 4F 614895; Dejerine-Sottas disease 145900 to Dejerine-Sottas disease, OMIM; 145900
Fetal anomalies v3.126 PRX Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'both mono- and biallelic' to 'biallelic' as only recessive cases have been reported in literature.

OMIM states AD/AR inheritance for Dejerine-Sottas disease as this can be caused by both heterozygous and homozygous variants in other genes (e.g. PMP22, EGR2) but seemingly not in PRX.
Fetal anomalies v3.126 PRX Arina Puzriakova Mode of inheritance for gene: PRX was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal muscle channelopathy v3.5 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Skeletal muscle channelopathy v3.5 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v3.125 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Skeletal muscle channelopathy v3.4 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Paroxysmal central nervous system disorders v3.10 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
COVID-19 research v1.141 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Distal myopathies v3.17 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Skeletal Muscle Channelopathies v1.46 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Severe Paediatric Disorders v1.180 CNBP Sarah Leigh Tag currently-ngs-unreportable was removed from gene: CNBP.
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Fetal anomalies v3.125 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Fetal anomalies v3.125 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v3.4 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Skeletal muscle channelopathy v3.4 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Distal myopathies v3.17 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Amber List (moderate evidence)
Distal myopathies v3.17 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Amber List (Moderate Evidence).
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh Deleted their comment
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh Deleted their comment
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh Deleted their comment
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Tag Q1_24_promote_green tag was added to STR: CNBP_CCTG.
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh commented on STR: CNBP_CCTG: As STR: CNBP_CCTG has been reviewed and confirmed by the NHS Genomic Medicine Service, it can be rated as Green on this panel.
Skeletal Muscle Channelopathies v1.46 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Green List (high evidence)
Skeletal Muscle Channelopathies v1.46 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.45 CNBP_CCTG Sarah Leigh Tag NGS Not Validated was removed from STR: CNBP_CCTG.
Fetal anomalies v3.124 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal muscle channelopathy v3.3 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Distal myopathies v3.16 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal Muscle Channelopathies v1.45 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Classified STR: CNBP_CCTG as Green List (high evidence)
Severe Paediatric Disorders v1.180 CNBP_CCTG Sarah Leigh Str: cnbp_cctg has been classified as Green List (High Evidence).
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh reviewed STR: CNBP_CCTG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh Entity copied from Skeletal Muscle Channelopathies v1.45
Severe Paediatric Disorders v1.179 CNBP_CCTG Sarah Leigh STR: CNBP_CCTG was added
STR: CNBP_CCTG was added to Severe Paediatric Disorders. Sources: Expert list,NHS GMS,Expert Review Red
STR, NGS Not Validated tags were added to STR: CNBP_CCTG.
Mode of inheritance for STR: CNBP_CCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: CNBP_CCTG were set to Myotonic dystrophy 2, OMIM:602668; Myotonic dystrophy type 2, MONDO:0011266
Retinal disorders v4.56 MIR204 Achchuthan Shanmugasundram Mode of inheritance for gene: MIR204 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disorders v4.156 SLC25A24 Achchuthan Shanmugasundram Tag Q3_23_MOI was removed from gene: SLC25A24.
Mitochondrial disorders v4.156 SLC25A24 Achchuthan Shanmugasundram Mode of inheritance for gene: SLC25A24 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.406 MTOR Sarah Leigh Publications for gene: MTOR were set to 26542245; 27830187; 25851998; 28892148; DOI: 10.4137/JGE.S12583; 27159400
Early onset or syndromic epilepsy v4.148 MTOR Sarah Leigh Publications for gene: MTOR were set to
Early onset or syndromic epilepsy v4.147 MTOR Sarah Leigh Phenotypes for gene: MTOR were changed from Focal cortical dysplasia, type II, somatic to Smith-Kingsmore syndrome, OMIM:616638; macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, MONDO:0014716; Focal cortical dysplasia, type II, somatic, OMIM:607341isolated focal cortical dysplasia type II, MONDO:0011818
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2A Saikat Santra reviewed gene: RNASEH2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2B Saikat Santra reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.122 RNASEH2C Saikat Santra reviewed gene: RNASEH2C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intracerebral calcification disorders, Inherited White Matter Disorders, Inherited basal ganglia disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.405 DHX37 Tracy Lester reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877, 35982159; Phenotypes: Intellectual disability, developmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Early onset or syndromic epilepsy v4.146 CACNB4 Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: CACNB4.
Adult onset leukodystrophy v3.24 RPS6KA3 Achchuthan Shanmugasundram Tag Q3_23_expert_review tag was added to gene: RPS6KA3.
Adult onset leukodystrophy v3.24 RNF216 Achchuthan Shanmugasundram Tag Q3_23_expert_review tag was added to gene: RNF216.
Likely inborn error of metabolism - targeted testing not possible v4.122 SLC6A20 Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: SLC6A20.
Likely inborn error of metabolism - targeted testing not possible v4.122 GSTZ1 Saikat Santra edited their review of gene: GSTZ1: Changed phenotypes to: Biochemical: hypersuccinylacetonaemia
Intellectual disability - microarray and sequencing v5.405 FAM111A Achchuthan Shanmugasundram Tag Q4_23_expert_review tag was added to gene: FAM111A.
Likely inborn error of metabolism - targeted testing not possible v4.122 GSTZ1 Saikat Santra gene: GSTZ1 was added
gene: GSTZ1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review,Eligibility statement prior genetic testing
Mode of inheritance for gene: GSTZ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSTZ1 were set to 27876694
Phenotypes for gene: GSTZ1 were set to Biochemical
Penetrance for gene: GSTZ1 were set to unknown
Review for gene: GSTZ1 was set to GREEN
Added comment: GSTZ1 is established as the molecular cause for maleylacetoacetate isomerase deficiency which is an established inherited metabolic disorder and associated with succinylacetone excretion so may be detected on newborn screening programmes for hereditary tyrosinaemia type1 (FAH). The committee established for developing the pathways for rolling this out recommended that genetic testing for GSTZ1 be made available via the R98 panel to help evaluate patients with mild hypersuccinylacetonaemia - but patients with elevated succinylacetone on routine metabolic testing would also benefit from this being available.
Sources: Literature, Expert Review, Eligibility statement prior genetic testing
Skeletal dysplasia v4.45 TP53 Sarah Leigh edited their review of gene: TP53: Added comment: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in
tumorigenesis, giving rise to the dedifferentiated component in DDCS.; Changed rating: AMBER
Skeletal dysplasia v4.45 TP53 Sarah Leigh Added comment: Comment on mode of inheritance: TP53 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.45 TP53 Sarah Leigh Mode of inheritance for gene: TP53 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Other
Skeletal dysplasia v4.44 TP53 Sarah Leigh Tag somatic tag was added to gene: TP53.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Added comment: Comment on mode of inheritance: IDH2 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Mode of inheritance for gene: IDH2 was changed from Other to Other
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Added comment: Comment on mode of inheritance: IDH2 variants associated with chondrosarcomas are somatic, occurring in the tumour material.
Skeletal dysplasia v4.44 IDH2 Sarah Leigh Mode of inheritance for gene: IDH2 was changed from Unknown to Other
Skeletal dysplasia v4.43 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.43 IDH2 Sarah Leigh edited their review of gene: IDH2: Changed rating: AMBER
Skeletal dysplasia v4.43 IDH2 Sarah Leigh Tag Q1_24_promote_green was removed from gene: IDH2.
Tag Q1_24_NHS_review was removed from gene: IDH2.
Tag somatic tag was added to gene: IDH2.
Skeletal dysplasia v4.43 TP53 Sarah Leigh Publications for gene: TP53 were set to PMID: 33147331
Skeletal dysplasia v4.42 TP53 Sarah Leigh Classified gene: TP53 as Amber List (moderate evidence)
Skeletal dysplasia v4.42 TP53 Sarah Leigh Gene: tp53 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.41 IDH2 Sarah Leigh Classified gene: IDH2 as Amber List (moderate evidence)
Skeletal dysplasia v4.41 IDH2 Sarah Leigh Gene: idh2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.40 IDH2 Sarah Leigh Phenotypes for gene: IDH2 were changed from Maffucci syndrome 614569; Enchondromatosis (Ollier) and Enchondromatosis with hermangiomata (Maffucci) 166000, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (614875); Ollier disease/ Dyschondroplasia 166000; D-2-hydroxyglutaric aciduria 2 613657 to D-2-hydroxyglutaric aciduria 2, OMIM:613657; d-2-hydroxyglutaric aciduria 2, MONDO:0013345
Skeletal dysplasia v4.39 IDH2 Sarah Leigh Tag Q1_24_promote_green tag was added to gene: IDH2.
Tag Q1_24_NHS_review tag was added to gene: IDH2.
Skeletal dysplasia v4.39 IDH2 Sarah Leigh edited their review of gene: IDH2: Added comment: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; Changed rating: GREEN
Skeletal dysplasia v4.39 IDH2 Sarah Leigh Publications for gene: IDH2 were set to 24049096; 22057234; 22057236
Brugada syndrome and cardiac sodium channel disease v3.8 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Brugada syndrome 5, OMIM:612838 to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Dilated Cardiomyopathy and conduction defects v1.85 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific ; Nonspecific Cardiac Conduction Defect to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Dilated Cardiomyopathy and conduction defects v1.84 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v3.10 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific (612838); Atrial fibrillation, familial, 13 (615377); Brugada syndrome 5 (612838); Epileptic encephalopathy, early infantile, 52 (617350); Epilepsy, generalized, with febrile seizures plus, type 1 (604233) to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Progressive cardiac conduction disease v2.6 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Cardiac conduction defect, nonspecific, OMIM:612838 to Cardiac conduction defect, nonspecific, OMIM:612838; Brugada syndrome 5, OMIM:612838; Atrial fibrillation, familial, 13, OMIM:615377
Brugada syndrome and cardiac sodium channel disease v3.7 SCN1B Arina Puzriakova Mode of inheritance for gene: SCN1B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brugada syndrome and cardiac sodium channel disease v3.6 SCN1B Arina Puzriakova Tag disputed tag was added to gene: SCN1B.
Early onset or syndromic epilepsy v4.146 SCN1B Arina Puzriakova Phenotypes for gene: SCN1B were changed from Epilepsy, generalized, with febrile seizures plus, type 1 604233 AD; Epileptic encephalopathy, early infantile, 52 617350 AR to Developmental and epileptic encephalopathy 52, OMIM:617350 (AR); Generalized epilepsy with febrile seizures plus, type 1, OMIM:604233 (AD)
Early onset or syndromic epilepsy v4.145 SCN1B Arina Puzriakova Publications for gene: SCN1B were set to 12011299; 16205844; 9697698
Hereditary neuropathy or pain disorder v3.74 COQ7 Lucy Jackson edited their review of gene: COQ7: Changed publications to: 36758993, 37077559
Hereditary neuropathy or pain disorder v3.74 COQ7 Lucy Jackson gene: COQ7 was added
gene: COQ7 was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to PMID: 36758993; 37077559
Phenotypes for gene: COQ7 were set to autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Review for gene: COQ7 was set to GREEN
Added comment: This gene is associated with autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Sources: NHS GMS
Sarcoma cancer susceptibility v1.23 T Arina Puzriakova Publications for gene: T were set to 19801981; 23064415
Sarcoma cancer susceptibility v1.22 T Arina Puzriakova Phenotypes for gene: T were changed from Familial Chordoma; Chordoma to Chordoma (disease), MONDO:0008978
Sarcoma susceptibility v1.77 T Arina Puzriakova Publications for gene: T were set to 23064415; 19801981; 34837714
Sarcoma susceptibility v1.76 T Arina Puzriakova Publications for gene: T were set to 23064415; 19801981
Cerebral vascular malformations v3.9 COL5A1 Dmitrijs Rots changed review comment from: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen; to: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen
Cerebral vascular malformations v3.9 COL5A1 Dmitrijs Rots gene: COL5A1 was added
gene: COL5A1 was added to Cerebral vascular malformations. Sources: Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: COL5A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL5A1 were set to PMID: 32938213
Phenotypes for gene: COL5A1 were set to Fibromuscular dysplasia, multifocal
Mode of pathogenicity for gene: COL5A1 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: COL5A1 was set to GREEN
Added comment: PMID: 32938213 describe 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries.
Enough evidence for green. Other mFMD included in the panel.
Sources: Radboud University Medical Center, Nijmegen
Childhood onset dystonia, chorea or related movement disorder v3.66 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Childhood onset dystonia, chorea or related movement disorder v3.66 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Childhood onset hereditary spastic paraplegia v4.37 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Childhood onset hereditary spastic paraplegia v4.37 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Ataxia and cerebellar anomalies - narrow panel v4.50 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Ataxia and cerebellar anomalies - narrow panel v4.50 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Severe microcephaly v4.53 ACBD6 Arina Puzriakova Entity copied from Intellectual disability - microarray and sequencing v5.405
Severe microcephaly v4.53 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Severe microcephaly. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Intellectual disability - microarray and sequencing v5.405 ACBD6 Arina Puzriakova Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.405 ACBD6 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability - microarray and sequencing v5.405 ACBD6 Arina Puzriakova Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.404 ACBD6 Arina Puzriakova Publications for gene: ACBD6 were set to 21937992; 32108178
Intellectual disability - microarray and sequencing v5.403 ACBD6 Arina Puzriakova Phenotypes for gene: ACBD6 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.402 ACBD6 Arina Puzriakova Tag Q1_24_promote_green tag was added to gene: ACBD6.
Intellectual disability - microarray and sequencing v5.402 ACBD6 Arina Puzriakova edited their review of gene: ACBD6: Added comment: - PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information.

- PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency.

- PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers.

- PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29).

Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.; Changed rating: GREEN; Changed publications to: 21937992, 32108178, 36457943, 37951597; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.402 ACBD6 Arina Puzriakova Added comment: Comment on publications: PMID: 32108178 (2020) paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Intellectual disability - microarray and sequencing v5.402 ACBD6 Arina Puzriakova Publications for gene: ACBD6 were set to 21937992; 32108178
Skeletal dysplasia v4.38 FBXW11 Achchuthan Shanmugasundram Tag Q4_21_NHS_review was removed from gene: FBXW11.
Tag Q4_23_NHS_review tag was added to gene: FBXW11.
Structural eye disease v3.72 GDF3 Achchuthan Shanmugasundram Tag Q4_23_demote_amber was removed from gene: GDF3.
Tag Q4_23_expert_review was removed from gene: GDF3.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Tag Q1_24_promote_green tag was added to gene: NEPRO.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Classified gene: NEPRO as Amber List (moderate evidence)
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with three different homozygous variants in NEPRO gene. Three unrelated cases were of Arabic/ partial Arabic descent, while the fourth case from India. The evidence available is sufficient enough to promote the rating to green in the next GMS review.
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Gene: nepro has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.37 NEPRO Achchuthan Shanmugasundram Phenotypes for gene: NEPRO were changed from Anauxetic dysplasia 3, MIM618853 to Anauxetic dysplasia 3, OMIM:618853
Skeletal dysplasia v4.36 NEPRO Achchuthan Shanmugasundram Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram changed review comment from: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.; to: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

PMID:37294112 reported a 7-year-old girl from an Arabic-speaking community in Eastern Africa with Anauxetic dysplasia 3 and another homozygous NEPRO variant (p.Arg94Cys). She was born to consanguineous parents, who reported that their shared ancestor was of Arab descent. This patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram edited their review of gene: NEPRO: Changed rating: GREEN; Changed publications to: 26633546, 29620724, 31250547, 37294112
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram reviewed gene: NEPRO: Rating: AMBER; Mode of pathogenicity: None; Publications: 26633546, 29620724, 31250547; Phenotypes: Anauxetic dysplasia 3, OMIM:618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Classified gene: GRK2 as Amber List (moderate evidence)
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families and some functional data available in support of the disease association. Hence, it should be rated amber with current evidence.
Skeletal ciliopathies v3.20 GRK2 Achchuthan Shanmugasundram Gene: grk2 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.19 GRK2 Achchuthan Shanmugasundram Phenotypes for gene: GRK2 were changed from Jeune asphyxiating thoracic dystrophy (ATD) to Jeune syndrome, MONDO:0018770
Skeletal ciliopathies v3.18 GRK2 Achchuthan Shanmugasundram reviewed gene: GRK2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Jeune syndrome, MONDO:0018770; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect was removed from gene: TRIP13.
Early onset or syndromic epilepsy v4.144 TRIP13 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: TRIP13.
Acute rhabdomyolysis v1.18 ACAD9 Anderson Steven Deleted their review
Acute rhabdomyolysis v1.18 ACAD9 Anderson Steven commented on gene: ACAD9
Early onset or syndromic epilepsy v4.144 PCLO Dmitrijs Rots reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability - microarray and sequencing v5.401 KIRREL3 Dmitrijs Rots reviewed gene: KIRREL3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37605258; Phenotypes: NDD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sarcoma susceptibility v1.75 TP53 Adrienne Flanagan reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31529158; Phenotypes: Solitary Fibrous Tumour; Mode of inheritance: None
Sarcoma susceptibility v1.75 TERT Adrienne Flanagan gene: TERT was added
gene: TERT was added to Sarcoma susceptibility. Sources: Literature,Other
Mode of inheritance for gene: TERT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TERT were set to PMID: 31529158
Phenotypes for gene: TERT were set to Solitary Fibrous Tumour
Review for gene: TERT was set to GREEN
Added comment: Solitary fibrous tumour (SFT) is a rare mesenchymal tumour with a wide anatomical distribution, including superficial and deep soft tissue, visceral organs and bone and is most common in adults. The tumours classified in the intermediate risk group by WHO grading system are difficult to prognosticate. Recent studies show that C228T TERT promoter (pTERT) mutation is associated with reduced survival in SFT. pTERT mutation is more common in intermediate and high-risk groups, and is associated with poorer outcome. Detection of the pTERT mutation has the potential to improve current prognostication and guide management of patients with intermediate-risk solitary fibrous tumours.
These findings were validated by a study presented at the 2023 joint winter meeting of Pathological Society with the RSM, abstract OF6:

