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Severe Paediatric Disorders v1.84 IFT122 Sarah Leigh reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.738 IFT122 Sarah Leigh reviewed gene: IFT122: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.738 IFT122 Sarah Leigh Publications for gene: IFT122 were set to
Craniosynostosis v2.55 IFT122 Sarah Leigh Publications for gene: IFT122 were set to 24689072; 20493458
Fetal anomalies v1.737 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from CRANIOECTODERMAL DYSPLASIA to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Craniosynostosis v2.54 IFT122 Sarah Leigh Phenotypes for gene: IFT122 were changed from cranioectodermal dysplasia; Cranioectodermal dysplasia type 1 218330 to Cranioectodermal dysplasia type 1 OMIM:218330; cranioectodermal dysplasia 1 MONDO:0021093
Intellectual disability v3.1385 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1384 COL6A1 Arina Puzriakova Mode of inheritance for gene: COL6A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ehlers Danlos syndromes v2.64 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1,OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Limb girdle muscular dystrophy v2.30 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy 1 158810 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital myopathy v2.60 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Congenital muscular dystrophy v2.19 COL6A1 Arina Puzriakova Phenotypes for gene: COL6A1 were changed from Bethlem myopathy, 158810; Ullrich congenital muscular dystrophy, 254090 to Bethlem myopathy 1, OMIM:158810; Ullrich congenital muscular dystrophy 1, OMIM:254090
Intellectual disability v3.1383 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Proteinuric renal disease v2.61 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Intellectual disability v3.1382 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria, familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Hearing loss v2.202 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780Hematuria,familial benign; Alportsyndrome,autosomalrecessive,203780Hematuria,familialbenign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained paediatric onset end-stage renal disease v1.23 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Hematuria,familial benign; Alport syndrome, autosomal recessive, 203780 to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Unexplained kidney failure in young people v1.99 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Alport syndrome, autosomal recessive, 203780; Hematuria,familial benign to Alport syndrome 2, autosomal recessive, OMIM:203780; Hematuria,familial benign, OMIM:141200
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from Cystic kidney disease, MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Cystic kidney disease v2.27 COL4A4 Arina Puzriakova Phenotypes for gene: COL4A4 were changed from cystic kidney disease MONDO:0002473 to Cystic kidney disease, MONDO:0002473
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Changing to BOTH monoallelic and biallelic, autosomal or pseudoautosomal because it is associated with two relevant disorders one which shows biallelic and one which shows monoallelic inheritance ( Alport syndrome 2, autosomal recessive is AR and Hematuria, familial benign is AD).
Unexplained kidney failure in young people v1.98 COL4A4 Arina Puzriakova Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy v1.417 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy v1.417 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.64 CPOX Ivone Leong Tag Q4_21_MOI tag was added to gene: CPOX.
Hereditary neuropathy NOT PMP22 copy number v1.64 CPOX Ivone Leong reviewed gene: CPOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.141 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II 604841; Marshall syndrome 154780; Fibrochondrogenesis 1 228520 to Stickler syndrome, type II, OMIM:604841; Marshall syndrome, OMIM:154780; Fibrochondrogenesis 1, OMIM:228520
Clefting v2.58 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Orofacial Clefting with skeletal features; Stickler Syndrome; Cleft palate to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Cataracts v2.86 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Marshall Syndrome; Stickler syndrome to Marshall Syndrome, OMIM:154780; Stickler syndrome, type II, OMIM:604841
Hearing loss v2.201 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, MIM#604841; Deafness, autosomal dominant 37, MIM#618533 to Deafness, autosomal dominant 37, OMIM:618533; Stickler syndrome, type II, OMIM:604841
Retinal disorders v2.223 COL11A1 Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Eye Disorders to Stickler syndrome, type II, OMIM:604841