https://www.pathsoc.org/_userfiles/pages/files/abstracts_booklet_winter_meeting_2023.pdf
Sources: Literature, Other
Intellectual disability - microarray and sequencing v5.401 ACBD6 Sarah Leigh Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.401 ACBD6 Sarah Leigh Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.401 ACBD6 Sarah Leigh Classified gene: ACBD6 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.401 ACBD6 Sarah Leigh Gene: acbd6 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.400 ACBD6 Sarah Leigh edited their review of gene: ACBD6: Added comment: ACBD6 variants have not been associated with a phenotype in OMIM, and as an autosomal recessive condition with Limited strength in Gen2Phen. Three variants have been reported in three unrelated cases with intellectual disability, however, in one of these carriers the ACBD6 variant was allelic with PRDX6 gene c.136del; p.(ValCysfs*23), therefore the contribution of the ACBD6 variant to intellectual disability is uncertain in this case (PMID: 21937992, 32108178).; Changed rating: AMBER
Intellectual disability - microarray and sequencing v5.400 ACBD6 Sarah Leigh Publications for gene: ACBD6 were set to 21937992
Limb disorders v4.14 FBXW11 Sarah Leigh Entity copied from Skeletal dysplasia v4.35
Limb disorders v4.14 FBXW11 Sarah Leigh gene: FBXW11 was added
gene: FBXW11 was added to Limb disorders. Sources: Literature,Expert Review Amber
Q4_21_NHS_review, Q4_23_promote_green tags were added to gene: FBXW11.
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:0030057
Penetrance for gene: FBXW11 were set to unknown
Skeletal dysplasia v4.35 IDH2 Adrienne Flanagan reviewed gene: IDH2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36042521; Phenotypes: Chondrosarcoma Conventional Central; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v4.35 TP53 Adrienne Flanagan gene: TP53 was added
gene: TP53 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TP53 were set to PMID: 33147331
Phenotypes for gene: TP53 were set to Central conventional chondrosrcoma
Review for gene: TP53 was set to GREEN
Added comment: Inactivating mutations in TP53 are common in dedifferentiated chondrosarcoma (DDCS) and, in a subset of cases, the TP53 mutation is restricted to the dedifferentiated nonchondrogenic component (8/11, 73% of the cases tested). Half of the tumours where the conventional chondrogenic component was paired with the high-grade non-chondrogenic component showed TP53 mutation in the chondrogenic area (3/6, 50%). These findings imply that TP53 alterations occur late in tumorigenesis, potentially with a TP53-mutant subclone that progresses to the dedifferentiated component in DDCS. Identification of TP53 mutation in an otherwise low-grade central chondrosarcoma may indicate the tumor is at increased risk of dedifferentiation.
Genetic testing for TP53 along with IDH1, IDH2 and TERT promoter mutations in central conventional chondrosarcoma could be useful in patient stratification.
Sources: Literature
Pigmentary skin disorders v3.6 LMNA Tom Cullup gene: LMNA was added
gene: LMNA was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: LMNA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LMNA were set to PMID: 12714972; https://www.ncbi.nlm.nih.gov/books/NBK1121/#; 12075506; 17848409
Phenotypes for gene: LMNA were set to Hutchinson-Gilford progeria syndrome (HGPS) (MIM 176670); Mandibuloacral dysplasia with type A lipodystrophy (MADA)
Penetrance for gene: LMNA were set to Complete
Mode of pathogenicity for gene: LMNA 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: LMNA was set to GREEN
Added comment: LMNA requested to be added to pigmentary disorders panel by Prof Kinsler, due to pigmentary lesions being an early sign of LMNA-progeria (AD).
Mottled pigmentation also a feature of MADA (AR).
Sources: Expert list
Unexplained young onset end-stage renal disease v3.37 CLCNKB Achchuthan Shanmugasundram Publications for gene: CLCNKB were set to
Unexplained young onset end-stage renal disease v3.36 CLCNKB Achchuthan Shanmugasundram Phenotypes for gene: CLCNKB were changed from Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 3, MONDO:0011822; Bartter disease type 4B, MONDO:0000909; Bartter syndrome, type 3, OMIM:607364 to Bartter syndrome, type 3, OMIM:607364; Bartter disease type 3, MONDO:0011822
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Tag monogenic-polygenic tag was added to gene: CLCNKB.
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Sarah Leigh in 'R256 Nephrocalcinosis or nephrolithiasis' and 'R198 Renal tubulopathies' panels, the mode of inheritance for CLCNKB should be BIALLELIC, autosomal or pseudoautosomal. Although digenic CLCNKB & CLCNKA variants are associated with Bartter syndrome, type 4b, digenic (OMIM:613090), this phenotype is not relevant to this panel and the current GMS rare disease bioinformatic pipeline does not allow for interpretation of digenic events.
Unexplained young onset end-stage renal disease v3.35 CLCNKB Achchuthan Shanmugasundram Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.34 CLCNKB Achchuthan Shanmugasundram edited their review of gene: CLCNKB: Changed publications to: 120550, 9326936, 15717167; Changed phenotypes to: Bartter syndrome, type 3, OMIM:607364, Bartter disease type 3, MONDO:0011822; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.34 WDR72 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis'(https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis' (https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 WDR72 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/) and 'R256 Nephrocalcinosis or nephrolithiasis'(https://panelapp.genomicsengland.co.uk/panels/149/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.; to: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Classified gene: RMND1 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/RMND1/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.34 RMND1 Achchuthan Shanmugasundram Gene: rmnd1 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.33 RMND1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RMND1.
Unexplained young onset end-stage renal disease v3.33 RMND1 Achchuthan Shanmugasundram gene: RMND1 was added
gene: RMND1 was added to Unexplained young onset end-stage renal disease. Sources: Literature
Mode of inheritance for gene: RMND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RMND1 were set to 31568715; 31889854; 32911714
Phenotypes for gene: RMND1 were set to Combined oxidative phosphorylation deficiency 11, OMIM:614922
Review for gene: RMND1 was set to GREEN
Added comment: PMID:31568715 - Four patients identified with pathogenic variants in RMND1 were reported with renal disease characterised by tubulopathy (3/4), renal tubular acidosis (2/4), interstitial nephritis (1/4), and/or end-stage renal disease (4/4) necessitating renal transplantation (2/4).

PMID:31889854 - A very rare homozygous pathogenic variant in RMND1 (p.Val211Met) was identified in a patient presenting with chronic kidney disease (CKD) and sensorineural hearing loss (SNHL).

PMID:32911714 - Compound heterozygous missense variants in RMND1 (p.Gly195Arg & p.Tyr273Ser) was identified in female siblings presenting with severe-to-profound bilateral SNHL, ovarian dysfunction and CKD that developed in the fourth decade of life.

This gene has been associated with relevant phenotypes in both OMIM (MIM #614922) and Gene2Phenotype. The clinical manifestations such as cystic kidneys, renal tubular acidosis and renal disease have been recorded as part of the OMIM phenotype.
Sources: Literature
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Classified gene: WDR72 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'R198 Renal tubulopathies' panel (https://panelapp.genomicsengland.co.uk/panels/292/gene/WDR72/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.32 WDR72 Achchuthan Shanmugasundram Gene: wdr72 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.31 WDR72 Achchuthan Shanmugasundram Phenotypes for gene: WDR72 were changed from Amelogenesis imperfecta, type IIA3, OMIM:613211 to hereditary distal renal tubular acidosis; distal renal tubular acidosis, MONDO:0015827; Amelogenesis imperfecta, type IIA3, OMIM:613211; amelogenesis imperfecta hypomaturation type 2A3, MONDO:0013181
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: WDR72.
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram edited their review of gene: WDR72: Changed phenotypes to: hereditary distal renal tubular acidosis, distal renal tubular acidosis, MONDO:0015827, Amelogenesis imperfecta, type IIA3, OMIM:613211, amelogenesis imperfecta hypomaturation type 2A3, MONDO:0013181
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram edited their review of gene: WDR72: Changed rating: GREEN
Unexplained young onset end-stage renal disease v3.30 WDR72 Achchuthan Shanmugasundram gene: WDR72 was added
gene: WDR72 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to 30028003; 30779877; 31959358; 33033857
Phenotypes for gene: WDR72 were set to Amelogenesis imperfecta, type IIA3, OMIM:613211
Review for gene: WDR72 was set to RED
Added comment: Reviews from Eleanor Williams in 'R198 Renal tubulopathies' panel:

Additional families reported with distal renal tubular acidosis, along with amelogenesis imperfecta.

PMID: 30779877 (Zhang et al 2019) - 6 families (1 African, 5 Turkish) identified using WES with biallelic WDR72 variants. The affected members showed generalized hypomaturation Amelogenesis imperfecta. 2 families, although unrelated, shared the same variant. 3 out of the 8 tested patients showed decreased serum pH, consistent with a diagnosis of renal tubular acidosis.

PMID: 31959358 - (Jobst-Schwan et al 2020) - 2 families (Indian, Turkish) with different homozygous variants in WDR72 identified by WES. All 3 affected individuals had Distal renal tubular acidosis. 1 individual is reported to have nephrocalcinosis.

PMID: 33033857 - Khandelwal et al 2021 - 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Genome analysis of 3 of the patients identified 3 different homozygous nonsense variants in WDR72. Ultrasound showed bilateral grade I medullary nephrocalcinosis in the 3 patients.
Created: 1 Mar 2023, 9:46 p.m. | Last Modified: 1 Mar 2023, 9:46 p.m.

Panel Version: 3.4

Comment on list classification: Rating this gene as amber as 2 reported families to date.
Created: 12 Feb 2019, 10:38 p.m.

No association with a renal phenotype in OMIM (only with Amelogenesis imperfecta) or Gene2Phenotype.

PMID: 30028003 (Rungroj et al 2018) report 2 families, of Thai and Indian ethnicities, with compound heterozygous and homozygous nonsense WDR72 variations respectively. Both were affected by hereditary distal renal tubular acidosis (dRTA). 3 different variants were found in WDR72; c.1777A>G:p.R593G and c.2522T>A:p.L841Q (predicted as disease causing or damaging, found as compound heterzygotes in family 1) and c.2686C>T:p.R896X. (protein truncating, homozygous in family 2). The truncating variant has been previously reported in a Pakistani family affected by hypomaturation AI, however no other clinical phenotypes in the patients were reported (PMID: 21196691).

Patients in family 1 presented with proximal muscle weakness and/or growth retardation at ages under 7 years. One member of family 1 also had nephrolithiasis and localized enamel hypoplasia. Family 2 has consanguineous parents with one affected child which presented with hypoplastic amelogenesis imperfect in addition to dRTA. She also showed nephrocalcinosis.
Created: 12 Feb 2019, 10:36 p.m. | Last Modified: 1 Mar 2023, 7:39 p.m.

Panel Version: 3.4
Sources: Expert Review
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Classified gene: SEC63 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'Cystic kidney disease' panel (https://panelapp.genomicsengland.co.uk/panels/283/gene/SEC63/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.29 SEC63 Achchuthan Shanmugasundram Gene: sec63 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.28 SEC63 Achchuthan Shanmugasundram Phenotypes for gene: SEC63 were changed from to Polycystic liver disease 2 with or without kidney cysts, OMIM:617004
Unexplained young onset end-stage renal disease v3.27 SEC63 Achchuthan Shanmugasundram Publications for gene: SEC63 were set to
Unexplained young onset end-stage renal disease v3.26 SEC63 Achchuthan Shanmugasundram Mode of inheritance for gene: SEC63 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.25 SEC63 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SEC63.
Unexplained young onset end-stage renal disease v3.25 SEC63 Achchuthan Shanmugasundram reviewed gene: SEC63: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886261; Phenotypes: Polycystic liver disease 2 with or without kidney cysts, OMIM:617004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.25 PRKCSH Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PRKCSH.
Unexplained young onset end-stage renal disease v3.25 PRKCSH Achchuthan Shanmugasundram Phenotypes for gene: PRKCSH were changed from to Polycystic liver disease 1 with or without kidney cysts, OMIM:174050
Unexplained young onset end-stage renal disease v3.24 PRKCSH Achchuthan Shanmugasundram Publications for gene: PRKCSH were set to
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Classified gene: PRKCSH as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Added comment: Comment on list classification: As this gene has been tagged for promotion to green rating in 'Cystic kidney disease' panel (https://panelapp.genomicsengland.co.uk/panels/283/gene/PRKCSH/), this gene should be promoted to green rating in this panel as well.
Unexplained young onset end-stage renal disease v3.23 PRKCSH Achchuthan Shanmugasundram Gene: prkcsh has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.22 PRKCSH Achchuthan Shanmugasundram Mode of inheritance for gene: PRKCSH was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PRKCSH Achchuthan Shanmugasundram reviewed gene: PRKCSH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24886261; Phenotypes: Polycystic liver disease 1 with or without kidney cysts, OMIM:174050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PDSS2 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green in 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/PDSS2/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/PDSS2/).
Unexplained young onset end-stage renal disease v3.21 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.21 FN1 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).
Unexplained young onset end-stage renal disease v3.21 FN1 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green in 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/FN1/).
Unexplained young onset end-stage renal disease v3.21 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R195 Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.21 APRT Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it is already green on 'Nephrocalcinosis or nephrolithiasis' panel (https://panelapp.genomicsengland.co.uk/panels/149/gene/APRT/).; to: This gene should be promoted to green rating in 'R257 Unexplained young onset end-stage renal disease' panel as it is already green on 'R256 Nephrocalcinosis or nephrolithiasis' panel (https://panelapp.genomicsengland.co.uk/panels/149/gene/APRT/).
Unexplained young onset end-stage renal disease v3.21 CASR Achchuthan Shanmugasundram edited their review of gene: CASR: Changed phenotypes to: Familial Hypocalciuric Hypercalcemia, Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,, Hypocalcemia (dominant), Familial Hypocalciuric Hypercalcemia (dominant), hypocalciuric hypercalcaemia
Unexplained young onset end-stage renal disease v3.21 YRDC Achchuthan Shanmugasundram reviewed gene: YRDC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 WNK4 Achchuthan Shanmugasundram reviewed gene: WNK4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IIB, 614491; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 TULP3 Achchuthan Shanmugasundram reviewed gene: TULP3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hepatorenocardiac degenerative fibrosis, OMIM:619902; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 TTR Achchuthan Shanmugasundram reviewed gene: TTR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, hereditary, transthyretin-related 105210; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 TRPM6 Achchuthan Shanmugasundram reviewed gene: TRPM6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 1, intestinal, 602014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 TPRKB Achchuthan Shanmugasundram reviewed gene: TPRKB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome 5, OMIM:617731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 STRADA Achchuthan Shanmugasundram reviewed gene: STRADA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC5A2 Achchuthan Shanmugasundram reviewed gene: SLC5A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal glucosuria, 233100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC4A4 Achchuthan Shanmugasundram reviewed gene: SLC4A4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal tubular acidosis, proximal, with ocular abnormalities, 604278, Proximal Renal Tubular Acidosis with Ocular Abnormalities, Proximal Renal Tubular Acidosis with Ocular Abnormalities (recessive).; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC4A1 Achchuthan Shanmugasundram reviewed gene: SLC4A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Renal tubular acidosis, distal, AD, 179800, distal renal tubular acidosis, Renal tubular acidosis, distal, AR 611590; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC34A3 Achchuthan Shanmugasundram reviewed gene: SLC34A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: hereditary hypophosphatemic rickets with hypercalciuria, MONDO:0009431, Hypophosphatemic rickets with hypercalciuria, OMIM:241530, HHRH; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC34A1 Achchuthan Shanmugasundram reviewed gene: SLC34A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286, Hypophosphatemic Nephrolithiasis/Osteoporosis (recessive), Hypophosphatemic Nephrolithiasis/Osteoporosis, Nephrolithiasis with osteoporosis and hypophosphatemia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC2A2 Achchuthan Shanmugasundram reviewed gene: SLC2A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fanconi-Bickel syndrome, OMIM:227810; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC12A3 Achchuthan Shanmugasundram reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Gitelman syndrome, MONDO:0009904, Gitelman syndrome, OMIM: 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SLC12A1 Achchuthan Shanmugasundram reviewed gene: SLC12A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 1, OMIM:601678, Bartter disease type 1, MONDO:0100344; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1G Achchuthan Shanmugasundram reviewed gene: SCNN1G: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1B Achchuthan Shanmugasundram reviewed gene: SCNN1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SCNN1A Achchuthan Shanmugasundram reviewed gene: SCNN1A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type I, 264350, ?Liddle syndrom 3, 618126, Bronchiectasis with or without elevated sweat chloride 2 613021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 SARS2 Achchuthan Shanmugasundram reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, OMIM:613845, Progressive Spastic Paresis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 RRAGD Achchuthan Shanmugasundram reviewed gene: RRAGD: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: salt wasting, hypomagnesaemia, cardiomyopathy, nephrocalcinosis, tubular renal disease-cardiomyopathy syndrome, MONDO:0019130; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 PHEX Achchuthan Shanmugasundram reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets, X-linked dominant 307800; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Unexplained young onset end-stage renal disease v3.21 NR3C2 Achchuthan Shanmugasundram reviewed gene: NR3C2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism type I, autosomal dominant, 177735, Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy, 605115 no inheritance pattern; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 MOCOS Achchuthan Shanmugasundram reviewed gene: MOCOS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Xanthinuria, type II, OMIM:603592; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 MAGED2 Achchuthan Shanmugasundram reviewed gene: MAGED2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter syndrome, type 5, antenatal, transient, 300971; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Unexplained young onset end-stage renal disease v3.21 LYZ Achchuthan Shanmugasundram reviewed gene: LYZ: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, renal 105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 LCAT Achchuthan Shanmugasundram reviewed gene: LCAT: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Norum disease, MONDO:0009515, LCAT DEFICIENCY, Norum disease, OMIM:245900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KLHL3 Achchuthan Shanmugasundram reviewed gene: KLHL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IID, 614495; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ16 Achchuthan Shanmugasundram reviewed gene: KCNJ16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypokalemic tubulopathy and deafness, OMIM:619406; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ10 Achchuthan Shanmugasundram reviewed gene: KCNJ10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: SESAME/EAST syndrome, 612780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 KCNJ1 Achchuthan Shanmugasundram reviewed gene: KCNJ1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: often initial transient hyperkalemia, Antenatal Bartter Syndrome, Type 2 Bartter syndrome, Bartter syndrome, type 2, 241200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT27 Achchuthan Shanmugasundram reviewed gene: IFT27: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Bardet-Biedl syndrome 19, OMIM:615996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT172 Achchuthan Shanmugasundram reviewed gene: IFT172: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Short-rib thoracic dysplasia 10 with or without polydactyly, OMIM:615630; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 IFT140 Achchuthan Shanmugasundram reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964, cystic kidney disease, MONDO:0002473, Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 HPRT1 Achchuthan Shanmugasundram reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Lesch-Nyhan syndrome, OMIM:300322, Hyperuricemia, HRPT-related, OMIM:300323; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Unexplained young onset end-stage renal disease v3.21 HNF4A Achchuthan Shanmugasundram reviewed gene: HNF4A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM:616026; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 GSN Achchuthan Shanmugasundram reviewed gene: GSN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, Finnish type, OMIM:105120; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 GON7 Achchuthan Shanmugasundram reviewed gene: GON7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Galloway-Mowat syndrome MONDO:0009627; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 GNA11 Achchuthan Shanmugasundram reviewed gene: GNA11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypocalcemia, autosomal dominant 2 615361; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FLCN Achchuthan Shanmugasundram reviewed gene: FLCN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: renal cell carcinoma, Birt-Hogg-Dube syndrome, OMIM:135150, renal oncocytoma, pneumothorax, renal cysts, cutaneous fibrofolliculoma, pulmonary cysts; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FGA Achchuthan Shanmugasundram reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, familial visceral, OMIM:105200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 FAM20A Achchuthan Shanmugasundram reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 FAH Achchuthan Shanmugasundram reviewed gene: FAH: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Tyrosinemia, type I, OMIM:276700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 DLG5 Achchuthan Shanmugasundram reviewed gene: DLG5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: DLG5-associated developmental disorder (biallelic), DLG5-associated developmental disorder (monoallelic); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 DAAM2 Achchuthan Shanmugasundram reviewed gene: DAAM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: steroid-resistant nephrotic syndrome MONDO:0044765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CYP24A1 Achchuthan Shanmugasundram reviewed gene: CYP24A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Infantile hypercalcaemia, Hypercalcemia, infantile, 143880, Infantile Hypercalcemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CUL3 Achchuthan Shanmugasundram reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Pseudohypoaldosteronism, type IIE, 214496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 CNNM2 Achchuthan Shanmugasundram reviewed gene: CNNM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: renal hypomagnesemia 6, MONDO:0013480, Hypomagnesemia, seizures, and mental retardation, MONDO:0014631, Hypomagnesemia 6, renal, OMIM:613882, Hypomagnesemia, seizures, and mental retardation, OMIM:616418; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN19 Achchuthan Shanmugasundram reviewed gene: CLDN19: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 5, renal, with ocular involvement, hypomagensemia with nephrocalcinosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN16 Achchuthan Shanmugasundram reviewed gene: CLDN16: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia 3, renal; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLDN10 Achchuthan Shanmugasundram reviewed gene: CLDN10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypokalemic-alkalotic salt-losing tubulopathy, HELIX syndrome, OMIM:617671; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CLCNKB Achchuthan Shanmugasundram reviewed gene: CLCNKB: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bartter disease type 4B, MONDO:0000909, Bartter syndrome, type 4b, digenic, OMIM:613090, Bartter syndrome, type 3, OMIM:607364, Bartter disease type 3, MONDO:0011822; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CFHR2 Achchuthan Shanmugasundram reviewed gene: CFHR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: C3 glomerulopathy, Immune complex MPGN, Immune-complex-mediated MPGN, IC-MPGN, C3G; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CASR Achchuthan Shanmugasundram reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Familial Hypocalciuric Hypercalcemia, Hypocalcemia (dominant), hypocalciuric hypercalcaemia, Familial Hypocalciuric Hypercalcemia (dominant), Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 CA2 Achchuthan Shanmugasundram reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 AVPR2 Achchuthan Shanmugasundram reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539, Diabetes insipidus, nephrogenic, OMIM:304800; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Unexplained young onset end-stage renal disease v3.21 ATP6V1B1 Achchuthan Shanmugasundram reviewed gene: ATP6V1B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: distal renal tubular acidosis, Renal tubular acidosis with deafness 267300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ATP6V0A4 Achchuthan Shanmugasundram reviewed gene: ATP6V0A4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ATP1A1 Achchuthan Shanmugasundram reviewed gene: ATP1A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypomagnesemia, seizures, and mental retardation 2 618314, Charcot-Marie-Tooth disease, axonal, type 2DD, 618036; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 AQP2 Achchuthan Shanmugasundram reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic, 125800, Nephrogenic diabetes insipidus; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 APOE Achchuthan Shanmugasundram reviewed gene: APOE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Lipoprotein glomerulopathy, OMIM:611771; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOC2 Achchuthan Shanmugasundram reviewed gene: APOC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOA2 Achchuthan Shanmugasundram reviewed gene: APOA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 APOA1 Achchuthan Shanmugasundram reviewed gene: APOA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Amyloidosis, 3 or more types OMIM:105200, familial visceral amyloidosis MONDO:0007099; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 AP2S1 Achchuthan Shanmugasundram reviewed gene: AP2S1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Familial hypocalciuric hypercalcemia type III 600740; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.21 ALG9 Achchuthan Shanmugasundram reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: cystic liver disease, cystic kidney disease, Gillessen-Kaesbach-Nishimura syndrome, 263210; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.21 ALG8 Achchuthan Shanmugasundram reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: cystic liver disease, Polycystic liver disease 3 with or without kidney cysts, 617874, cystic kidney disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.21 ALG5 Achchuthan Shanmugasundram reviewed gene: ALG5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Polycystic kidney disease 7, OMIM:620056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v3.20 FAH Achchuthan Shanmugasundram Phenotypes for gene: FAH were changed from Tyrosinemia, type I,OMIM:276700 to Tyrosinemia, type I, OMIM:276700
Unexplained young onset end-stage renal disease v3.19 FAH Achchuthan Shanmugasundram Phenotypes for gene: FAH were changed from Tyrosinemia, type I to Tyrosinemia, type I,OMIM:276700
Unexplained young onset end-stage renal disease v3.18 WNK4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: WNK4.
Unexplained young onset end-stage renal disease v3.18 YRDC Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: YRDC.
Unexplained young onset end-stage renal disease v3.18 TTR Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TTR.
Unexplained young onset end-stage renal disease v3.18 TULP3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TULP3.
Unexplained young onset end-stage renal disease v3.18 TRPM6 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TRPM6.
Unexplained young onset end-stage renal disease v3.18 TPRKB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: TPRKB.
Unexplained young onset end-stage renal disease v3.18 STRADA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: STRADA.
Unexplained young onset end-stage renal disease v3.18 SLC5A2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC5A2.
Unexplained young onset end-stage renal disease v3.18 SLC4A4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC4A4.
Unexplained young onset end-stage renal disease v3.18 SLC4A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC4A1.
Unexplained young onset end-stage renal disease v3.18 SLC34A3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC34A3.
Unexplained young onset end-stage renal disease v3.18 SLC34A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC34A1.
Unexplained young onset end-stage renal disease v3.18 SLC2A2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC2A2.
Unexplained young onset end-stage renal disease v3.18 SLC12A3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC12A3.
Unexplained young onset end-stage renal disease v3.18 SLC12A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SLC12A1.
Unexplained young onset end-stage renal disease v3.18 SCNN1G Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1G.
Unexplained young onset end-stage renal disease v3.18 SCNN1B Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1B.
Unexplained young onset end-stage renal disease v3.18 SCNN1A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SCNN1A.
Unexplained young onset end-stage renal disease v3.18 SARS2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: SARS2.
Unexplained young onset end-stage renal disease v3.18 RRAGD Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RRAGD.
Unexplained young onset end-stage renal disease v3.18 PHEX Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PHEX.
Unexplained young onset end-stage renal disease v3.18 NR3C2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NR3C2.
Unexplained young onset end-stage renal disease v3.18 MOCOS Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MOCOS.
Unexplained young onset end-stage renal disease v3.18 MAGED2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MAGED2.
Unexplained young onset end-stage renal disease v3.18 LYZ Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: LYZ.
Unexplained young onset end-stage renal disease v3.18 LCAT Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: LCAT.
Unexplained young onset end-stage renal disease v3.18 KLHL3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KLHL3.
Unexplained young onset end-stage renal disease v3.18 KCNJ16 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ16.
Unexplained young onset end-stage renal disease v3.18 KCNJ10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ10.
Unexplained young onset end-stage renal disease v3.18 KCNJ1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: KCNJ1.
Unexplained young onset end-stage renal disease v3.18 IFT27 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT27.
Unexplained young onset end-stage renal disease v3.18 IFT172 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT172.
Unexplained young onset end-stage renal disease v3.18 IFT140 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IFT140.
Unexplained young onset end-stage renal disease v3.18 HPRT1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HPRT1.
Unexplained young onset end-stage renal disease v3.18 HNF4A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HNF4A.
Unexplained young onset end-stage renal disease v3.18 GSN Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GSN.
Unexplained young onset end-stage renal disease v3.18 GON7 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GON7.
Unexplained young onset end-stage renal disease v3.18 GNA11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: GNA11.
Unexplained young onset end-stage renal disease v3.18 FLCN Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FLCN.
Unexplained young onset end-stage renal disease v3.18 FGA Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FGA.
Unexplained young onset end-stage renal disease v3.18 FAM20A Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FAM20A.
Unexplained young onset end-stage renal disease v3.18 FAH Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FAH.
Unexplained young onset end-stage renal disease v3.18 DLG5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DLG5.
Unexplained young onset end-stage renal disease v3.18 DAAM2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DAAM2.
Unexplained young onset end-stage renal disease v3.18 CYP24A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CYP24A1.
Unexplained young onset end-stage renal disease v3.18 CUL3 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CUL3.
Unexplained young onset end-stage renal disease v3.18 CNNM2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CNNM2.
Unexplained young onset end-stage renal disease v3.18 CLDN19 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN19.
Unexplained young onset end-stage renal disease v3.18 CLDN16 Achchuthan Shanmugasundram Phenotypes for gene: CLDN16 were changed from Hypomagnesemia 3, renal 248250; Hypomagnesemia 3, renal to Hypomagnesemia 3, renal, OMIM: 248250
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN16.
Unexplained young onset end-stage renal disease v3.17 CLDN10 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN10.
Unexplained young onset end-stage renal disease v3.17 CLCNKB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLCNKB.
Unexplained young onset end-stage renal disease v3.17 CFHR2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CFHR2.
Unexplained young onset end-stage renal disease v3.17 CA2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CA2.
Unexplained young onset end-stage renal disease v3.17 CASR Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CASR.
Unexplained young onset end-stage renal disease v3.17 AVPR2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: AVPR2.
Unexplained young onset end-stage renal disease v3.17 ATP6V1B1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP6V1B1.
Unexplained young onset end-stage renal disease v3.17 ATP6V0A4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP6V0A4.
Unexplained young onset end-stage renal disease v3.17 ATP1A1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ATP1A1.
Unexplained young onset end-stage renal disease v3.17 APOE Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOE.
Unexplained young onset end-stage renal disease v3.17 APOC2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOC2.
Unexplained young onset end-stage renal disease v3.17 APOA2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOA2.
Unexplained young onset end-stage renal disease v3.17 APOA1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APOA1.
Unexplained young onset end-stage renal disease v3.17 AP2S1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: AP2S1.
Unexplained young onset end-stage renal disease v3.17 ALG9 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG9.
Unexplained young onset end-stage renal disease v3.17 ALG8 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG8.
Unexplained young onset end-stage renal disease v3.17 ALG5 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: ALG5.
Unexplained young onset end-stage renal disease v3.17 YRDC Achchuthan Shanmugasundram gene: YRDC was added
gene: YRDC was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome MONDO:0009627
Unexplained young onset end-stage renal disease v3.17 WNK4 Achchuthan Shanmugasundram gene: WNK4 was added
gene: WNK4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB, 614491
Unexplained young onset end-stage renal disease v3.17 TULP3 Achchuthan Shanmugasundram gene: TULP3 was added
gene: TULP3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TULP3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TULP3 were set to Hepatorenocardiac degenerative fibrosis, OMIM:619902
Unexplained young onset end-stage renal disease v3.17 TTR Achchuthan Shanmugasundram gene: TTR was added
gene: TTR was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TTR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TTR were set to Amyloidosis, hereditary, transthyretin-related 105210
Unexplained young onset end-stage renal disease v3.17 TRPM6 Achchuthan Shanmugasundram gene: TRPM6 was added
gene: TRPM6 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal, 602014
Unexplained young onset end-stage renal disease v3.17 TPRKB Achchuthan Shanmugasundram gene: TPRKB was added
gene: TPRKB was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TPRKB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TPRKB were set to Galloway-Mowat syndrome 5, OMIM:617731
Unexplained young onset end-stage renal disease v3.17 STRADA Achchuthan Shanmugasundram gene: STRADA was added
gene: STRADA was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: STRADA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STRADA were set to Polyhydramnios, megalencephaly, and symptomatic epilepsy, 611087
Unexplained young onset end-stage renal disease v3.17 SLC5A2 Achchuthan Shanmugasundram gene: SLC5A2 was added