Cytopenia - NOT Fanconi anaemia v1.43 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1381 CLPB Dmitrijs Rots reviewed gene: CLPB: Rating: ; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 34140661; Phenotypes: Neutropenia, intellectual disability; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Severe microcephaly v2.267 DPP6 Ivone Leong Tag Q4_21_expert_review tag was added to gene: DPP6.
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Proteinuric renal disease v2.60 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Proteinuric renal disease v2.59 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained paediatric onset end-stage renal disease v1.22 TRIM8 Ivone Leong Tag Q4_21_rating tag was added to gene: TRIM8.
Unexplained paediatric onset end-stage renal disease v1.22 TRIM8 Ivone Leong Classified gene: TRIM8 as Amber List (moderate evidence)
Unexplained paediatric onset end-stage renal disease v1.22 TRIM8 Ivone Leong Gene: trim8 has been classified as Amber List (Moderate Evidence).
Unexplained paediatric onset end-stage renal disease v1.21 TRIM8 Ivone Leong changed review comment from: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.; to: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Unexplained paediatric onset end-stage renal disease v1.21 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Unexplained paediatric onset end-stage renal disease v1.21 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Unexplained paediatric onset end-stage renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Proteinuric renal disease v2.59 TRIM8 Ivone Leong Entity copied from Unexplained kidney failure in young people v1.97
Proteinuric renal disease v2.59 TRIM8 Ivone Leong gene: TRIM8 was added
gene: TRIM8 was added to Proteinuric renal disease. Sources: Expert Review Green,Literature
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIM8 were set to 33508234; 32531461; 32193649; 33508234
Phenotypes for gene: TRIM8 were set to nephrotic syndrome; epilepsy; Focal segmental glomerulosclerosis and neurodevelopmental syndrome, OMIM:619428
Mode of pathogenicity for gene: TRIM8 was set to Other
Growth failure in early childhood v1.90 MAPK1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: MAPK1.
Tag Q4_21_phenotype tag was added to gene: MAPK1.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong Tag watchlist tag was added to gene: PI4KA.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong edited their review of gene: PI4KA: Changed rating: AMBER
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong commented on gene: PI4KA: This gene is rated Amber as not all affected individuals have IBD. Until more evidence is available this gene has been given an Amber rating.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.25 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Growth failure in early childhood v1.90 MRAS Ivone Leong Tag Q4_21_expert_review tag was added to gene: MRAS.
Growth failure in early childhood v1.90 SETD5 Ivone Leong Tag Q4_21_expert_review tag was added to gene: SETD5.
Tag Q4_21_phenotype tag was added to gene: SETD5.
Growth failure in early childhood v1.90 SETD5 Ivone Leong Classified gene: SETD5 as Amber List (moderate evidence)
Growth failure in early childhood v1.90 SETD5 Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype (confirmed). As the severity of some of these cases were not stated in the publications, this gene has been added to the panel as Amber and have been flagged to be reviewed by the GMS expert review panel.
Growth failure in early childhood v1.90 SETD5 Ivone Leong Gene: setd5 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v1.89 SETD5 Ivone Leong Phenotypes for gene: SETD5 were changed from Mental retardation, autosomal dominant 23, OMIM:615761 to Mental retardation, autosomal dominant 23, OMIM:615761; growth retardation; bone fragility
Growth failure in early childhood v1.88 SETD5 Ivone Leong Phenotypes for gene: SETD5 were changed from intellectual disability; developmental delay; growth retardation; bone fragility to Mental retardation, autosomal dominant 23, OMIM:615761
Growth failure in early childhood v1.87 SETD5 Ivone Leong Publications for gene: SETD5 were set to PMID: 28881385
Hypertrophic cardiomyopathy - teen and adult v2.30 GYG1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: GYG1.
Hypertrophic cardiomyopathy - teen and adult v2.30 GYG1 Ivone Leong Tag watchlist tag was added to gene: GYG1.
Hypertrophic cardiomyopathy - teen and adult v2.30 GYG1 Ivone Leong Classified gene: GYG1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy - teen and adult v2.30 GYG1 Ivone Leong Added comment: Comment on list classification: New gene added by Oliver Watkinson (NHS). THis gene is associated with a phenotype in OMIM but not Gene2Phenotype. While there are >3 unrelated cases of affected patients with HCM there are other patients with variants in this gene who do not have any cardiomyopathy phenotype. As indicated by Oliver Watkinson, the sister of an affected patient had the same genotype but was unaffected. Based on the available evidence this gene has been given an Amber rating until more cases are available.
Hypertrophic cardiomyopathy - teen and adult v2.30 GYG1 Ivone Leong Gene: gyg1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.736 LRIT3 Zornitza Stark reviewed gene: LRIT3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Night blindness, congenital stationary (complete), 1F, autosomal recessive 615058; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to DDG2P. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Hereditary spastic paraplegia - childhood onset v2.84 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Fetal anomalies v1.736 AAAS Zornitza Stark edited their review of gene: AAAS: Changed rating: RED
Fetal anomalies v1.736 AAAS Zornitza Stark reviewed gene: AAAS: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Achalasia-addisonianism-alacrimia syndrome, MIM#231550; Mode of inheritance: None
Genetic epilepsy syndromes v2.449 CELF2 Dmitrijs Rots reviewed gene: CELF2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: DEE; Mode of inheritance: None
Hereditary neuropathy NOT PMP22 copy number v1.64 GBF1 Dmitrijs Rots reviewed gene: GBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial dysautonomia v1.15 DST Dmitrijs Rots reviewed gene: DST: Rating: AMBER; Mode of pathogenicity: None; Publications: PubMed: 30371979; Phenotypes: Neuropathy, hereditary sensory and autonomic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.64 TECPR2 Dmitrijs Rots gene: TECPR2 was added
gene: TECPR2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TECPR2 were set to PubMed: 33847017
Phenotypes for gene: TECPR2 were set to Hereditary sensory and autonomic neuropathy
Penetrance for gene: TECPR2 were set to unknown
Review for gene: TECPR2 was set to GREEN
Added comment: Neuser et al. (2021) reported clinical findings in 17 patients, including 2 sib pairs, from 15 families segregating HSAN9.
Sources: Literature
Familial dysautonomia v1.15 TECPR2 Dmitrijs Rots reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 33847017; Phenotypes: Sensory neuropathy, autonomic neuropathy; Mode of inheritance: None
Primary immunodeficiency v2.480 DEF6 Dmitrijs Rots reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32562707; Phenotypes: ; Mode of inheritance: None
Cutaneous photosensitivity with a likely genetic cause v1.8 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 ANAPC1 Tom Cullup reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31303264; Phenotypes: Rothmund-Thomson syndrome type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.26 AXIN2 Tom Cullup gene: AXIN2 was added
gene: AXIN2 was added to Ectodermal dysplasia. Sources: Other
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXIN2 were set to 15042511
Phenotypes for gene: AXIN2 were set to OLIGODONTIA-COLORECTAL CANCER SYNDROME
Penetrance for gene: AXIN2 were set to unknown
Review for gene: AXIN2 was set to GREEN
Added comment: Sources: Other
Rare genetic inflammatory skin disorders v1.40 ECM1 Tom Cullup gene: ECM1 was added
gene: ECM1 was added to Rare genetic inflammatory skin disorders. Sources: Other
Mode of inheritance for gene: ECM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECM1 were set to 11929856
Phenotypes for gene: ECM1 were set to Urbach-Wiethe disease
Penetrance for gene: ECM1 were set to Complete
Review for gene: ECM1 was set to GREEN
Added comment: Sources: Other
Neurological ciliopathies v1.20 TMEM218 Tom Cullup reviewed gene: TMEM218: Rating: GREEN; Mode of pathogenicity: None; Publications: 33791682; Phenotypes: JOUBERT SYNDROME 39; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Multiple monogenic benign skin tumours v1.12 NOTCH3 Tom Cullup gene: NOTCH3 was added
gene: NOTCH3 was added to Multiple monogenic benign skin tumours. Sources: Other
Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH3 were set to 23731542
Phenotypes for gene: NOTCH3 were set to MYOFIBROMATOSIS, INFANTILE, 2
Penetrance for gene: NOTCH3 were set to unknown
Review for gene: NOTCH3 was set to AMBER
Added comment: Request to add PDGFRB and NOTCH3 to MMBST panel - phenotype appropriate, but may need to broaden eligibility criteria simultaneously.
Sources: Other
Multiple monogenic benign skin tumours v1.12 PDGFRB Tom Cullup reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23731537, 23731542; Phenotypes: MYOFIBROMATOSIS, INFANTILE, 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v1.68 ASPRV1 Tom Cullup reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32516568; Phenotypes: ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders v1.16 NDUFB11 Tom Cullup gene: NDUFB11 was added
gene: NDUFB11 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: NDUFB11 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: NDUFB11 were set to 33670341
Phenotypes for gene: NDUFB11 were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: NDUFB11 were set to unknown
Review for gene: NDUFB11 was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 COX7B Tom Cullup gene: COX7B was added