gene: SLC5A2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC5A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC5A2 were set to Renal glucosuria, 233100
Unexplained young onset end-stage renal disease v3.17 SLC4A4 Achchuthan Shanmugasundram gene: SLC4A4 was added
gene: SLC4A4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC4A4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC4A4 were set to Renal tubular acidosis, proximal, with ocular abnormalities, 604278; Proximal Renal Tubular Acidosis with Ocular Abnormalities; Proximal Renal Tubular Acidosis with Ocular Abnormalities (recessive).
Unexplained young onset end-stage renal disease v3.17 SLC4A1 Achchuthan Shanmugasundram gene: SLC4A1 was added
gene: SLC4A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC4A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC4A1 were set to Renal tubular acidosis, distal, AR 611590; distal renal tubular acidosis; Renal tubular acidosis, distal, AD, 179800
Unexplained young onset end-stage renal disease v3.17 SLC34A3 Achchuthan Shanmugasundram gene: SLC34A3 was added
gene: SLC34A3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC34A3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: SLC34A3 were set to hereditary hypophosphatemic rickets with hypercalciuria, MONDO:0009431; HHRH; Hypophosphatemic rickets with hypercalciuria, OMIM:241530
Unexplained young onset end-stage renal disease v3.17 SLC34A1 Achchuthan Shanmugasundram gene: SLC34A1 was added
gene: SLC34A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC34A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SLC34A1 were set to Nephrolithiasis with osteoporosis and hypophosphatemia; Hypophosphatemic Nephrolithiasis/Osteoporosis (recessive); Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286; Hypophosphatemic Nephrolithiasis/Osteoporosis
Unexplained young onset end-stage renal disease v3.17 SLC2A2 Achchuthan Shanmugasundram gene: SLC2A2 was added
gene: SLC2A2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC2A2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC2A2 were set to Fanconi-Bickel syndrome, OMIM:227810
Unexplained young onset end-stage renal disease v3.17 SLC12A3 Achchuthan Shanmugasundram gene: SLC12A3 was added
gene: SLC12A3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC12A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC12A3 were set to Gitelman syndrome, OMIM: 263800; Gitelman syndrome, MONDO:0009904
Unexplained young onset end-stage renal disease v3.17 SLC12A1 Achchuthan Shanmugasundram gene: SLC12A1 was added
gene: SLC12A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SLC12A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC12A1 were set to Bartter syndrome, type 1, OMIM:601678; Bartter disease type 1, MONDO:0100344
Unexplained young onset end-stage renal disease v3.17 SCNN1G Achchuthan Shanmugasundram gene: SCNN1G was added
gene: SCNN1G was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1G was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1G were set to Pseudohypoaldosteronism, type I, 264350
Unexplained young onset end-stage renal disease v3.17 SCNN1B Achchuthan Shanmugasundram gene: SCNN1B was added
gene: SCNN1B was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1B were set to Pseudohypoaldosteronism, type I, 264350
Unexplained young onset end-stage renal disease v3.17 SCNN1A Achchuthan Shanmugasundram gene: SCNN1A was added
gene: SCNN1A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SCNN1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SCNN1A were set to Pseudohypoaldosteronism, type I, 264350; ?Liddle syndrom 3, 618126; Bronchiectasis with or without elevated sweat chloride 2 613021
Unexplained young onset end-stage renal disease v3.17 SARS2 Achchuthan Shanmugasundram gene: SARS2 was added
gene: SARS2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SARS2 were set to Progressive Spastic Paresis; Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, OMIM:613845
Unexplained young onset end-stage renal disease v3.17 RRAGD Achchuthan Shanmugasundram gene: RRAGD was added
gene: RRAGD was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RRAGD were set to salt wasting; tubular renal disease-cardiomyopathy syndrome, MONDO:0019130; cardiomyopathy; hypomagnesaemia; nephrocalcinosis
Mode of pathogenicity for gene: RRAGD was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Unexplained young onset end-stage renal disease v3.17 PHEX Achchuthan Shanmugasundram gene: PHEX was added
gene: PHEX was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: PHEX were set to Hypophosphatemic rickets, X-linked dominant 307800
Unexplained young onset end-stage renal disease v3.17 NR3C2 Achchuthan Shanmugasundram gene: NR3C2 was added
gene: NR3C2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: NR3C2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NR3C2 were set to Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy, 605115 no inheritance pattern; Pseudohypoaldosteronism type I, autosomal dominant, 177735
Unexplained young onset end-stage renal disease v3.17 MOCOS Achchuthan Shanmugasundram gene: MOCOS was added
gene: MOCOS was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: MOCOS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MOCOS were set to Xanthinuria, type II, OMIM:603592
Unexplained young onset end-stage renal disease v3.17 MAGED2 Achchuthan Shanmugasundram gene: MAGED2 was added
gene: MAGED2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: MAGED2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MAGED2 were set to Bartter syndrome, type 5, antenatal, transient, 300971
Unexplained young onset end-stage renal disease v3.17 LYZ Achchuthan Shanmugasundram gene: LYZ was added
gene: LYZ was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: LYZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LYZ were set to Amyloidosis, renal 105200
Unexplained young onset end-stage renal disease v3.17 LCAT Achchuthan Shanmugasundram gene: LCAT was added
gene: LCAT was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: LCAT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LCAT were set to Norum disease, OMIM:245900; Norum disease, MONDO:0009515; LCAT DEFICIENCY
Unexplained young onset end-stage renal disease v3.17 KLHL3 Achchuthan Shanmugasundram gene: KLHL3 was added
gene: KLHL3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KLHL3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: KLHL3 were set to Pseudohypoaldosteronism, type IID, 614495
Unexplained young onset end-stage renal disease v3.17 KCNJ16 Achchuthan Shanmugasundram gene: KCNJ16 was added
gene: KCNJ16 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ16 were set to Hypokalemic tubulopathy and deafness, OMIM:619406
Unexplained young onset end-stage renal disease v3.17 KCNJ10 Achchuthan Shanmugasundram gene: KCNJ10 was added
gene: KCNJ10 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ10 were set to SESAME/EAST syndrome, 612780
Unexplained young onset end-stage renal disease v3.17 KCNJ1 Achchuthan Shanmugasundram gene: KCNJ1 was added
gene: KCNJ1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KCNJ1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ1 were set to often initial transient hyperkalemia; Antenatal Bartter Syndrome; Bartter syndrome, type 2, 241200; Type 2 Bartter syndrome
Unexplained young onset end-stage renal disease v3.17 IFT27 Achchuthan Shanmugasundram gene: IFT27 was added
gene: IFT27 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT27 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFT27 were set to ?Bardet-Biedl syndrome 19, OMIM:615996
Unexplained young onset end-stage renal disease v3.17 IFT172 Achchuthan Shanmugasundram gene: IFT172 was added
gene: IFT172 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT172 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFT172 were set to Short-rib thoracic dysplasia 10 with or without polydactyly, OMIM:615630
Unexplained young onset end-stage renal disease v3.17 IFT140 Achchuthan Shanmugasundram gene: IFT140 was added
gene: IFT140 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: IFT140 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: IFT140 were set to Short-rib thoracic dysplasia 9 with or without polydactyly, OMIM:266920; cystic kidney disease, MONDO:0002473; short-rib thoracic dysplasia 9 with or without polydactyly, MONDO:0009964
Unexplained young onset end-stage renal disease v3.17 HPRT1 Achchuthan Shanmugasundram gene: HPRT1 was added
gene: HPRT1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: HPRT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: HPRT1 were set to Lesch-Nyhan syndrome, OMIM:300322; Hyperuricemia, HRPT-related, OMIM:300323
Unexplained young onset end-stage renal disease v3.17 HNF4A Achchuthan Shanmugasundram gene: HNF4A was added
gene: HNF4A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: HNF4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: HNF4A were set to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM:616026
Unexplained young onset end-stage renal disease v3.17 GSN Achchuthan Shanmugasundram gene: GSN was added
gene: GSN was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GSN was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: GSN were set to Amyloidosis, Finnish type, OMIM:105120
Unexplained young onset end-stage renal disease v3.17 GON7 Achchuthan Shanmugasundram gene: GON7 was added
gene: GON7 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome MONDO:0009627
Unexplained young onset end-stage renal disease v3.17 GNA11 Achchuthan Shanmugasundram gene: GNA11 was added
gene: GNA11 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: GNA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GNA11 were set to Hypocalcemia, autosomal dominant 2 615361
Unexplained young onset end-stage renal disease v3.17 FLCN Achchuthan Shanmugasundram gene: FLCN was added
gene: FLCN was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FLCN were set to Birt-Hogg-Dube syndrome, OMIM:135150; renal cell carcinoma; renal cysts; pneumothorax; renal oncocytoma; pulmonary cysts; cutaneous fibrofolliculoma
Unexplained young onset end-stage renal disease v3.17 FGA Achchuthan Shanmugasundram gene: FGA was added
gene: FGA was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FGA were set to Amyloidosis, familial visceral, OMIM:105200
Unexplained young onset end-stage renal disease v3.17 FAM20A Achchuthan Shanmugasundram gene: FAM20A was added
gene: FAM20A was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FAM20A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAM20A were set to Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690
Unexplained young onset end-stage renal disease v3.17 FAH Achchuthan Shanmugasundram gene: FAH was added
gene: FAH was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAH were set to Tyrosinemia, type I
Unexplained young onset end-stage renal disease v3.17 DLG5 Achchuthan Shanmugasundram gene: DLG5 was added
gene: DLG5 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: DLG5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DLG5 were set to DLG5-associated developmental disorder (monoallelic); DLG5-associated developmental disorder (biallelic)
Unexplained young onset end-stage renal disease v3.17 DAAM2 Achchuthan Shanmugasundram gene: DAAM2 was added
gene: DAAM2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: DAAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DAAM2 were set to steroid-resistant nephrotic syndrome MONDO:0044765
Unexplained young onset end-stage renal disease v3.17 CYP24A1 Achchuthan Shanmugasundram gene: CYP24A1 was added
gene: CYP24A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CYP24A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYP24A1 were set to Infantile hypercalcaemia; Infantile Hypercalcemia; Hypercalcemia, infantile, 143880
Unexplained young onset end-stage renal disease v3.17 CUL3 Achchuthan Shanmugasundram gene: CUL3 was added
gene: CUL3 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CUL3 were set to Pseudohypoaldosteronism, type IIE, 214496
Unexplained young onset end-stage renal disease v3.17 CNNM2 Achchuthan Shanmugasundram gene: CNNM2 was added
gene: CNNM2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CNNM2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: CNNM2 were set to Hypomagnesemia, seizures, and mental retardation, OMIM:616418; renal hypomagnesemia 6, MONDO:0013480; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631; Hypomagnesemia 6, renal, OMIM:613882
Mode of pathogenicity for gene: CNNM2 was set to Other
Unexplained young onset end-stage renal disease v3.17 CLDN19 Achchuthan Shanmugasundram gene: CLDN19 was added
gene: CLDN19 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN19 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN19 were set to hypomagensemia with nephrocalcinosis; Hypomagnesemia 5, renal, with ocular involvement
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram Added phenotypes Hypomagnesemia 3, renal 248250 for gene: CLDN16
Unexplained young onset end-stage renal disease v3.17 CLDN16 Achchuthan Shanmugasundram gene: CLDN16 was added
gene: CLDN16 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN16 were set to Hypomagnesemia 3, renal
Unexplained young onset end-stage renal disease v3.17 CLDN10 Achchuthan Shanmugasundram gene: CLDN10 was added
gene: CLDN10 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLDN10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CLDN10 were set to HELIX syndrome, OMIM:617671; Hypokalemic-alkalotic salt-losing tubulopathy
Unexplained young onset end-stage renal disease v3.17 CLCNKB Achchuthan Shanmugasundram gene: CLCNKB was added
gene: CLCNKB was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CLCNKB was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: CLCNKB were set to Bartter syndrome, type 4b, digenic, OMIM:613090; Bartter disease type 3, MONDO:0011822; Bartter disease type 4B, MONDO:0000909; Bartter syndrome, type 3, OMIM:607364
Unexplained young onset end-stage renal disease v3.17 CFHR2 Achchuthan Shanmugasundram gene: CFHR2 was added
gene: CFHR2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CFHR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CFHR2 were set to Immune complex MPGN; IC-MPGN; C3 glomerulopathy; C3G; Immune-complex-mediated MPGN
Unexplained young onset end-stage renal disease v3.17 CASR Achchuthan Shanmugasundram gene: CASR was added
gene: CASR was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CASR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CASR were set to Hypocalcemia (dominant); Hypocalciuric hypercalcemia, type I, 145980Hyperparathyroidism, neonatal, 239200Hypocalcemia, autosomal dominant, 601198Hypocalcemia, autosomal dominant, with Bartter syndrome, 601198{Epilepsy idiopathic generalized, susceptibility to,; Familial Hypocalciuric Hypercalcemia (dominant); hypocalciuric hypercalcaemia; Familial Hypocalciuric Hypercalcemia
Mode of pathogenicity for gene: CASR was set to Other
Unexplained young onset end-stage renal disease v3.17 CA2 Achchuthan Shanmugasundram gene: CA2 was added
gene: CA2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis
Unexplained young onset end-stage renal disease v3.17 AVPR2 Achchuthan Shanmugasundram gene: AVPR2 was added
gene: AVPR2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AVPR2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: AVPR2 were set to Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539; Diabetes insipidus, nephrogenic, OMIM:304800
Mode of pathogenicity for gene: AVPR2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Unexplained young onset end-stage renal disease v3.17 ATP6V1B1 Achchuthan Shanmugasundram gene: ATP6V1B1 was added
gene: ATP6V1B1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP6V1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP6V1B1 were set to Renal tubular acidosis with deafness 267300; distal renal tubular acidosis
Unexplained young onset end-stage renal disease v3.17 ATP6V0A4 Achchuthan Shanmugasundram gene: ATP6V0A4 was added
gene: ATP6V0A4 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP6V0A4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP6V0A4 were set to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Unexplained young onset end-stage renal disease v3.17 ATP1A1 Achchuthan Shanmugasundram gene: ATP1A1 was added
gene: ATP1A1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATP1A1 were set to Hypomagnesemia, seizures, and mental retardation 2 618314; Charcot-Marie-Tooth disease, axonal, type 2DD, 618036
Unexplained young onset end-stage renal disease v3.17 AQP2 Achchuthan Shanmugasundram gene: AQP2 was added
gene: AQP2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AQP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: AQP2 were set to Nephrogenic diabetes insipidus; Diabetes insipidus, nephrogenic, 125800
Unexplained young onset end-stage renal disease v3.17 APOE Achchuthan Shanmugasundram gene: APOE was added
gene: APOE was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APOE were set to Lipoprotein glomerulopathy, OMIM:611771
Unexplained young onset end-stage renal disease v3.17 APOC2 Achchuthan Shanmugasundram gene: APOC2 was added
gene: APOC2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.17 APOA2 Achchuthan Shanmugasundram gene: APOA2 was added
gene: APOA2 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.17 APOA1 Achchuthan Shanmugasundram gene: APOA1 was added
gene: APOA1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: APOA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APOA1 were set to Amyloidosis, 3 or more types OMIM:105200; familial visceral amyloidosis MONDO:0007099
Unexplained young onset end-stage renal disease v3.17 AP2S1 Achchuthan Shanmugasundram gene: AP2S1 was added
gene: AP2S1 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: AP2S1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AP2S1 were set to Familial hypocalciuric hypercalcemia type III 600740
Unexplained young onset end-stage renal disease v3.17 ALG9 Achchuthan Shanmugasundram gene: ALG9 was added
gene: ALG9 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG9 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: ALG9 were set to cystic liver disease; cystic kidney disease; Gillessen-Kaesbach-Nishimura syndrome, 263210
Unexplained young onset end-stage renal disease v3.17 ALG8 Achchuthan Shanmugasundram gene: ALG8 was added
gene: ALG8 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALG8 were set to cystic liver disease; cystic kidney disease; Polycystic liver disease 3 with or without kidney cysts, 617874
Unexplained young onset end-stage renal disease v3.17 ALG5 Achchuthan Shanmugasundram gene: ALG5 was added
gene: ALG5 was added to Unexplained young onset end-stage renal disease. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ALG5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ALG5 were set to Polycystic kidney disease 7, OMIM:620056
Unexplained young onset end-stage renal disease v3.16 FN1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: FN1.
Unexplained young onset end-stage renal disease v3.16 PDSS2 Achchuthan Shanmugasundram Classified gene: PDSS2 as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v3.16 PDSS2 Achchuthan Shanmugasundram Gene: pdss2 has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v3.15 PDSS2 Achchuthan Shanmugasundram Phenotypes for gene: PDSS2 were changed from to Coenzyme Q10 deficiency, primary, 3, OMIM:614652; Leigh syndrome, MONDO:0009723
Unexplained young onset end-stage renal disease v3.14 PDSS2 Achchuthan Shanmugasundram Mode of inheritance for gene: PDSS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.13 PDSS2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: PDSS2.
Unexplained young onset end-stage renal disease v3.13 PDSS2 Achchuthan Shanmugasundram reviewed gene: PDSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coenzyme Q10 deficiency, primary, 3, OMIM:614652, Leigh syndrome, MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.13 FN1 Achchuthan Shanmugasundram reviewed gene: FN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glomerulopathy with fibronectin deposits 2, OMIM:601894; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Unexplained young onset end-stage renal disease v3.13 CD151 Achchuthan Shanmugasundram Phenotypes for gene: CD151 were changed from Nephropathy with pretibial epidermolysis bullosa and deafness 609057 to Epidermolysis bullosa simplex 7, with nephropathy and deafness, OMIM:609057
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CD151.
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram changed review comment from: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/); to: This gene should be promoted to green rating in this panel as it has already been rated green on 'Proteinuric renal disease' panel (https://panelapp.genomicsengland.co.uk/panels/106/gene/CD151/).
Unexplained young onset end-stage renal disease v3.12 CD151 Achchuthan Shanmugasundram reviewed gene: CD151: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epidermolysis bullosa simplex 7, with nephropathy and deafness, OMIM:609057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v3.12 APRT Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: APRT.
Unexplained young onset end-stage renal disease v3.12 APRT Achchuthan Shanmugasundram Phenotypes for gene: APRT were changed from interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723 to Adenine phosphoribosyltransferase deficiency, OMIM:614723
Unexplained young onset end-stage renal disease v3.11 APRT Achchuthan Shanmugasundram reviewed gene: APRT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adenine phosphoribosyltransferase deficiency, OMIM:614723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Classified gene: CRAT as Amber List (moderate evidence)
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case each with NBIA and Leigh syndrome. Hence, this gene can be promoted to amber with current evidence.
Mitochondrial disorders v4.155 CRAT Achchuthan Shanmugasundram Gene: crat has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Classified gene: CRAT as Amber List (moderate evidence)
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is one case with NBIA and Leigh syndrome. Hence, this gene can be promoted to amber with current evidence.
Mitochondrial disorders v4.154 CRAT Achchuthan Shanmugasundram Gene: crat has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.153 CRAT Achchuthan Shanmugasundram edited their review of gene: CRAT: Changed phenotypes to: ?Neurodegeneration with brain iron accumulation 8, OMIM:617917, Leigh syndrome, MONDO:0009723
Mitochondrial disorders v4.153 CRAT Achchuthan Shanmugasundram Phenotypes for gene: CRAT were changed from ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, OMIM:MONDO:0009723 to ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, MONDO:0009723
Mitochondrial disorders v4.152 CRAT Achchuthan Shanmugasundram Phenotypes for gene: CRAT were changed from ?Neurodegeneration with brain iron accumulation 8 617917 to ?Neurodegeneration with brain iron accumulation 8, OMIM:617917; Leigh syndrome, OMIM:MONDO:0009723
Mitochondrial disorders v4.151 CRAT Achchuthan Shanmugasundram Publications for gene: CRAT were set to 29395073; 29903433; 31448845
Mitochondrial disorders v4.151 CRAT Achchuthan Shanmugasundram Publications for gene: CRAT were set to 29903433; 29395073
Mitochondrial disorders v4.150 CRAT Achchuthan Shanmugasundram Mode of inheritance for gene: CRAT was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.149 CRAT Achchuthan Shanmugasundram reviewed gene: CRAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Neurodegeneration with brain iron accumulation 8, OMIM:617917, Leigh syndrome, OMIM:MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Deleted their comment
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Classified gene: OXA1L as Amber List (moderate evidence)
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is a single family and functional evidence available in support of the association of OXA1L to this panel. Hence, this gene should be promoted to amber.
Mitochondrial disorders v4.149 OXA1L Achchuthan Shanmugasundram Gene: oxa1l has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Classified gene: OXA1L as Amber List (moderate evidence)
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there is a single family and functional evidence available in support of the association of OXA1L to this panel. Hence, this gene should be promoted to amber.
Mitochondrial disorders v4.148 OXA1L Achchuthan Shanmugasundram Gene: oxa1l has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.147 OXA1L Achchuthan Shanmugasundram Publications for gene: OXA1L were set to
Mitochondrial disorders v4.146 OXA1L Achchuthan Shanmugasundram reviewed gene: OXA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Classified gene: FGL2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer and reported in PMID:36243222, there is a child with early-onset systemic inflammation, autoantibodies, and vasculitis and homozygous truncating FGL2 variant and functional evidence are available in support of the disease association. Hence, this gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.162 FGL2 Achchuthan Shanmugasundram Gene: fgl2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.161 FGL2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.161 FGL2 Achchuthan Shanmugasundram Phenotypes for gene: FGL2 were changed from autoinflammatory syndrome, MONDO:0019751 to autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v4.160 FGL2 Achchuthan Shanmugasundram Phenotypes for gene: FGL2 were changed from immunedysregulation; autoimmunity; arthritis; Treg dysfunction; leukocytoclastic vasculitis to autoinflammatory syndrome, MONDO:0019751
Primary immunodeficiency or monogenic inflammatory bowel disease v4.159 FGL2 Achchuthan Shanmugasundram reviewed gene: FGL2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36243222; Phenotypes: autoinflammatory syndrome, MONDO:0019751; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.159 CBLB Achchuthan Shanmugasundram Phenotypes for gene: CBLB were changed from immunedysregulation; autoimmunity; hypothyroidism; diabetes mellitus type I; vitiligo; urticaria; HLH; ITP; autoimmune hemolytic anemia to Autoimmune disease, multisystem, infantile-onset, 3, OMIM:620430
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Classified gene: CBLB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer and reported in PMID:36006710, there are three unrelated cases and functional evidence are available for the association of biallelic CBLB variants with infantile-onset autoimmune disease (MIM #620430). Hence, this gene should be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.158 CBLB Achchuthan Shanmugasundram Gene: cblb has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 CBLB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CBLB.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 CBLB Achchuthan Shanmugasundram reviewed gene: CBLB: Rating: GREEN; Mode of pathogenicity: None; Publications: 36006710; Phenotypes: Autoimmune disease, multisystem, infantile-onset, 3, OMIM:620430; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.399 RPL10 Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998
Intellectual disability - microarray and sequencing v5.399 RPL10 Achchuthan Shanmugasundram Phenotypes for gene: RPL10 were changed from Mental retardation, X-linked, syndromic, 35, 300998 to Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998
Intellectual disability - microarray and sequencing v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability - microarray and sequencing v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability - microarray and sequencing v5.398 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability - microarray and sequencing v5.397 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788; 25316788; 25316788; 35876338
Intellectual disability - microarray and sequencing v5.397 RPL10 Achchuthan Shanmugasundram Publications for gene: RPL10 were set to 25316788
Intellectual disability - microarray and sequencing v5.396 RPL10 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Sarah Leigh and Dmitrijs Rots, all the cases reported previously in literature and recently in PMID:35876338 were males with hemizygous RPL10 variants. The females were carriers and showed fully skewed X inactivation of the mutation-bearing X chromosomes.