gene: COX7B was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: COX7B was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: COX7B were set to 33670341
Phenotypes for gene: COX7B were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: COX7B were set to unknown
Review for gene: COX7B was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Pigmentary skin disorders v1.16 HCCS Tom Cullup gene: HCCS was added
gene: HCCS was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: HCCS was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: HCCS were set to 33670341
Phenotypes for gene: HCCS were set to Linear Skin Defects with Multiple Congenital Anomalies
Penetrance for gene: HCCS were set to unknown
Review for gene: HCCS was set to GREEN
Added comment: XLD - lethal in males
Sources: Other
Structural eye disease v1.83 ASPH Tom Cullup reviewed gene: ASPH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24768550; Phenotypes: Traboulsi syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pigmentary skin disorders v1.16 SMARCAL1 Tom Cullup gene: SMARCAL1 was added
gene: SMARCAL1 was added to Pigmentary skin disorders. Sources: Other
Mode of inheritance for gene: SMARCAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCAL1 were set to 11799392
Phenotypes for gene: SMARCAL1 were set to SCHIMKE IMMUNOOSSEOUS DYSPLASIA
Penetrance for gene: SMARCAL1 were set to Complete
Review for gene: SMARCAL1 was set to GREEN
Added comment: Sources: Other
Pigmentary skin disorders v1.16 DDX3X Tom Cullup gene: DDX3X was added
gene: DDX3X was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: DDX3X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: DDX3X were set to 30349862
Phenotypes for gene: DDX3X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE
Penetrance for gene: DDX3X were set to unknown
Review for gene: DDX3X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 USP9X Tom Cullup gene: USP9X was added
gene: USP9X was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: USP9X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: USP9X were set to 26833328
Phenotypes for gene: USP9X were set to INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 99, SYNDROMIC, FEMALE-RESTRICTED
Penetrance for gene: USP9X were set to unknown
Review for gene: USP9X was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 PHF6 Tom Cullup gene: PHF6 was added
gene: PHF6 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: PHF6 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PHF6 were set to 24092917
Phenotypes for gene: PHF6 were set to BORJESON-FORSSMAN-LEHMANN SYNDROME; Fine and whorled Blaschko-linear hypo or hyperpigmentation
Penetrance for gene: PHF6 were set to unknown
Review for gene: PHF6 was set to GREEN
Added comment: Sources: Expert list
Pigmentary skin disorders v1.16 TFE3 Tom Cullup gene: TFE3 was added
gene: TFE3 was added to Pigmentary skin disorders. Sources: Expert list
Mode of inheritance for gene: TFE3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TFE3 were set to 32409512
Phenotypes for gene: TFE3 were set to Intellectual disability with pigmentary mosaicism and storage disorder-like features
Penetrance for gene: TFE3 were set to unknown
Review for gene: TFE3 was set to GREEN
Added comment: Sources: Expert list
Mosaic skin disorders - deep sequencing v1.5 PTPN11 Tom Cullup edited their review of gene: PTPN11: Added comment: Request upgrade to green in order that panel updates can be made in preparation for publication of case series, without delay waiting for next PanelApp update cycle.; Changed rating: GREEN; Changed publications to: Mosaic case series currently under publication review - expected to be published by end of 2021; Changed phenotypes to: Phakomatosis pigmentovascularis (PPV), Noonan syndrome with lentigines (LEOPARD)(151100), Speckled lentiginous naevus syndrome (deletion)
DDG2P v2.50 PLCB4 Kate Downes reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 22560091, PMID: 23315542, PMID: 28328130, PMID: 23913798; Phenotypes: Auriculocondylar syndrome 2 (OMIM: 614669); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Albinism or congenital nystagmus v1.19 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Classified gene: CLCN7 as Amber List (moderate evidence)
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.
Lysosomal storage disorder v1.76 CLCN7 Arina Puzriakova Gene: clcn7 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.75 CLCN7 Arina Puzriakova gene: CLCN7 was added
gene: CLCN7 was added to Lysosomal storage disorder. Sources: Literature
watchlist tags were added to gene: CLCN7.
Mode of inheritance for gene: CLCN7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CLCN7 were set to 31155284
Phenotypes for gene: CLCN7 were set to Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Mode of pathogenicity for gene: CLCN7 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: CLCN7 was set to AMBER
Added comment: Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

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

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature
Fetal anomalies v1.736 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600; Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541
Severe microcephaly v2.266 BRD4 Ivone Leong Phenotypes for gene: BRD4 were changed from Cornelia de Lange-like syndrome to Cornelia de Lange-like syndrome, MONDO:0016033
Severe microcephaly v2.265 BRD4 Ivone Leong Classified gene: BRD4 as Amber List (moderate evidence)
Severe microcephaly v2.265 BRD4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not OMIM. Based on the available evidence this gene has been given an Amber rating.
Severe microcephaly v2.265 BRD4 Ivone Leong Gene: brd4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 BRD4 Ivone Leong Tag watchlist tag was added to gene: BRD4.
Hydrocephalus v2.123 HYLS1 Ivone Leong Tag Q4_21_expert_review tag was added to gene: HYLS1.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Classified gene: TNFRSF11A as Amber List (moderate evidence)
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. Based on the expert review there is enough evidnece for this gene to be Green on this panel.
Hydrocephalus v2.123 TNFRSF11A Ivone Leong Gene: tnfrsf11a has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.122 TNFRSF11A Ivone Leong Tag Q4_21_rating tag was added to gene: TNFRSF11A.
Intellectual disability v3.1378 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, 611490; Osteopetrosis, autosomal dominant 2, 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1377 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency v2.480 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Primary immunodeficiency v2.479 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Defects in Intrinsic and Innate Immunity; Osteopetrosis with hypocalcemia, neurologic features to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.735 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from CLCN7-RELATED OSTEOPETROSIS to CLCN7-RELATED OSTEOPETROSIS; Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Biallelic' to 'Both mono- and biallelic' at the next review. At least 2 recessive cases and >3 dominant cases reported with osteopetrosis.
Fetal anomalies v1.734 CLCN7 Arina Puzriakova Mode of inheritance for gene: CLCN7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.733 CLCN7 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN7.
Skeletal dysplasia v2.140 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 611490; Osteopetrosis, autosomal dominant 2 166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Osteopetrosis v1.27 CLCN7 Arina Puzriakova Phenotypes for gene: CLCN7 were changed from Osteopetrosis, autosomal recessive 4 OMIM:611490; Osteopetrosis, autosomal dominant 2 OMIM:166600 to Osteopetrosis, autosomal recessive 4, OMIM:611490; Osteopetrosis, autosomal dominant 2, OMIM:166600
Intellectual disability v3.1376 BLOC1S1 Ivone Leong Tag watchlist tag was added to gene: BLOC1S1.
Genetic epilepsy syndromes v2.449 ARFGEF1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Genetic epilepsy syndromes v2.449 ARFGEF1 Ivone Leong Entity copied from Intellectual disability v3.1376
Genetic epilepsy syndromes v2.449 ARFGEF1 Ivone Leong gene: ARFGEF1 was added
gene: ARFGEF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ARFGEF1.
Mode of inheritance for gene: ARFGEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARFGEF1 were set to 34113008
Phenotypes for gene: ARFGEF1 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1376 ARFGEF1 Ivone Leong Phenotypes for gene: ARFGEF1 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Classified gene: ARFGEF1 as Amber List (moderate evidence)
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (probable) but not in OMIM. There are >3 unrelated cases. ID in patients ranged from mild to moderate, which does not satisfy the criteria for this panel (moderate to severe); however, as this is one of the presenting features this gene has will be recommended to be Green at the next review.
Intellectual disability v3.1375 ARFGEF1 Ivone Leong Gene: arfgef1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1374 ARFGEF1 Ivone Leong Tag Q4_21_rating tag was added to gene: ARFGEF1.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Classified gene: TMEM251 as Amber List (moderate evidence)
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Gene: tmem251 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.138 TMEM251 Eleanor Williams Phenotypes for gene: TMEM251 were changed from Dysostosis multiplex‐like skeletal dysplasia; severe short stature to Dysostosis multiplex, Ain-Naz type, OMIM:19345; severe short stature
Skeletal dysplasia v2.137 TMEM251 Eleanor Williams reviewed gene: TMEM251: Rating: AMBER; Mode of pathogenicity: None; Publications: 33252156; Phenotypes: Dysostosis multiplex, Ain-Naz type, OMIM:19345; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.50 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from HEREDITARY SENSORY & AUTONOMIC NEUROPATHY TYPE VIII 616488 to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy v1.417 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Hereditary neuropathy NOT PMP22 copy number v1.64 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from hereditary sensory & autonomic neuropathy type VIII to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1374 PRDM12 Sarah Leigh Mode of inheritance for gene: PRDM12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1373 PRDM12 Sarah Leigh Phenotypes for gene: PRDM12 were changed from NA to Neuropathy, hereditary sensory and autonomic, type VIII OMIM:616488; congenital insensitivity to pain-hypohidrosis syndrome MONDO:0014662
Intellectual disability v3.1372 PRDM12 Sarah Leigh Publications for gene: PRDM12 were set to
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Inborn errors of metabolism v2.188 EHBP1L1 Sarah Leigh Tag Q4_21_rating tag was added to gene: EHBP1L1.
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Fetal anomalies v1.733 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Inborn errors of metabolism v2.188 EHBP1L1 Sarah Leigh Entity copied from Fetal hydrops v1.39
Inborn errors of metabolism v2.188 EHBP1L1 Sarah Leigh gene: EHBP1L1 was added
gene: EHBP1L1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to 34645488; 26833786; https://dmdd.org.uk/mutants/Ehbp1l1
Phenotypes for gene: EHBP1L1 were set to non-immune hydrops fetalis MONDO:0009369
Penetrance for gene: EHBP1L1 were set to unknown
Fetal hydrops v1.39 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to 34645488
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh edited their review of gene: EHBP1L1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least two variants reported in two unrelated families with non-immune hydrops fetalis (NIHF) resulting in recurrent fetal loss. Two Ehbp1l1−/− mouse models shared phenotypic features with the affected patients, including early death, abnormal intestinal microvilli, subcutaneous edema, perimembraneous ventricular septic defect, and thin myocardium (PMID 26833786, https://dmdd.org.uk/mutants/Ehbp1l1).; Changed rating: GREEN