In addition, this gene has been associated with relevant phenotypes in both OMIM (MIM #300998) and Gene2Phenotype (with 'definitive' rating on the DD panel). The MOI has been recorded as 'X-linked recessive' in OMIM.

The MOI should therefore be updated 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' in the next GMS review.
Intellectual disability - microarray and sequencing v5.396 RPL10 Achchuthan Shanmugasundram Mode of inheritance for gene: RPL10 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v5.395 RPL10 Achchuthan Shanmugasundram Tag Q4_23_MOI tag was added to gene: RPL10.
Intellectual disability - microarray and sequencing v5.395 RPL10 Achchuthan Shanmugasundram reviewed gene: RPL10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked syndromic 35, OMIM:300998; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability - microarray and sequencing v5.395 RELN Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.; to: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability - microarray and sequencing v5.395 RELN Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: The MOI should be updated from "BIALLELIC, autosomal or pseudoautosomal"to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are three unrelated cases with monoallelic RELN variants and intellectual disability reported in the literature.
Intellectual disability - microarray and sequencing v5.395 RELN Achchuthan Shanmugasundram Mode of inheritance for gene: RELN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.394 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.394 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.393 RELN Achchuthan Shanmugasundram Tag Q4_23_MOI tag was added to gene: RELN.
Intellectual disability - microarray and sequencing v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.393 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), 257320; LISSENCEPHALY 2 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.392 RELN Achchuthan Shanmugasundram Publications for gene: RELN were set to
Intellectual disability - microarray and sequencing v5.391 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 35769015; Phenotypes: Lissencephaly 2 (Norman-Roberts type), OMIM:257320, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh changed review comment from: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; to: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen or Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh changed review comment from: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022). This is because the ALS Gene Curation Expert Panel will only score protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; to: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022), because the ALS Gene Curation Expert Panel only scores protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: DNAJC7.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh edited their review of gene: DNAJC7: Added comment: To date, DNAJC7 variants have not been associated with a phenotype in OMIM, Gen2Phen, Mondo. Numerous DNAJC7 variants have been reported in amyotrophic lateral sclerosis (ALS) patients (PMID: 31768050; 35039179;34233860; 32897108; 37870677; 35456894). ClinGen classifies the gene disease association between DNAJC7 variants and ALS as Limited (27th Oct 2022). This is because the ALS Gene Curation Expert Panel will only score protein truncating variants in DNAJC7 as part of the gene disease association classification process. In a survey of variants from various international sources, Farhan et al (PMID: 31768050) collated five DNAJC7 truncating variants in ALS patients.; Changed rating: GREEN
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Classified gene: DNAJC7 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Adult onset neurodegenerative disorder v4.45 DNAJC7 Sarah Leigh Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.391 CLDN11 Achchuthan Shanmugasundram Deleted their comment
Childhood onset hereditary spastic paraplegia v4.36 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Intellectual disability - microarray and sequencing v5.391 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.391 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.391 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.390 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.390 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Intellectual disability - microarray and sequencing v5.390 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.389 CLDN11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN11.
Intellectual disability - microarray and sequencing v5.389 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Intellectual disability - microarray and sequencing. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. These patients exhibit global developmental delay, particularly motor and speech delay. Intellectual disability was maximally mild in two of three individuals and the intelligence is in a low-normal range in third individual, although IQ testing was not performed in them.

Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes global developmental delay and impaired intellectual development (mild) as clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Adult onset neurodegenerative disorder v4.44 DNAJC7 Sarah Leigh Publications for gene: DNAJC7 were set to https://doi.org/10.1212/NXG.0000000000000503
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Adult onset neurodegenerative disorder v4.43 DNAJC7 Sarah Leigh Classified gene: DNAJC7 as Amber List (moderate evidence)
Adult onset neurodegenerative disorder v4.43 DNAJC7 Sarah Leigh Gene: dnajc7 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.36 RHOB Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID: 32989326 reports RHOB p.Ser73Phe as being gain of function.
Childhood onset hereditary spastic paraplegia v4.36 RHOB Sarah Leigh Mode of pathogenicity for gene: RHOB 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
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh reviewed gene: RHOB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh Classified gene: RHOB as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.35 RHOB Sarah Leigh Gene: rhob has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: KIAA0586.
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Classified gene: KIAA0586 as Amber List (moderate evidence)
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal ciliopathies v3.18 KIAA0586 Sarah Leigh Gene: kiaa0586 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v3.17 KIAA0586 Sarah Leigh reviewed gene: KIAA0586: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes nystagmus as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram Entity copied from Childhood onset hereditary spastic paraplegia v4.34
Albinism or congenital nystagmus v3.4 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Albinism or congenital nystagmus. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: CLDN11.
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Classified gene: CLDN11 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated patients) for the promotion of this gene to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.33 CLDN11 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: CLDN11.
Childhood onset hereditary spastic paraplegia v4.33 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Classified gene: CDKN2A as Amber List (moderate evidence)
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Added comment: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumours, including cutaneous melanoma, pancreatic cancer and tumours of the nervous system such as astrocytomas.

Onset is typically in adulthood but following specialist review, it was agreed that it is appropriate to include the CDKN2A gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.14 CDKN2A Arina Puzriakova Gene: cdkn2a has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v3.26 CLDN11 Achchuthan Shanmugasundram Phenotypes for gene: CLDN11 were changed from Hypomyelinating leukodystrophy to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Childhood solid tumours v4.13 CDKN2A Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: CDKN2A.
Tag Q4_23_NHS_review tag was added to gene: CDKN2A.
Childhood solid tumours v4.13 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from cutaneous melanoma; pancreatic cancer; astrocytomas to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Melanoma pertinent cancer susceptibility v1.2 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from Malignant Melanoma to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Adult solid tumours for rare disease v1.39 CDKN2A Arina Puzriakova Phenotypes for gene: CDKN2A were changed from Familial Malignant Melanoma and Tumors of the Nervous system, Familial Uveal Melanoma to {Melanoma, cutaneous malignant, 2}, OMIM:155601; {Melanoma and neural system tumor syndrome}, OMIM:155755; {Melanoma-pancreatic cancer syndrome}, OMIM:606719
Skeletal ciliopathies v3.17 KIAA0586 Sarah Leigh Publications for gene: KIAA0586 were set to 26166481
Skeletal ciliopathies v3.16 KIAA0586 Sarah Leigh Phenotypes for gene: KIAA0586 were changed from Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546 to Short-rib thoracic dysplasia 14 with polydactyly, OMIM:616546; short-rib thoracic dysplasia 14 with polydactyly, MONDO:0014688
Skeletal ciliopathies v3.15 KIAA0586 Sarah Leigh Classified gene: KIAA0586 as Amber List (moderate evidence)
Skeletal ciliopathies v3.15 KIAA0586 Sarah Leigh Gene: kiaa0586 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.146 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh edited their review of gene: COX5A: Added comment: To date, two COX5A variants have been associated with Mitochondrial complex IV deficiency, nuclear type 20 (OMIM:619064) in two unrelated cases (PMID: 28247525;35246835). Analysis of patient fibroblasts has revealed a reduced enzymatic activity and protein levels of complex IV and several of its subunits, plus, lentiviral complementation rescues the complex IV deficiency (PMID: 28247525;35246835).; Changed rating: GREEN
Childhood solid tumours v4.12 BAP1 Arina Puzriakova changed review comment from: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).; to: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review, it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova changed review comment from: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel, as reviewed by Terri McVeigh (The Royal Marsden NHS).; to: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel. Rare paediatric cases are reported, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Classified gene: BAP1 as Amber List (moderate evidence)
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Added comment: Comment on list classification: Well-established tumour suppressor gene associated with a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma, cutaneous melanoma, malignant mesothelioma on exposure to asbestos, and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.

Onset is typically in adulthood but following specialist review it was agreed that it is appropriate to include the BAP1 gene on this panel, as reviewed by Terri McVeigh (The Royal Marsden NHS).
Childhood solid tumours v4.12 BAP1 Arina Puzriakova Gene: bap1 has been classified as Amber List (Moderate Evidence).
Childhood solid tumours v4.11 BAP1 Arina Puzriakova Tag Q4_23_promote_green tag was added to gene: BAP1.
Tag Q4_23_NHS_review tag was added to gene: BAP1.
Pigmentary skin disorders v3.6 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from TPDS; Melanoma susceptility; TUMOR PREDISPOSITION SYNDROME to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Inherited renal cancer v1.27 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Tumor predisposition syndrome, OMIM:614327; BAP1-related tumor predisposition syndrome, MONDO:0013692; Renal cell carcinoma (disease), MONDO:0005086; Clear cell renal carcinoma, MONDO:0005005 to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Familial melanoma v2.4 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Adult solid tumours for rare disease v1.38 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Melanocytic Tumor syndrome, Familial Uveal Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Melanoma pertinent cancer susceptibility v1.1 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Malignant Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Childhood solid tumours v4.11 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from uveal melanoma; mesothelioma; cholangiocarcioma; cutaneous melanoma; renal cell carcinoma; meningioma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Adult solid tumours cancer susceptibility v2.28 BAP1 Arina Puzriakova Phenotypes for gene: BAP1 were changed from Melanocytic Tumor syndrome, Familial Uveal Melanoma to Tumor predisposition syndrome 1, OMIM:614327; {Uveal melanoma, susceptibility to, 2}, OMIM:606661
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.122 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.85 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex IV deficiency v3.14 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.146 COX5A Sarah Leigh Classified gene: COX5A as Amber List (moderate evidence)
Mitochondrial disorders v4.146 COX5A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.146 COX5A Sarah Leigh Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.145 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Likely inborn error of metabolism - targeted testing not possible v4.121 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Mitochondrial disorder with complex IV deficiency v3.13 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Possible mitochondrial disorder - nuclear genes v3.84 COX5A Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX5A.
Tag Q4_23_NHS_review tag was added to gene: COX5A.
Likely inborn error of metabolism - targeted testing not possible v4.121 COX5A Sarah Leigh Mode of inheritance for gene: COX5A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.145 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Likely inborn error of metabolism - targeted testing not possible v4.120 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from No OMIM phenotype to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorder with complex IV deficiency v3.13 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from Pulmonary arterial hypertension, lactic acidemia, and failure to thrive to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.144 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Possible mitochondrial disorder - nuclear genes v3.84 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525; 35246835
Likely inborn error of metabolism - targeted testing not possible v4.119 COX5A Sarah Leigh Publications for gene: COX5A were set to
Mitochondrial disorder with complex IV deficiency v3.12 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Classified gene: ALK as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:32989326 reported a large cohort study of cerebral palsy, where two patients were identified with monoallelic ALK variants and presented with spastic diplegia with mild tremor or spastic-dystonic diplegia. Hence, this gene can be rated amber with current evidence.
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Gene: alk has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.31 ALK Achchuthan Shanmugasundram reviewed gene: ALK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: spastic diplegia, MONDO:0001167; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Possible mitochondrial disorder - nuclear genes v3.83 COX5A Sarah Leigh Phenotypes for gene: COX5A were changed from Pulmonary arterial hypertension, lactic acidemia, and failure to thrive to ?Mitochondrial complex IV deficiency, nuclear type 20, OMIM:619064; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.82 COX5A Sarah Leigh Publications for gene: COX5A were set to 28247525
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.388 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from None to None
Intellectual disability - microarray and sequencing v5.387 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Intellectual disability - microarray and sequencing v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability - microarray and sequencing v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability - microarray and sequencing v5.386 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability - microarray and sequencing v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 17506106; 24075189; 25457163; 27120018; 30281527; 30880327
Intellectual disability - microarray and sequencing v5.385 RARB Achchuthan Shanmugasundram Publications for gene: RARB were set to 24075189
Intellectual disability - microarray and sequencing v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.384 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092 to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.383 RARB Achchuthan Shanmugasundram Phenotypes for gene: RARB were changed from MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA to Microphthalmia, syndromic 12, OMIM:615524; neurodevelopmental disorder, MONDO:0700092
Intellectual disability - microarray and sequencing v5.382 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.382 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability - microarray and sequencing v5.382 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.381 RARB Achchuthan Shanmugasundram Mode of pathogenicity for gene: RARB was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability - microarray and sequencing v5.380 COX11 Sarah Leigh commented on gene: COX11: The three unrelated case of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) so far reported, all had significant cognitive impairment and 2/3 of the cases had hypotonia (PMID: 36030551;38068960).
Intellectual disability - microarray and sequencing v5.380 YARS Achchuthan Shanmugasundram changed review comment from: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber. However, 'watchlist' tag has been added to review this gene in future with any new evidence.; to: As reviewed by Sarah Leigh, none of the previously reported cases presented with intellectual disability, although the family reported in PMID:30304524 had expressive language delay and the older brother reported in PMID:27633801 had mild delays.

As reviewed by Dmitrijs Rots, all 12 patients from six families identified with homozygous p.Arg367Trp variant had neurodevelopmental phenotype including intellectual disability. As all these families were identified with the same homozygous variant, the rating should remain amber.
Intellectual disability - microarray and sequencing v5.380 YARS Achchuthan Shanmugasundram reviewed gene: YARS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2, OMIM:619418; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: Epileptic seizures have been seen in 2/3 unrelated cases of Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275) carrying two different COX11 variants (PMID: 36030551;38068960).; Changed rating: AMBER
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Tag Q4_23_promote_green was removed from gene: COX11.
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Possible mitochondrial disorder - nuclear genes v3.81 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Tag Q4_23_NHS_review tag was added to gene: COX11.
Mitochondrial disorders v4.143 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorders v4.143 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v4.143 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorder with complex IV deficiency v3.11 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh Entity copied from Mitochondrial disorders v4.142
Early onset or syndromic epilepsy v4.144 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Early onset or syndromic epilepsy. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Intellectual disability - microarray and sequencing v5.380 COX11 Sarah Leigh Entity copied from Mitochondrial disorders v4.142
Intellectual disability - microarray and sequencing v5.380 COX11 Sarah Leigh gene: COX11 was added
gene: COX11 was added to Intellectual disability - microarray and sequencing. Sources: NHS GMS,Expert Review Amber
Q4_23_promote_green tags were added to gene: COX11.
Mode of inheritance for gene: COX11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX11 were set to 36030551; 38068960
Phenotypes for gene: COX11 were set to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.142 COX11 Sarah Leigh Classified gene: COX11 as Amber List (moderate evidence)
Mitochondrial disorders v4.142 COX11 Sarah Leigh Gene: cox11 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.141 COX11 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: COX11.
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh reviewed gene: COX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mitochondrial disorders v4.141 COX11 Sarah Leigh edited their review of gene: COX11: Added comment: COX11 variants have been associated with Mitochondrial complex IV deficiency, nuclear type 23 (OMIM:620275), but not with a phenotype in Gen2Phen. At least four COX11 variants have been reported in three unrelated cases of OMIM:620275 (PMIDs: 36030551;38068960), together with supportive functional studies in patient's fibroblasts and Saccharomyces cerevisiae.; Changed rating: GREEN
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh reviewed gene: COX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v3.80 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.141 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v3.10 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.140 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520 to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.79 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520 to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorders v4.139 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Mitochondrial disorder with complex IV deficiency v3.9 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Possible mitochondrial disorder - nuclear genes v3.78 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551; 38068960
Rhabdomyolysis and metabolic muscle disorders v3.48 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Rhabdomyolysis and metabolic muscle disorders v3.47 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to 25929793
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Classified gene: MECP2 as Amber List (moderate evidence)
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of MECP2 with severe microcephaly, this gene can be promoted to green rating in the next GMS review.
Severe microcephaly v4.52 MECP2 Achchuthan Shanmugasundram Gene: mecp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v4.51 MECP2 Achchuthan Shanmugasundram Phenotypes for gene: MECP2 were changed from Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673 to Rett syndrome, OMIM:312750; Encephalopathy, neonatal severe, OMIM:300673; Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055; Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260
Severe microcephaly v4.50 MECP2 Achchuthan Shanmugasundram Publications for gene: MECP2 were set to
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MECP2.
Severe microcephaly v4.49 MECP2 Achchuthan Shanmugasundram reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32393352, 34351885; Phenotypes: Rett syndrome, OMIM:312750, Encephalopathy, neonatal severe, OMIM:300673, Intellectual developmental disorder, X-linked syndromic 13, OMIM:300055, Intellectual developmental disorder, X-linked syndromic, Lubs type, OMIM:300260; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mitochondrial disorders v4.138 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Possible mitochondrial disorder - nuclear genes v3.77 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Mitochondrial disorder with complex IV deficiency v3.8 COX11 Sarah Leigh Publications for gene: COX11 were set to 36030551
Mitochondrial disorders v4.137 COX11 Sarah Leigh Publications for gene: COX11 were set to
Mitochondrial disorder with complex IV deficiency v3.7 COX11 Sarah Leigh Publications for gene: COX11 were set to
Possible mitochondrial disorder - nuclear genes v3.76 COX11 Sarah Leigh Publications for gene: COX11 were set to
Possible mitochondrial disorder - nuclear genes v3.75 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.136 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex IV deficiency v3.6 COX11 Sarah Leigh Mode of inheritance for gene: COX11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.135 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Mitochondrial disorder with complex IV deficiency v3.5 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Possible mitochondrial disorder - nuclear genes v3.74 COX11 Sarah Leigh Phenotypes for gene: COX11 were changed from No OMIM phenotype to Mitochondrial complex IV deficiency, nuclear type 23, OMIM:620275; Mitochondrial complex IV deficiency, nuclear type 23, MONDO:0859520
Breast cancer pertinent cancer susceptibility v2.8 ATRIP Arina Puzriakova Publications for gene: ATRIP were set to 36977412
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova changed review comment from: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.; to: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

This association is also now listed in Gene2Phenotype with a 'moderate' disease confidence category for breast cancer susceptibility.

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova Tag watchlist was removed from gene: ATRIP.
Tag Q4_23_promote_green tag was added to gene: ATRIP.
Tag Q4_23_expert_review tag was added to gene: ATRIP.
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Classified gene: VPS33A as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.118 VPS33A Sarah Leigh Gene: vps33a has been classified as Amber List (Moderate Evidence).
Breast cancer pertinent cancer susceptibility v2.7 ATRIP Arina Puzriakova commented on gene: ATRIP: As reviewed by Dmitrijs Rots (Children's Clinical University Hospital), the previously mentioned metanalysis paper has now been published (PMID: 37592023). This showed that for cases in the Breast Cancer Association Consortium (BCAC) dataset there were 13 carriers of ATRIP protein-truncating variants variants and 9 carriers in UK Biobank (UKB); in controls there were 3 carriers in BCAC and 57 in UKB (p = 0.000106).