Fetal hydrops v1.38 EHBP1L1 Sarah Leigh Publications for gene: EHBP1L1 were set to PMID: 34645488
Fetal hydrops v1.37 EHBP1L1 Sarah Leigh Phenotypes for gene: EHBP1L1 were changed from Non immune hydrops to non-immune hydrops fetalis MONDO:0009369
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Classified gene: EHBP1L1 as Amber List (moderate evidence)
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal hydrops v1.36 EHBP1L1 Sarah Leigh Gene: ehbp1l1 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy - teen and adult v2.29 GYG1 Ivone Leong Phenotypes for gene: GYG1 were changed from to ?Glycogen storage disease XV, OMIM:613507; hypertrophic cardiomyopathy, MONDO:0005045
Hypertrophic cardiomyopathy - teen and adult v2.28 GYG1 Ivone Leong Publications for gene: GYG1 were set to 27718144
Hypertrophic cardiomyopathy - teen and adult v2.27 GYG1 Oliver Watkinson reviewed gene: GYG1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27718144, 20357282, 31628455; Phenotypes: Hypertrophic Cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy - teen and adult v2.27 GYG1 Oliver Watkinson gene: GYG1 was added
gene: GYG1 was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
Mode of inheritance for gene: GYG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GYG1 were set to 27718144
Penetrance for gene: GYG1 were set to Incomplete
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their review
DDG2P v2.49 ATN1 Dmitrijs Rots Deleted their comment
DDG2P v2.49 ATN1 Dmitrijs Rots reviewed gene: ATN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh changed review comment from: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature; to: Two rare missense IFT140 variants (p.Leu693Phe & p.Lys390Arg) reported in a case of primary ciliary dyskinesia, both variats predicted to be benign by Polyphen & SIFT (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.50 IFT140 Sarah Leigh gene: IFT140 was added
gene: IFT140 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: IFT140 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT140 were set to 34556108
Phenotypes for gene: IFT140 were set to Short-rib thoracic dysplasia 9 with or without polydactyly OMIM:266920
Review for gene: IFT140 was set to RED
Added comment: Two IFT140 variants reported in a case of primary ciliary dyskinesia (PMID 34556108).
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.49 PLK4 Sarah Leigh Publications for gene: PLK4 were set to 22503633; 34556108
Respiratory ciliopathies including non-CF bronchiectasis v1.48 PLK4 Sarah Leigh gene: PLK4 was added
gene: PLK4 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: PLK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLK4 were set to 22503633; 34556108
Phenotypes for gene: PLK4 were set to Microcephaly and chorioretinopathy, autosomal recessive 2 OMIM:616171; microcephaly and chorioretinopathy 2 MONDO:0014516
Review for gene: PLK4 was set to RED
Added comment: Two PLK4 variants reported in a case of primary ciliary dyskinesia (PMID: 34556108).
Sources: Literature
Intellectual disability v3.1371 ZC4H2 Ivone Leong reviewed gene: ZC4H2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1371 ZC4H2 Ivone Leong Tag Q4_21_MOI tag was added to gene: ZC4H2.
Fetal anomalies v1.732 ZC4H2 Ivone Leong Publications for gene: ZC4H2 were set to
Fetal anomalies v1.731 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Arthrogryposis v3.130 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from Wieacker-Wolff syndrome 314580 to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Intellectual disability v3.1371 ZC4H2 Ivone Leong Phenotypes for gene: ZC4H2 were changed from ARTHROGRYPOSIS MULTIPLEX CONGENITA AND INTELLECTUAL DISABILITY to Wieacker-Wolff syndrome, OMIM:314580; Wieacker-Wolff syndrome, female-restricted, OMIM:301041
Infantile enterocolitis & monogenic inflammatory bowel disease v1.24 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease; 32686289; 25943627; 24942515; 29501442
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Added comment: Comment on publications: Previously: 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease
Infantile enterocolitis & monogenic inflammatory bowel disease v1.23 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055 - pathogenic variant in this gene reported in a patient using whole exome sequencing screening in 147 pediatric patients with monogenic Inflammatory Bowel Disease.
Gastrointestinal epithelial barrier disorders v1.61 XIAP Ivone Leong Publications for gene: XIAP were set to 21173700; 17080092; 27537055
Gastrointestinal epithelial barrier disorders v1.60 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Infantile enterocolitis & monogenic inflammatory bowel disease v1.22 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v2.478 XIAP Ivone Leong Publications for gene: XIAP were set to 26581487; 21119115; 23973892; 17080092; 21173700; 22228567; 23131490; 25943627; 31754776
Primary immunodeficiency v2.477 XIAP Ivone Leong reviewed gene: XIAP: Rating: ; Mode of pathogenicity: None; Publications: 32686289, 25943627, 24942515, 29501442; Phenotypes: ; Mode of inheritance: None
Intracerebral calcification disorders v1.30 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514 - identification of AP1S2 variants in a large 4-generation French family, and a Scottish family, marked calcifications of the basal ganglia were reported in affected individuals in both families; 18428203 - an additional two families reported "Studying four patients in two unrelated families in which AP1S2 nonsense and splicesite
mutations segregated, we found that affected individuals presented, in addition to previously described features,
with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that
the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be
progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically
recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive
behavior, brain calcifications, and elevated CSF protein levels."
Structural basal ganglia disorders v1.22 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
White matter disorders and cerebral calcification - narrow panel v1.208 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17617514; 1842820
Childhood onset dystonia or chorea or related movement disorder v1.160 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 23756445; 17617514; 18428203
Intellectual disability v3.1370 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to
Hydrocephalus v2.122 AP1S2 Arina Puzriakova Publications for gene: AP1S2 were set to 17186471
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: AP1S2.
Fetal anomalies v1.730 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from MENTAL RETARDATION X-LINKED TYPE 59 to Pettigrew syndrome, OMIM:304340
Fetal anomalies v1.729 AP1S2 Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles.

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

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

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

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

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

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

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

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

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

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

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

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

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
OFD IX

Publications

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.
Neurological ciliopathies v1.19 ARL3 Ivone Leong Publications for gene: ARL3 were set to 30269812; 16565502
Adult onset movement disorder v1.124 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340; Dystonia to Pettigrew syndrome, OMIM:304340
Neurodegenerative disorders - adult onset v2.201 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Hereditary ataxia - adult onset v2.89 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 OMIM:304340; syndromic X-linked intellectual disability 5 MONDO:0010574 to Pettigrew syndrome, OMIM:304340
Intracerebral calcification disorders v1.29 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Hereditary ataxia v1.245 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
Ataxia and cerebellar anomalies - narrow panel v2.240 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340
White matter disorders and cerebral calcification - narrow panel v1.207 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Calcifications in basal ganglia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Calcifications in basal ganglia
Childhood onset dystonia or chorea or related movement disorder v1.158 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Dystonia; Mental retardation, X-linked syndromic 5, 304340 to Pettigrew syndrome, OMIM:304340; Dystonia
Intellectual disability v3.1368 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic, Fried type, 300630; MENTAL RETARDATION X-LINKED TYPE 59 (MRX59) to Pettigrew syndrome, OMIM:304340
Structural basal ganglia disorders v1.20 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5 304340 to Pettigrew syndrome, OMIM:304340
Hydrocephalus v2.119 AP1S2 Arina Puzriakova Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, OMIM:304340 to Pettigrew syndrome, OMIM:304340
Congenital muscular dystrophy v2.18 MYMK Ivone Leong commented on gene: MYMK
Congenital muscular dystrophy v2.18 MYMK Ivone Leong Tag Q3_21_expert_review tag was added to gene: MYMK.
Tag Q3_21_phenotype tag was added to gene: MYMK.
Growth failure in early childhood v1.86 GGPS1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