I am uncertain whether this is sufficient evidence to add the ATRIP gene as Green to the panel and therefore this will be flagged for further GMS expert review.
Likely inborn error of metabolism - targeted testing not possible v4.117 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 28013294; 27547915; 31070736
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome OMIM:617303; mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: This gene has been copied from Lysosomal storage disorder panel:
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian population. Supportive functional studies were also presented (PMID 31070736).
Sarah Leigh (Genomics England Curator), 17 Mar 2021
Single variant (R498W) reported in the Turkish and Yakut population. Functional studies support association of this gene to lysosomal dysfunction. Sources: Expert list
Zornitza Stark (Australian Genomics), 22 Jul 2020
Sources: Other
Lysosomal storage disorder v3.3 VPS33A Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian poputation. Supportive functional studies were also presented (PMID 31070736). ; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian population. Supportive functional studies were also presented (PMID 31070736).
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Classified gene: VPS16 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.116 VPS16 Sarah Leigh Gene: vps16 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.115 VPS16 Sarah Leigh Added comment: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion for this allelic requirement. Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases. VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Likely inborn error of metabolism - targeted testing not possible v4.115 VPS16 Sarah Leigh Mode of inheritance for gene: VPS16 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.114 VPS16 Sarah Leigh gene: VPS16 was added
gene: VPS16 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS16.
Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS16 were set to 33938619; 34013567
Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291
Review for gene: VPS16 was set to GREEN
Added comment: Copied from Lysosomal storage disorder panel: Four individuals from three families were identified (PMIDs: 33938619; 34013567) exhibiting a mucopolysaccharidosis (MPS)-like lysosomal storage phenotype with short stature, coarse facies, DD or regression, peripheral neuropathy, skeletal dysplasia, neutropenia, and high-normal glycosaminoglycan excretion. All harboured homozygous variants in VPS16 which segregated with disease, including a missense variant in a sib pair (c.540G>T; p.Trp180Cys) and a recurrent intronic variant (c.2272‐18C>A) in two supposedly unrelated patients (although both of Middle Eastern descent). Fibroblasts of the two patients with the intronic variant showed accumulation of lysosomal compartments and autophagosomes with significantly decreased VPS16 mRNA and protein levels, as well as HOPS/CORVET complexes. Cellular phenotypes were rescued upon re-expression of wild-type VPS16. ----- Heterozygous variants, as well as a homozygous missense variant (c.156C>A) found in a consanguineous Chinese family (PMID:27174565), have been found to cause dystonia with variable onset (OMIM:619291). It has been suggested that the discrepancies in patient phenotypes are due to different mechanisms of pathogenicity, where variants causing dystonia do not affect the levels of endolysosomal tethering (HOPS/CORVET) complexes. More research is needed to clarify the mechanisms underlying VPS16-related dystonia as only limited functional data is currently available - Steel et al. 2020 (PMID:32808683) did perform electron microscopic studies of lymphocytes and fibroblasts derived from 2 unrelated patients, which showed vacuolar abnormalities suggestive of impaired lysosomal function. Sources: Literature
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.113 CLCN7 Sarah Leigh Entity copied from Lysosomal storage disorder v3.3
Likely inborn error of metabolism - targeted testing not possible v4.113 CLCN7 Sarah Leigh gene: CLCN7 was added
gene: CLCN7 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Likely inborn error of metabolism - targeted testing not possible v4.112 KCTD7 Sarah Leigh gene: KCTD7 was added
gene: KCTD7 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Mode of inheritance for gene: KCTD7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCTD7 were set to Epilepsy, progressive myoclonic 3, with or without intracellular inclusions OMIM:611726; progressive myoclonic epilepsy type 3 MONDO:0012721
Review for gene: KCTD7 was set to RED
Added comment: Although this gene is rated as Green on the Neuronal ceroid lipofuscinosis panel, it is not considered to be a metabolic gene and so is rated Red on this panel.
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh Tag Q4_22_promote_green was removed from gene: GRN.
Tag Q4_23_promote_green tag was added to gene: GRN.
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh reviewed gene: GRN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Neuronal ceroid lipofuscinosis v2.6 GRN Sarah Leigh Tag Q4_23_promote_green was removed from gene: GRN.
Tag Q4_22_promote_green tag was added to gene: GRN.
Neuronal ceroid lipofuscinosis v2.6 GRN Sarah Leigh Tag Q4_22_promote_green was removed from gene: GRN.
Tag Q4_23_promote_green tag was added to gene: GRN.
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh Entity copied from Neuronal ceroid lipofuscinosis v2.6
Likely inborn error of metabolism - targeted testing not possible v4.111 GRN Sarah Leigh gene: GRN was added
gene: GRN was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert Review Amber,NHS GMS,London North GLH
Q4_22_promote_green tags were added to gene: GRN.
Mode of inheritance for gene: GRN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRN were set to 22608501; 27021778; 28000352; 28404863; 30922528; 31855245
Phenotypes for gene: GRN were set to Ceroid lipofuscinosis, neuronal, 11 OMIM:614706; neuronal ceroid lipofuscinosis 11 MONDO:0013866
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh edited their review of gene: CTSF: Added comment: Emma Ashton (Great Ormond Street Hospital) ([email protected]); Variants in this GENE are reported as part of current diagnostic practice.; Changed rating: GREEN; Set current diagnostic: yes
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Classified gene: CTSF as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.110 CTSF Sarah Leigh Gene: ctsf has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.109 CTSF Sarah Leigh gene: CTSF was added
gene: CTSF was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: CTSF.
Mode of inheritance for gene: CTSF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTSF were set to 23297359; 25274848
Phenotypes for gene: CTSF were set to Ceroid lipofuscinosis, neuronal, 13, Kufs type OMIM:615362; neuronal ceroid lipofuscinosis 13 MONDO:0014147
Neuronal ceroid lipofuscinosis v2.6 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 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
Intellectual disability - microarray and sequencing v5.379 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Intellectual disability - microarray and sequencing v5.379 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from None to None
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: PMID 33217309 reports gain of function associated with CLCN6 variants.; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Neuronal ceroid lipofuscinosis v2.5 CLCN6 Sarah Leigh Added comment: Comment on mode of pathogenicity: PMID 33217309 reports gain of function associated with CLCN6 variants.
Neuronal ceroid lipofuscinosis v2.5 CLCN6 Sarah Leigh Mode of pathogenicity for gene: CLCN6 was changed from to None
Intellectual disability - microarray and sequencing v5.378 CLCN6 Sarah Leigh Classified gene: CLCN6 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.378 CLCN6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability - microarray and sequencing v5.378 CLCN6 Sarah Leigh Gene: clcn6 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.377 CLCN6 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: CLCN6.
Intellectual disability - microarray and sequencing v5.377 CLCN6 Sarah Leigh edited their review of gene: CLCN6: Added comment: Review copied from Neuronal ceroid lipofuscinosis panel: PMID 33217309: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. Previously, monoallelic variants reported in 3 families with BPEI, but functional data/segregation not compelling. Mouse knockout model has features of NCL (Zornitza Stark (Australian Genomics), 9 Dec 2020).; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh commented on gene: CLCN6: Although this gene is rated as Green on the Neuronal ceroid lipofuscinosis panel, it is not considered to be a metabolic gene and so is rated Red on this panel.
Intellectual disability - microarray and sequencing v5.377 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Intellectual disability - microarray and sequencing. Sources: Other
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309; 16950870
Phenotypes for gene: CLCN6 were set to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities OMIM:619173
Review for gene: CLCN6 was set to RED
Added comment: Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.108 CLCN6 Sarah Leigh gene: CLCN6 was added
gene: CLCN6 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN6 were set to 29667327; 26658788; 25794116; 21107136; 33217309; 16950870
Phenotypes for gene: CLCN6 were set to Neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities OMIM:619173
Review for gene: CLCN6 was set to RED
Added comment: Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Classified gene: LMF1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.107 LMF1 Sarah Leigh Gene: lmf1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh changed review comment from: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segrates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.; to: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segregates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh commented on gene: LMF1: PMID 17994020 and 19820022, both report homozygous terminating variants in severe hypertriglyceridemia, together with functional studies that showed significant reduction of LPL activity. PMID 30885219: heterozygous LMF1 c.1024C > T (p.Arg342*; rs776584760) in a patient with Hypertriglyceridemia and acute pancreatitis (HTG-AP). PMID: 30420299 reports at least 2 likely pathogenic (terminating variants) heterozygous LMF1 variants from 13 variants in severe hypertriglyceridemia patients. PMID: 29910226 reports a compound heterozygous variants (c.257C>T, p.P86L & c.1184C>T,p.T395I) which segrates with hypertriglyceridemia in the family. However PMID: 22239554 reports that a number of missense variants don't have an effect.
Likely inborn error of metabolism - targeted testing not possible v4.106 LMF1 Sarah Leigh gene: LMF1 was added
gene: LMF1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: LMF1.
Mode of inheritance for gene: LMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LMF1 were set to 17994020; 19820022; 30885219; 30420299; 29910226; 22239554
Phenotypes for gene: LMF1 were set to Lipase deficiency, combined OMIM:246650; lipase deficiency, combined MONDO:0009527
Review for gene: LMF1 was set to GREEN
gene: LMF1 was marked as current diagnostic
Added comment: LMF1 Familial chylomicronaemia syndrome (FCS) panel.
Maggie Williams (North Bristol NHS Trust) [email protected]: Variants in this GENE are reported as part of current diagnostic practice
Sources: Expert list
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Classified gene: GPIHBP1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.105 GPIHBP1 Sarah Leigh Gene: gpihbp1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.104 GPIHBP1 Sarah Leigh gene: GPIHBP1 was added
gene: GPIHBP1 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Expert list
Q4_23_promote_green tags were added to gene: GPIHBP1.
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D OMIM:615947; hyperlipoproteinemia, type 1D MONDO:0014412
Review for gene: GPIHBP1 was set to GREEN
Added comment: GPIHBP1 copied from Familial chylomicronaemia syndrome (FCS) panel.
Maggie Williams (North Bristol NHS Trust)([email protected]): Variants in this GENE are reported as part of current diagnostic practice
Sources: Expert list
Likely inborn error of metabolism - targeted testing not possible v4.103 OSTC Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.103 OSTC Sarah Leigh gene: OSTC was added
gene: OSTC was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Red
Mode of inheritance for gene: OSTC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSTC were set to 32267060
Phenotypes for gene: OSTC were set to Oligosaccharyltransferase complex-congenital disorders of glycosylation
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Classified gene: EDEM3 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism - targeted testing not possible v4.102 EDEM3 Sarah Leigh Gene: edem3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.101 EDEM3 Sarah Leigh gene: EDEM3 was added
gene: EDEM3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: EDEM3.
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493
Review for gene: EDEM3 was set to GREEN
Added comment: Reviews copied from entry on Congenital disorders of glycosylation panel.
There is sufficient evidence to promote this gene to Green at the next GMS panel update. EDEM3 is associated with a relevant phenotype in OMIM (MIM# 619493) and G2P with a 'strong' confidence level assertion. 12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms. (Arina Puzriakova (Genomics England Curator), 18 Jul 2022).
PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional studies show loss of EDEM3 enzymatic activity. Sources: Literature (Zornitza Stark (Australian Genomics), 7 Aug 2021).
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.100 CAMLG Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.100 CAMLG Sarah Leigh gene: CAMLG was added
gene: CAMLG was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation, type IIz, OMIM:620201
Likely inborn error of metabolism - targeted testing not possible v4.99 ALG10 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.99 ALG10 Sarah Leigh gene: ALG10 was added
gene: ALG10 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Red
Mode of inheritance for gene: ALG10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALG10 were set to 33798445
Phenotypes for gene: ALG10 were set to Progressive myoclonus epilepsy; CDG
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Classified gene: HADHB as Amber List (moderate evidence)
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Possible mitochondrial disorder - nuclear genes v3.73 HADHB Achchuthan Shanmugasundram Gene: hadhb has been classified as Amber List (Moderate Evidence).
Possible mitochondrial disorder - nuclear genes v3.72 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency, 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Possible mitochondrial disorder - nuclear genes v3.71 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to
Possible mitochondrial disorder - nuclear genes v3.70 HADHB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HADHB.
Possible mitochondrial disorder - nuclear genes v3.70 HADHB Achchuthan Shanmugasundram reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35403730; Phenotypes: Mitochondrial trifunctional protein deficiency 2, OMIM:620300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: HADHB.
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Classified gene: HADHB as Amber List (moderate evidence)
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Mitochondrial disorders v4.134 HADHB Achchuthan Shanmugasundram Gene: hadhb has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v4.133 HADHB Achchuthan Shanmugasundram Phenotypes for gene: HADHB were changed from Trifunctional protein deficiency, 609015 to Mitochondrial trifunctional protein deficiency 2, OMIM:620300
Mitochondrial disorders v4.132 HADHB Achchuthan Shanmugasundram Publications for gene: HADHB were set to
Mitochondrial disorders v4.131 HADHB Achchuthan Shanmugasundram reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35403730; Phenotypes: Mitochondrial trifunctional protein deficiency 2, OMIM:620300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.98 MAN2B2 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.98 MAN2B2 Sarah Leigh gene: MAN2B2 was added
gene: MAN2B2 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: MAN2B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAN2B2 were set to 31775018; 35637269
Phenotypes for gene: MAN2B2 were set to congenital disorder of glycosylation, MONDO:0015286
Likely inborn error of metabolism - targeted testing not possible v4.97 COG3 Sarah Leigh Entity copied from Congenital disorders of glycosylation v4.16
Likely inborn error of metabolism - targeted testing not possible v4.97 COG3 Sarah Leigh gene: COG3 was added
gene: COG3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Corneal abnormalities v1.13 PDGFRB Eleanor Williams gene: PDGFRB was added
gene: PDGFRB was added to Corneal abnormalities. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PDGFRB were set to 33450762
Review for gene: PDGFRB was set to RED
Added comment: PMID: 33450762 - Bedrup et al 2021 - report a case of a dominant activating substitution in PDGFRB, NM_002609.3(PDGFRB):c.1996A > T, p.(Asn666Tyr), in a family with Ocular pterygium-digital keloid dysplasia (OPDKD) in which ingrowth of vascularized connective tissue on the cornea leads to severely reduced vision. The variant is affecting the same codon as reported for Penttinen syndrome (which causes widespread destruction of connective tissue causing severe disfigurement). However, unlike the Penttinen syndrome substitution, it was found that the OPDKD substitution is highly activated only at 32°C which is in cocordance with the fact that OPDKD are restricted to body parts (cornea and digits) with lower and more variable temperature than the core temperature.
Sources: Literature
Corneal dystrophy v3.10 PDGFRB Eleanor Williams gene: PDGFRB was added
gene: PDGFRB was added to Corneal dystrophy. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PDGFRB were set to 33450762
Review for gene: PDGFRB was set to RED
Added comment: PMID: 33450762 - Bedrup et al 2021 - report a case of a dominant activating substitution in PDGFRB, NM_002609.3(PDGFRB):c.1996A > T, p.(Asn666Tyr), in a family with Ocular pterygium-digital keloid dysplasia (OPDKD) in which ingrowth of vascularized connective tissue on the cornea leads to severely reduced vision. The variant is affecting the same codon as reported for Penttinen syndrome (which causes widespread destruction of connective tissue causing severe disfigurement). However, unlike the Penttinen syndrome substitution, it was found that the OPDKD substitution is highly activated only at 32°C which is in cocordance with the fact that OPDKD are restricted to body parts (cornea and digits) with lower and more variable temperature than the core temperature.
Sources: Literature
Hereditary neuropathy or pain disorder v3.74 PDK3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenfollowing NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Fetal anomalies v3.124 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Intellectual disability - microarray and sequencing v5.376 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Possible mitochondrial disorder - nuclear genes v3.70 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Likely inborn error of metabolism - targeted testing not possible v4.96 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM :617873 to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 35, OMIM :617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Mitochondrial disorders v4.131 TRIT1 Eleanor Williams Phenotypes for gene: TRIT1 were changed from Combined oxidative phosphorylation deficiency 35, OMIM:617873 to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Classified gene: TRIT1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v4.143 TRIT1 Eleanor Williams Gene: trit1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.142 TRIT1 Eleanor Williams gene: TRIT1 was added
gene: TRIT1 was added to Early onset or syndromic epilepsy. Sources: Literature
Q4_23_promote_green tags were added to gene: TRIT1.
Mode of inheritance for gene: TRIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIT1 were set to 28185376; 24901367
Phenotypes for gene: TRIT1 were set to Combined oxidative phosphorylation deficiency 35, OMIM:617873; combined oxidative phosphorylation deficiency 35, MONDO:0054742
Added comment: Associated with Combined oxidative phosphorylation deficiency 35, OMIM: 617873 (AR)

4 cases reported with biallelic variants in this gene and a syndromic phenotype that includes epilepsy.

PMID: 28185376 - Kernohan et al 2017 - report 4 individuals from 3 unrelated families with recessive mutations in TRIT1 identified by WES and confirmed by Sanger sequencing. Parents were heterozygous for the variants. All patients presented with syndrome features which included microcephaly, profound developmental delay, hypotonia, epilepsy, and brain anomalies.

PMID: 24901367 - Yarham et al 2014 - used WES to identify a homozygous p.Arg323Gln mutation in the TRIT1 gene in 2 affected children that segregates within a consanguineous UK-Pakistani family. The children encephalopathy and myoclonic epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Early onset or syndromic epilepsy v4.141 ASL Eleanor Williams Publications for gene: ASL were set to 36994644; 21744316; 28251416
Early onset or syndromic epilepsy v4.140 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; seizure, HP:0001250
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation of green rating subject to GMS review. 13 cases reported with ASA with epilepsy as a feature and variants in the ASL gene.
Early onset or syndromic epilepsy v4.139 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams commented on gene: ASL
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. 7/10 patients are reported to show spasticity although it is not reporterd whether they all shared the same founder variant in ASL.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.

More recent retrospectives show that tremors and/or dystonia is reported in some individuals with Argininosuccinic aciduria. 6 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53  years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively).

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Ataxia and cerebellar anomalies - narrow panel v4.49 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.
PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Early onset or syndromic epilepsy v4.138 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Seizure; Neurodevelopmental delay; Intellectual disability; Autism; Abnormality of movement; Ataxia; Hepatomegaly; Elevated hepatic transaminase; Renal tubular dysfunction; Abnormal hair morphology to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Intellectual disability - microarray and sequencing v5.375 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria 207900 to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber, with a recommendation of green rating subject to GMS review. 6 patients with tremor and/or dystonia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023 and PMID: 28251416 - Baruteau et al 2017).
Childhood onset dystonia, chorea or related movement disorder v3.65 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.64 ASL Eleanor Williams Mode of inheritance for gene: ASL was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v3.63 ASL Eleanor Williams Phenotypes for gene: ASL were changed from to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; tremor, HP:0001337; Dystonia, HP:0001332
Childhood onset dystonia, chorea or related movement disorder v3.62 ASL Eleanor Williams Publications for gene: ASL were set to
Childhood onset dystonia, chorea or related movement disorder v3.61 ASL Eleanor Williams reviewed gene: ASL: Rating: ; Mode of pathogenicity: None; Publications: 12384776, 17326097, 29326055, 38044746, 28251416; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.49 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 patients including 2 out of 7 patients with ataxia (patients 25 and 33, c.437G>A; c.446+1G>A and c.348+1G>A; c.532G>A respectively). Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective analysis of patients with ASA prior to March 2013 and then prospective analysis of patients until December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant (c.35G>A;p.(Arg12Gln), c.377G>A;p.(Arg126G1n) and c.1138A>G;p.(Lys380Glu) respectively.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram changed review comment from: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, these were the first patients reported with axonal polyneuropathy.; to: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, axonal polyneuropathy reported in these two brothers were not reported in any previous cases.
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive, OMIM:618770; axonal neuropathy, MONDO:0004183
Hereditary neuropathy or pain disorder v3.73 PCYT2 Achchuthan Shanmugasundram Publications for gene: PCYT2 were set to PMID: 35243002
Hereditary neuropathy or pain disorder v3.72 PCYT2 Achchuthan Shanmugasundram Classified gene: PCYT2 as Red List (low evidence)
Hereditary neuropathy or pain disorder v3.72 PCYT2 Achchuthan Shanmugasundram Gene: pcyt2 has been classified as Red List (Low Evidence).
Hereditary neuropathy or pain disorder v3.71 PCYT2 Achchuthan Shanmugasundram reviewed gene: PCYT2: Rating: RED; Mode of pathogenicity: None; Publications: 35243002; Phenotypes: Spastic paraplegia 82, autosomal recessive, OMIM:618770, axonal neuropathy, MONDO:0004183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Classified gene: EMILIN1 as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families in support of the association of monoallelic EMILIN1 variants with peripheral neuropathy and hence this gene should be rated amber with current evidence.
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Gene: emilin1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v3.70 EMILIN1 Achchuthan Shanmugasundram Phenotypes for gene: EMILIN1 were changed from Peripheral neuropathy; aortic aneurysm to Neuronopathy, distal hereditary motor, autosomal dominant 10, OMIM:620080
Hereditary neuropathy or pain disorder v3.69 EMILIN1 Achchuthan Shanmugasundram reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 10, OMIM:620080; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants. Microcephaly was severe (-4 to -6 SD) in all three patients measured and hence this gene should be rated amber with current evidence.
Intellectual disability - microarray and sequencing v5.374 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.; to: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Severe microcephaly v4.49 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Early onset or syndromic epilepsy v4.137 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Intellectual disability - microarray and sequencing v5.374 COG3 Achchuthan Shanmugasundram Entity copied from Congenital disorders of glycosylation v4.16
Intellectual disability - microarray and sequencing v5.374 COG3 Achchuthan Shanmugasundram gene: COG3 was added
gene: COG3 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to 37711075
Phenotypes for gene: COG3 were set to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Classified gene: COG3 as Amber List (moderate evidence)
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated cases reported with biallelic COG3 variants and hence this gene should be rated amber with current evidence.
Congenital disorders of glycosylation v4.16 COG3 Achchuthan Shanmugasundram Gene: cog3 has been classified as Amber List (Moderate Evidence).
Congenital disorders of glycosylation v4.15 COG3 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #620546), but not yet in Gene2Phenotype.
Congenital disorders of glycosylation v4.15 COG3 Achchuthan Shanmugasundram Phenotypes for gene: COG3 were changed from Congenital disorder of glycosylation, type IIbb, OMIM:620546 to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.14 COG3 Achchuthan Shanmugasundram Phenotypes for gene: COG3 were changed from Congenital disorder of glycosylation, type IIbb, MIM# 620546 to Congenital disorder of glycosylation, type IIbb, OMIM:620546
Congenital disorders of glycosylation v4.13 COG3 Achchuthan Shanmugasundram reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: None; Publications: 37711075; Phenotypes: Congenital disorder of glycosylation, type IIbb, OMIM:620546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.157 FOXI3 Achchuthan Shanmugasundram Mode of inheritance for gene: FOXI3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram edited their review of gene: FOXI3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Classified gene: FOXI3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are two unrelated families reported with monoallelic FOXI3 variant. However, the variant was inherited from apparently unaffected father in patient 2, which shows reduced penetrance. In addition, evidence from mouse model shows that FOXI3 is involved in thymus development. Hence, this gene should be rated amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.156 FOXI3 Achchuthan Shanmugasundram Gene: foxi3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 FOXI3 Achchuthan Shanmugasundram reviewed gene: FOXI3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.; to: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members. This gene should therefore be rated amber with the current evidence.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Deleted their comment
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Classified gene: SGSM3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Gene: sgsm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Classified gene: SGSM3 as No list
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are eight families reported with the same variant from the same Ashkenazi Jewish ancestry and the variant co-segregated with the disease in all family members.

The 'founder-effect' tag has been added as 1 in 52 Ashkenazi Jews carry the variant.
Intellectual disability - microarray and sequencing v5.373 SGSM3 Achchuthan Shanmugasundram Gene: sgsm3 has been removed from the panel.
Intellectual disability - microarray and sequencing v5.372 SGSM3 Achchuthan Shanmugasundram Tag founder-effect tag was added to gene: SGSM3.
Intellectual disability - microarray and sequencing v5.372 SGSM3 Achchuthan Shanmugasundram Phenotypes for gene: SGSM3 were changed from Neurodevelopmental disorder (MONDO:0700092), SGSM3-related to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Intellectual disability - microarray and sequencing v5.371 SGSM3 Achchuthan Shanmugasundram reviewed gene: SGSM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder, MONDO:0700092, intellectual disability, MONDO:0001071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Classified gene: NUS1 as Amber List (moderate evidence)
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As there is sufficient evidence available for the association of monoallelic NUS1 variants with intellectual disability and epilepsy, this gene can be promoted to green rating in the next GMS review.
Likely inborn error of metabolism - targeted testing not possible v4.95 NUS1 Achchuthan Shanmugasundram Gene: nus1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.94 NUS1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Dmitrijs Rots, there are more than three unrelated cases and functional evidence available in support of the association of monoallelic NUS1 variants with intellectual disability and epilepsy. This autosomal dominant disorder has been recorded in both OMIM (MIM #617831) and Gene2Phenotype (with 'strong' rating in the DD panel).

However, there is only one family and supporting functional evidence available for the association of biallelic variants with congenital disorder of glycosylation. This phenotype has already been recorded in OMIM (MIM #617082), but not in Gene2Phenotype.

Hence, the MOI should be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.
Likely inborn error of metabolism - targeted testing not possible v4.94 NUS1 Achchuthan Shanmugasundram Mode of inheritance for gene: NUS1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Likely inborn error of metabolism - targeted testing not possible v4.93 NUS1 Achchuthan Shanmugasundram Publications for gene: NUS1 were set to 25066056; 31656175; 32334381; 32485575; 33731878
Likely inborn error of metabolism - targeted testing not possible v4.93 NUS1 Achchuthan Shanmugasundram Publications for gene: NUS1 were set to 25066056
Likely inborn error of metabolism - targeted testing not possible v4.92 NUS1 Achchuthan Shanmugasundram Phenotypes for gene: NUS1 were changed from ?Congenital disorder of glycosylation, type 1aa OMIM:617082; congenital disorder of glycosylation, type IAA MONDO:0014904 to Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831; ?Congenital disorder of glycosylation, type 1aa, OMIM:617082
Likely inborn error of metabolism - targeted testing not possible v4.91 NUS1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: NUS1.
Likely inborn error of metabolism - targeted testing not possible v4.91 NUS1 Achchuthan Shanmugasundram reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 55, with seizures, OMIM:617831, ?Congenital disorder of glycosylation, type 1aa, OMIM:617082; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Classified gene: DLG4 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there are nine unrelated cases reported with monoallelic DLG4 variants and ataxia. Hence, this gene can be promoted to green rating in the next GMS review.
Ataxia and cerebellar anomalies - narrow panel v4.49 DLG4 Achchuthan Shanmugasundram Gene: dlg4 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v4.48 DLG4 Achchuthan Shanmugasundram Phenotypes for gene: DLG4 were changed from Intellectual developmental disorder, autosomal dominant 62 to Intellectual developmental disorder, autosomal dominant 62, OMIM:618793
Ataxia and cerebellar anomalies - narrow panel v4.47 DLG4 Achchuthan Shanmugasundram Publications for gene: DLG4 were set to PMID: 33597769
Ataxia and cerebellar anomalies - narrow panel v4.46 DLG4 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: DLG4.
Ataxia and cerebellar anomalies - narrow panel v4.46 DLG4 Achchuthan Shanmugasundram reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal dominant 62, OMIM:618793; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Classified gene: MCTS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there is sufficient evidence available (five unrelated cases) for the association of hemizygous MCTS1 variants with MSMD. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.155 MCTS1 Achchuthan Shanmugasundram Gene: mcts1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.154 MCTS1 Achchuthan Shanmugasundram Phenotypes for gene: MCTS1 were changed from MSMD; non tubercular mycobacteria infection; BCGtis; BCG infection to Inherited susceptibility to mycobacterial diseases, MONDO:0019146
Primary immunodeficiency or monogenic inflammatory bowel disease v4.153 MCTS1 Achchuthan Shanmugasundram Publications for gene: MCTS1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MCTS1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MCTS1.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MCTS1 Achchuthan Shanmugasundram reviewed gene: MCTS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37875108; Phenotypes: Inherited susceptibility to mycobacterial diseases, MONDO:0019146; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Classified gene: MECOM as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Boaz Palterer, there are more than three unrelated cases with either B cell deficiency and/ or hypogammaglobulinemia. Hence, this gene can be promoted to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.152 MECOM Achchuthan Shanmugasundram Gene: mecom has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 MECOM Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: MECOM.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 MECOM Achchuthan Shanmugasundram reviewed gene: MECOM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, OMIM:616738; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thalassaemia and other haemoglobinopathies v1.7 HBG2 Arina Puzriakova Classified gene: HBG2 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.7 HBG2 Arina Puzriakova Gene: hbg2 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.7 HBG2 Arina Puzriakova Classified gene: HBG2 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.7 HBG2 Arina Puzriakova Gene: hbg2 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.6 HBG2 Arina Puzriakova gene: HBG2 was added
gene: HBG2 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG2.
Mode of inheritance for gene: HBG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: HBG2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel for HBG1 gene (also relevant to HBG2):

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.6 HBG2 Arina Puzriakova gene: HBG2 was added
gene: HBG2 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG2.
Mode of inheritance for gene: HBG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: HBG2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel for HBG1 gene (also relevant to HBG2):

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Rare anaemia v3.6 HBG2 Arina Puzriakova Phenotypes for gene: HBG2 were changed from Globin Disorder; 141749 Globin Disorder; Fetal hemoglobin quantitative trait locus 1,141749; Fetal hemoglobin quantitative trait locus 1; 141749 Hereditary persistance of fetal haemoglobin; Cyanosis, transient neonatal, 613977 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; Globin Disorder
Cytopenias and congenital anaemias v1.114 HBG2 Arina Puzriakova Phenotypes for gene: HBG2 were changed from Globin Disorder; Cyanosis, transient neonatal, 613977; Fetal hemoglobin quantitative trait locus 1,141749 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Cyanosis, transient neonatal, OMIM:613977; Globin Disorder
Thalassaemia and other haemoglobinopathies v1.5 HBG1 Arina Puzriakova Classified gene: HBG1 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.5 HBG1 Arina Puzriakova Gene: hbg1 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.5 HBG1 Arina Puzriakova Classified gene: HBG1 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.5 HBG1 Arina Puzriakova Gene: hbg1 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.4 HBG1 Arina Puzriakova gene: HBG1 was added
gene: HBG1 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG1.
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: HBG1 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.4 HBG1 Arina Puzriakova gene: HBG1 was added
gene: HBG1 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBG1.
Mode of inheritance for gene: HBG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Review for gene: HBG1 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"delta beta thalassemia can result from deletions within or encompassing the beta-globin gene cluster (see HBB, 141900) on chromosome 11p15, including deletions that also encompass the delta-globin gene (142000), or from point mutations in the promoter regions of either the HBG1 (142200) or the HBG2 (142250) gene"
Sources: NHS GMS
Cytopenias and congenital anaemias v1.113 HBG1 Arina Puzriakova Phenotypes for gene: HBG1 were changed from Globin Disorder; Fetal hemoglobin quantitative trait locus 1, 141749 to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Hereditary persistance of fetal haemoglobin; Globin Disorder
Rare anaemia v3.5 HBG1 Arina Puzriakova Phenotypes for gene: HBG1 were changed from Fetal hemoglobin quantitative trait locus 1; 141749 Hereditary persistance of fetal haemoglobin; 141749 Globin Disorder; Fetal hemoglobin quantitative trait locus 1, 141749; Globin Disorder to Fetal hemoglobin quantitative trait locus 1, OMIM:141749; Hereditary persistance of fetal haemoglobin; Globin Disorder
Thalassaemia and other haemoglobinopathies v1.3 HBA2 Arina Puzriakova Classified gene: HBA2 as Amber List (moderate evidence)
Thalassaemia and other haemoglobinopathies v1.3 HBA2 Arina Puzriakova Gene: hba2 has been classified as Amber List (Moderate Evidence).
Haemoglobinopathy trait or carrier testing v1.3 HBA2 Arina Puzriakova Classified gene: HBA2 as Amber List (moderate evidence)
Haemoglobinopathy trait or carrier testing v1.3 HBA2 Arina Puzriakova Gene: hba2 has been classified as Amber List (Moderate Evidence).
Thalassaemia and other haemoglobinopathies v1.2 HBA2 Arina Puzriakova gene: HBA2 was added
gene: HBA2 was added to Thalassaemia and other haemoglobinopathies. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBA2.
Mode of inheritance for gene: HBA2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Review for gene: HBA2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below regarding MOI from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"There are two alpha globin genes (HBA1 and HBA2), which are encoded in tandem on chromosome 16. Different Mutations in HBA1/HBA2 are associated with different α-thalassemias and different mode of inheritance: 1) α-thalassemia silent carrier: deletion/mutation that leads to loss of 1 α-globin gene (either HBA1 or HBA2) 2) α-thalassemia trait: deletion/mutations that leads to the loss of 2 α-globin genes either in cis (--/αα) or in trans (-α/-α); 3) Hemoglobin H disease is caused by contiguous gene deletion of HBA1 and HBA2 genes on one chromosome, and a defect (deletional / inactivating small indel /single nucleotide variant), in either HBA1 or HBA2 on the other chromosome; 4) 'homozygous alpha-thalassemia' (fatal hydrops fetalis): usually caused by deletions on both chromosomes, leading no/little production of alpha globin and death in utero. The phenotypes relevant to this panel are the α-thalassemia trait and the Hemoglobin H disease. Mostly caused by deletions but rare cases of small indels or point mutations leading to decreased production of the alpha globin chains have been described (16798638, 15481890, 15182057 for example)"
Sources: NHS GMS
Haemoglobinopathy trait or carrier testing v1.2 HBA2 Arina Puzriakova gene: HBA2 was added
gene: HBA2 was added to Haemoglobinopathy trait or carrier testing. Sources: NHS GMS
Q4_23_promote_green tags were added to gene: HBA2.
Mode of inheritance for gene: HBA2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Review for gene: HBA2 was set to GREEN
Added comment: This gene has been added to the panel at the request of the NHSE specialist group. There is sufficient evidence to promote this gene to Green at the next GMS panel update.

-----
Copied review below regarding MOI from Arianna Tucci (UCL) on Cytopenias and congenital anaemias (159) panel:

"There are two alpha globin genes (HBA1 and HBA2), which are encoded in tandem on chromosome 16. Different Mutations in HBA1/HBA2 are associated with different α-thalassemias and different mode of inheritance: 1) α-thalassemia silent carrier: deletion/mutation that leads to loss of 1 α-globin gene (either HBA1 or HBA2) 2) α-thalassemia trait: deletion/mutations that leads to the loss of 2 α-globin genes either in cis (--/αα) or in trans (-α/-α); 3) Hemoglobin H disease is caused by contiguous gene deletion of HBA1 and HBA2 genes on one chromosome, and a defect (deletional / inactivating small indel /single nucleotide variant), in either HBA1 or HBA2 on the other chromosome; 4) 'homozygous alpha-thalassemia' (fatal hydrops fetalis): usually caused by deletions on both chromosomes, leading no/little production of alpha globin and death in utero. The phenotypes relevant to this panel are the α-thalassemia trait and the Hemoglobin H disease. Mostly caused by deletions but rare cases of small indels or point mutations leading to decreased production of the alpha globin chains have been described (16798638, 15481890, 15182057 for example)"
Sources: NHS GMS
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 AICDA Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.151 AICDA Arina Puzriakova Mode of inheritance for gene: AICDA was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.150 AICDA Arina Puzriakova Publications for gene: AICDA were set to 12958596; 21700883; 27701145
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova Tag recurrent-variant tag was added to gene: AICDA.
Tag Q4_23_MOI tag was added to gene: AICDA.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 35748970, 15893695, 35271747; Phenotypes: Immunodeficiency with hyper-IgM, type 2, OMIM:605258; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Tag Q4_23_promote_green tag was added to gene: ASL.
Tag Q4_23_NHS_review tag was added to gene: ASL.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Comment on list classification: Promoting this gene to amber as there are 2 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023). Consulting with the Genomics England clinical team whether it would be appropriate to rate green.; to: Comment on list classification: Promoting this gene to amber with a recommendation for green rating as there are 5 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023 and PMID: 28251416 - Baruteau et al 2017).
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied. Ataxia was first noticed at a median age of 8.5 years. The genotype was available for 19 patients, including 3 of those with Ataxia (patients 1, 4 and 14) each with a different homozygous missense variant.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Mitochondrial disorders v4.130 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Likely inborn error of metabolism - targeted testing not possible v4.91 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Mitochondrial disorder with complex V deficiency v2.14 ATP5E Sarah Leigh Tag Q4_23_promote_green tag was added to gene: ATP5E.
Undiagnosed metabolic disorders v1.609 ATP5E Sarah Leigh Classified gene: ATP5E as Green List (high evidence)
Undiagnosed metabolic disorders v1.609 ATP5E Sarah Leigh Gene: atp5e has been classified as Green List (High Evidence).
Mitochondrial disorder with complex V deficiency v2.14 ATP5E Sarah Leigh Publications for gene: ATP5E were set to
Mitochondrial disorders v4.130 ATP5E Sarah Leigh Publications for gene: ATP5E were set to 20566710
Mitochondrial disorders v4.129 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Mitochondrial disorders v4.128 ATP5E Sarah Leigh Classified gene: ATP5E as Amber List (moderate evidence)
Mitochondrial disorders v4.128 ATP5E Sarah Leigh Gene: atp5e has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.91 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Mitochondrial disorder with complex V deficiency v2.13 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Undiagnosed metabolic disorders v1.608 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Undiagnosed metabolic disorders v1.607 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Mitochondrial disorder with complex V deficiency v2.12 ATP5E Sarah Leigh reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 34954817, 20566710; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.90 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Mitochondrial disorders v4.127 ATP5E Sarah Leigh edited their review of gene: ATP5E: Added comment: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; Changed rating: GREEN; Changed publications to: 27604308, 34954817, 20566710
Possible mitochondrial disorder - nuclear genes v3.69 ATP5E Sarah Leigh Phenotypes for gene: ATP5E were changed from ?Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, 614053 to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, OMIM:614053; mitochondrial complex V (ATP synthase) deficiency nuclear type 3, MONDO:0013547
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh changed review comment from: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name:ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.; to: PMID: 34954817 reports two further cases of OMIM: 614053 who are both homozygous for ATP5E (new gene name: ATP5F1E) variant c.35A>G, p.Tyr12Cys (rs387906929), previously reported in PubMed: 20566710. Personal communication with the lead author of PMID: 34954817, confirmed that none of these cases were related to one another and so represent independent occurrences of this variant.
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh Tag Q4_23_expert_review was removed from gene: ATP5E.
Tag Q4_23_NHS_review tag was added to gene: ATP5E.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not mentioned as a phenotypic feature.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy.

The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g.

PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA.

PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature.

PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients; c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. Ataxia is not specifically mentioned as a phenotypic feature, although 7/50 patients were reported to show spasticity.

More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported.

PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 7 were reported to show ataxia and 4 of these individuals presented with ataxia by age 11 or less. Homozygous or compound het ASL variants were recorded in 25/60 paitents including 2 out of 7 patients with ataxia. Genotype data was not available for other patients.

PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Ataxia was reported in 9 out of 52 patients studied.

(PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. )
Possible mitochondrial disorder - nuclear genes v3.68 ATP5E Sarah Leigh reviewed gene: ATP5E: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Classified gene: ASL as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber as there are 2 cases of patients with ataxia and variants identified in the ASL gene (from PMID: 38044746 - Gurung et al 2023). Consulting with the Genomics England clinical team whether it would be appropriate to rate green.
Ataxia and cerebellar anomalies - narrow panel v4.46 ASL Eleanor Williams Gene: asl has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism - targeted testing not possible v4.90 ASL Eleanor Williams Publications for gene: ASL were set to 27604308
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh Entity copied from Childhood onset dystonia, chorea or related movement disorder v3.61
Early onset or syndromic epilepsy v4.136 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Early onset or syndromic epilepsy. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Intellectual disability - microarray and sequencing v5.371 SHQ1 Sarah Leigh Entity copied from Childhood onset dystonia, chorea or related movement disorder v3.61
Intellectual disability - microarray and sequencing v5.371 SHQ1 Sarah Leigh gene: SHQ1 was added
gene: SHQ1 was added to Intellectual disability - microarray and sequencing. Sources: Literature,Expert Review Amber
Q4_23_promote_green tags were added to gene: SHQ1.
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611; 36189577
Phenotypes for gene: SHQ1 were set to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Classified gene: SHQ1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v3.61 SHQ1 Sarah Leigh Gene: shq1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh Tag Q4_23_promote_green tag was added to gene: SHQ1.
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh commented on gene: SHQ1: SHQ1 variants are associated with Neurodevelopmental disorder with dystonia and seizures, OMIM:619922 and Dystonia 35, childhood-onset, OMIM:619921, but not with a phenotype in Gen2Phen. At least 10 SHQ1 variants have been reported (PMIDs: 29178645 34542157; 36810590; 36847845) in eight unrelated cases. The phenotypic features were dystonia (7/7 cases examined), hypotonia (6/7 cases examined), intellectual disability (7/8 cases examined), and seizures (in 4/6 cases and 2 further unrelated cases where remaining affected siblings did not have seizures (1/2 and 3/4)(PMID: 36847845).
Ataxia and cerebellar anomalies - narrow panel v4.45 ASL Eleanor Williams Publications for gene: ASL were set to 38044746; 36994644; 28251416
Ataxia and cerebellar anomalies - narrow panel v4.44 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Ataxia to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815; Ataxia, HP:0001251
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh reviewed gene: SHQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism - targeted testing not possible v4.89 ASL Eleanor Williams Phenotypes for gene: ASL were changed from Argininosuccinic aciduria; Argininosuccinic aciduria (Urea cycle disorders and inherited hyperammonaemias) to Argininosuccinic aciduria, OMIM:207900; argininosuccinic aciduria, MONDO:0008815
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh Publications for gene: SHQ1 were set to 34542157; 29178645; 36810590; 36847845; 36416405; 37475611
Childhood onset dystonia, chorea or related movement disorder v3.59 SHQ1 Sarah Leigh Publications for gene: SHQ1 were set to 34542157; 29178645
Childhood onset dystonia, chorea or related movement disorder v3.58 SHQ1 Sarah Leigh Phenotypes for gene: SHQ1 were changed from Dystonia; Neurodegeneration to ?Dystonia 35, childhood-onset, OMIM:619921; dystonia 35, childhood-onset, MONDO:0030958; Neurodevelopmental disorder with dystonia and seizures, OMIM:619922; neurodevelopmental disorder with dystonia and seizures, MONDO:0859258
Childhood onset dystonia, chorea or related movement disorder v3.57 SHQ1 Sarah Leigh Classified gene: SHQ1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v3.57 SHQ1 Sarah Leigh Gene: shq1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.141 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Hyper IgM syndrome with lymphoid hyperplasia; Primary Immune Deficiencies; Immunodeficiency with hyper-IgM, type 2, 605258; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies; Immunodeficiency with hyper-IgM, type 2; CSR defects and Hyper IgM (HIGM) syndromes to Immunodeficiency with hyper-IgM, type 2, OMIM:605258; Hyper IgM syndrome with lymphoid hyperplasia; Primary Immune Deficiencies; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies; Immunodeficiency with hyper-IgM, type 2; CSR defects and Hyper IgM (HIGM) syndromes
Gastrointestinal epithelial barrier disorders v1.74 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Early Onset Inflammatory Bowel Disease; Immunodeficiency with hyper-IgM, type 2 605258 to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Infantile enterocolitis & monogenic inflammatory bowel disease v1.40 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Immunodeficiency with hyper-IgM, type 2 605258 to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Primary immunodeficiency or monogenic inflammatory bowel disease v4.149 AICDA Arina Puzriakova Phenotypes for gene: AICDA were changed from Immunodeficiency with hyper-IgM, type 2; Hyper IgM syndrome with lymphoid hyperplasia; Immunodeficiency with hyper-IgM, type 2, 605258; Primary Immune Deficiencies; CSR defects and Hyper IgM (HIGM) syndromes; Bacterial infections, enlarged lymph nodes and germinal centers; Predominantly Antibody Deficiencies to Immunodeficiency with hyper-IgM, type 2, OMIM:605258
Intellectual disability - microarray and sequencing v5.370 FBXW11 Sarah Leigh Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914 to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:003005
Skeletal dysplasia v4.35 FBXW11 Sarah Leigh Phenotypes for gene: FBXW11 were changed from Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914 to Neurodevelopmental, jaw, eye, and digital syndrome, OMIM:618914; neurodevelopmental, jaw, eye, and digital syndrome, MONDO:0030057
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Tag Q4_21_NHS_review tag was added to gene: FBXW11.
Tag Q4_23_promote_green tag was added to gene: FBXW11.
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Classified gene: FBXW11 as Amber List (moderate evidence)
Skeletal dysplasia v4.34 FBXW11 Sarah Leigh Gene: fbxw11 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v4.33 FBXW11 Sarah Leigh Entity copied from Intellectual disability - microarray and sequencing v5.369
Skeletal dysplasia v4.33 FBXW11 Sarah Leigh gene: FBXW11 was added
gene: FBXW11 was added to Skeletal dysplasia. Sources: Literature,Expert Review Green
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit; Neurodevelopmental, jaw, eye, and digital syndrome MIM#618914
Penetrance for gene: FBXW11 were set to unknown
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Classified gene: RETREG1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of RETREG1 gene with spastic paraplegia and hence this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Gene: retreg1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v4.30 RETREG1 Achchuthan Shanmugasundram Phenotypes for gene: RETREG1 were changed from to Neuropathy, hereditary sensory and autonomic, type IIB, OMIM:613115
Childhood onset hereditary spastic paraplegia v4.29 RETREG1 Achchuthan Shanmugasundram Publications for gene: RETREG1 were set to 24327336
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: RETREG1.
Tag Q4_23_NHS_review tag was added to gene: RETREG1.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram changed review comment from: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter); to: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter).

Gavin Ryan also mentioned in his review that LoF homozygous variant in this gene was identified via Diagnostic Discovery in 100K and GMS WGS patient with features of Progressive spasticity, facial hypotonia, dysarthria, and fatiguable weakness.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram commented on gene: RETREG1: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter)
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram reviewed gene: RETREG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24327336, 30643655; Phenotypes: Neuropathy, hereditary sensory and autonomic, type IIB, OMIM:613115; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric disorders - additional genes v3.9 NOTCH3 Arina Puzriakova Classified gene: NOTCH3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v3.9 NOTCH3 Arina Puzriakova Gene: notch3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v3.8 NOTCH3 Arina Puzriakova gene: NOTCH3 was added
gene: NOTCH3 was added to Paediatric disorders - additional genes. Sources: NHS GMS
Q4_23_promote_green, Q4_23_expert_review tags were added to gene: NOTCH3.
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 25394726
Phenotypes for gene: NOTCH3 were set to Lateral meningocele syndrome, OMIM:130720
Mode of pathogenicity for gene: NOTCH3 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: NOTCH3 was set to GREEN
Added comment: Monoallelic variants in the NOTCH3 gene are associated with multiple phenotypes including CADASIL (MIM# 125310), Lateral Meningocele syndrome (MIM# 130720), and Myofibromatosis (MIM# 615293).

Currently, CADASIL and myofibromatosis phenotypes are covered by several PanelApp panels; however, Lateral Meningocele syndrome is not - there is enough evidence to support inclusion of this gene-disease association on a diagnostic-grade panel.

At least 5 unrelated de novo cases have been reported in literature (PMID: 25394726). All variants are truncating and cluster in the last exon of NOTCH3. Truncated proteins are predicted to cause increased notch signalling.
An additional case was identified in Genomics England's Clinical Variant Archive (CVA) dataset via the Diagnostic Discovery initiative. The participant was recruited with Lateral Meningocele syndrome (inclusive of hypertelorism, high palate, dural ectasia, high pitched voice) and a diagnostically reported variant in the last exon of this gene was returned, lending further support to adding this gene to the panel.

R27 appears to be the most phenotypically relevant panel for detecting Lateral Meningocele syndrome; however, the possibility of incidental findings of CADASIL needs to be considered. Both phenotypes are caused by GoF variants but those associated with CADASIL are located in exons 2-24 whereas variants in Lateral Meningocele found in exon 33 (last exon).

Given the risk of incidental findings without a mechanism to delineate the types of variants that are prioritised via each panel, the best route for inclusion of Lateral Meningocele syndrome in PanelApp will be flagged for further NHSE expert discussion at the next GMS panel update release.
Sources: NHS GMS
Retinal disorders v4.55 TTC21B Achchuthan Shanmugasundram Classified gene: TTC21B as Amber List (moderate evidence)
Retinal disorders v4.55 TTC21B Achchuthan Shanmugasundram Gene: ttc21b has been classified as Amber List (Moderate Evidence).
Retinal disorders v4.54 TTC21B Achchuthan Shanmugasundram Phenotypes for gene: TTC21B were changed from Eye Disorders to Retinal dystrophy, HP:0000556
Retinal disorders v4.53 TTC21B Achchuthan Shanmugasundram Publications for gene: TTC21B were set to 21068128; 33599192
Retinal disorders v4.52 TTC21B Achchuthan Shanmugasundram Publications for gene: TTC21B were set to
Retinal disorders v4.51 TTC21B Achchuthan Shanmugasundram Mode of inheritance for gene: TTC21B was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v4.50 TTC21B Achchuthan Shanmugasundram reviewed gene: TTC21B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Retinal dystrophy, HP:0000556; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability - microarray and sequencing v5.369 TRPC5 Sarah Leigh changed review comment from: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).; to: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 variants have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Childhood solid tumours v4.10 NOTCH3 Arina Puzriakova Phenotypes for gene: NOTCH3 were changed from Infantile myofibromatosis to ?Myofibromatosis, infantile 2, OMIM:615293
Inherited white matter disorders v1.177 NOTCH3 Arina Puzriakova Mode of inheritance for gene: NOTCH3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.369 TRPC5 Sarah Leigh Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.369 TRPC5 Sarah Leigh Added comment: Comment on list classification: This gene is rated amber, despite six published variants being reported in unrelated cases with a neurodevelopmental disorder, this is because it is unclear in the publications, how many of these cases actually have intellectual disability.
Intellectual disability - microarray and sequencing v5.369 TRPC5 Sarah Leigh Gene: trpc5 has been classified as Amber List (Moderate Evidence).
CADASIL v1.4 NOTCH3 Arina Puzriakova Mode of pathogenicity for gene: NOTCH3 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
Primary immunodeficiency or monogenic inflammatory bowel disease v4.148 STAT6 Achchuthan Shanmugasundram Publications for gene: STAT6 were set to 36884218
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: There is sufficient evidence available (12 unrelated families and functional data) for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Classified gene: STAT6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.147 STAT6 Achchuthan Shanmugasundram Gene: stat6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: STAT6.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Deleted their comment
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram edited their review of gene: STAT6: Added comment: As reviewed by Dmitrijs Rots, PMID:36884218 reported 16 cases from 10 families with heterozygous STAT6 variants and severe early-onset allergic disease consisting of clinical features including severe, treatment-resistant atopic dermatitis (15/16) and food allergies (15/16) were the most common clinical manifestations, followed by asthma (11/16) and eosinophilic gastrointestinal disease (10/16) and severe episodes of anaphylaxis (9/16).

PMID:36216080 reported heterozygous STAT6 variant with early-onset multiorgan allergies in a family with
3 affected members and PMID:36758835 reported another child with severe atopic dermatitis, eosinophilia and elevated IgE. All these publications also provided extensive functional data which confirms the mechanism as gain-of-function.

This gene has already been associated with relevant phenotypes in OMIM (MIM #620532), but not yet in Gene2Phenotype.; Changed publications to: 36216080, 36758835, 36884218
White matter disorders and cerebral calcification - narrow panel v3.25 NOTCH3 Arina Puzriakova Mode of inheritance for gene: NOTCH3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.368 TRPC5 Sarah Leigh commented on gene: TRPC5: To date, TRPC5 variants have not been associated with a phenotype in OMIM, however, Gen2Phen lists TRPC5 as having an Limited association with the phenotype of TRPC5-related neurodevelopmental disorder. Six TRPC5 have been reported to be associated with a neurodevelopmental disorder, which has a range of phenotypic features, including intellectual disability and autism spectrum disorder (PMIDs: 36323681;33504798;28191890;23033978).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.146 STAT6 Achchuthan Shanmugasundram Phenotypes for gene: STAT6 were changed from allergic disease, MONDO:0005271 to Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, OMIM:620532
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram edited their review of gene: STAT6: Changed phenotypes to: Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, OMIM:620532
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.; to: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review. In addition, functional evidence shows that the mechanism is gain-of-function.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Classified gene: STAT6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.145 STAT6 Achchuthan Shanmugasundram Gene: stat6 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.144 STAT6 Achchuthan Shanmugasundram Phenotypes for gene: STAT6 were changed from Primary Atopic Disorder; Atopy; Vascular anomalies; Atopic dermamatitis; Allergy; Atopy; Hyper-IgE; elevated IgE; Eosinophilic esophagitis; Food allergies to allergic disease, MONDO:0005271
Primary immunodeficiency or monogenic inflammatory bowel disease v4.143 STAT6 Achchuthan Shanmugasundram Publications for gene: STAT6 were set to
Intellectual disability - microarray and sequencing v5.368 TRPC5 Sarah Leigh Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.368 TRPC5 Sarah Leigh Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.142 STAT6 Achchuthan Shanmugasundram Mode of inheritance for gene: STAT6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 STAT6 Achchuthan Shanmugasundram reviewed gene: STAT6: 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: 36884218; Phenotypes: allergic disease, MONDO:0005271; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Classified gene: KCNA5 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Added comment: Comment on list classification: PMID:34536415 reported a 17-year old female patient with early-onset pulmonary and cutaneous vasculitis and biallelic KCNA5 variant (c. 1545C>A) and supporting functional evidence.

Biallelic KCNA5 variants have not yet been associated with any phenotypes either in OMIM or Gene2Phenotype.

This gene should be rated amber with current evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.141 KCNA5 Achchuthan Shanmugasundram Gene: kcna5 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.140 KCNA5 Achchuthan Shanmugasundram Phenotypes for gene: KCNA5 were changed from autoimmunity; autoinflammation to early-onset pulmonary and cutaneous vasculitis, MONDO:0800137
Primary immunodeficiency or monogenic inflammatory bowel disease v4.139 KCNA5 Achchuthan Shanmugasundram Publications for gene: KCNA5 were set to PMID: 35748970; PMID: 34536415
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 KCNA5 Achchuthan Shanmugasundram reviewed gene: KCNA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 34536415; Phenotypes: early-onset pulmonary and cutaneous vasculitis, MONDO:0800137; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 IL23R Achchuthan Shanmugasundram Classified gene: IL23R as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.138 IL23R Achchuthan Shanmugasundram Gene: il23r has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Classified gene: IL23R as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.
Primary immunodeficiency or monogenic inflammatory bowel disease v4.137 IL23R Achchuthan Shanmugasundram Gene: il23r has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v4.136 IL23R Achchuthan Shanmugasundram Phenotypes for gene: IL23R were changed from Susceptibility to mycobacteria and Salmonella to inherited susceptibility to mycobacterial diseases, MONDO:0019146; chronic mucocutaneous candidiasis, MONDO:0015279
Primary immunodeficiency or monogenic inflammatory bowel disease v4.135 IL23R Achchuthan Shanmugasundram Publications for gene: IL23R were set to 30578351; 31953710
Primary immunodeficiency or monogenic inflammatory bowel disease v4.134 IL23R Achchuthan Shanmugasundram Tag Q4_23_promote_green tag was added to gene: IL23R.