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

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

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

Currently there is uncertain clinical relevance of this gene to growth failure phenotype. Therefore, this gene has been given an Amber rating until more evidence is available.
Growth failure in early childhood v1.86 GGPS1 Ivone Leong Tag Q4_21_rating was removed from gene: GGPS1.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Classified gene: GGPS1 as Green List (high evidence)
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green according to my previous review.
Primary ovarian insufficiency v1.51 GGPS1 Ivone Leong Gene: ggps1 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

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

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

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

There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Tag Q4_21_rating was removed from gene: GGPS1.
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Primary ovarian insufficiency v1.50 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Primary ovarian insufficiency. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Growth failure in early childhood v1.86 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Growth failure in early childhood v1.86 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Growth failure in early childhood. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Hearing loss v2.200 GGPS1 Ivone Leong Entity copied from Congenital muscular dystrophy v2.18
Hearing loss v2.200 GGPS1 Ivone Leong gene: GGPS1 was added
gene: GGPS1 was added to Hearing loss. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: GGPS1.
Mode of inheritance for gene: GGPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GGPS1 were set to 32403198
Phenotypes for gene: GGPS1 were set to Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, OMIM:619518
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Tag Q4_21_rating tag was added to gene: GGPS1.
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Classified gene: GGPS1 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.18 GGPS1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype.

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

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

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

Therefore, this gene has been given an Amber rating.
Cardiomyopathies - including childhood onset v1.57 GSN Ivone Leong Gene: gsn has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1367 BLOC1S1 Dmitrijs Rots gene: BLOC1S1 was added
gene: BLOC1S1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to PMID: 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Review for gene: BLOC1S1 was set to GREEN
Added comment: 4 cases with similar phenotype and inheritance reported
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.57 MYH1 Dmitrijs Rots gene: MYH1 was added
gene: MYH1 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Literature
Mode of inheritance for gene: MYH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYH1 were set to PMID: 33755318
Phenotypes for gene: MYH1 were set to Rhabdomyolysis
Penetrance for gene: MYH1 were set to unknown
Mode of pathogenicity for gene: MYH1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MYH1 was set to AMBER
Added comment: One patient reported with some statistical evidence and known horse "model" with same phenotype.
Sources: Literature
Fetal hydrops v1.35 EHBP1L1 Dmitrijs Rots gene: EHBP1L1 was added
gene: EHBP1L1 was added to Fetal hydrops. Sources: Literature
Mode of inheritance for gene: EHBP1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHBP1L1 were set to PMID: 34645488
Phenotypes for gene: EHBP1L1 were set to Non immune hydrops
Penetrance for gene: EHBP1L1 were set to unknown
Review for gene: EHBP1L1 was set to GREEN
Added comment: 2 families with confirming mouse data
Sources: Literature
Intellectual disability v3.1367 FAAH2 Dmitrijs Rots reviewed gene: FAAH2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34645488; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Mild cognitive impairment has been reported in some patients with CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ID. There is also controversy regarding any link between CLCN2 and epilepsy.
Intellectual disability v3.1367 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.448 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628
Intellectual disability v3.1366 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Intellectual disability v3.1365 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Genetic epilepsy syndromes v2.447 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Monoallelic' only. Seizures have been linked with monoallelic variants (MIM# 607628) although there is debate regarding this gene-disease relationship, hence the current Red rating on this panel. Autosomal recessive pathogenic variants are also associated with Leukoencephalopathy (MIM# 615651) which does not include epilepsy.
Genetic epilepsy syndromes v2.447 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders - adult onset v2.200 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Features of neurodegeneration are seen in CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes are relevant to this panel.
Neurodegenerative disorders - adult onset v2.200 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegenerative disorders - adult onset v2.199 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; Leukoencephalopathy with ataxia, OMIM:615651 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia - adult onset v2.88 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary ataxia v1.244 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628 to Leukoencephalopathy with ataxia, OMIM:615651
Neurodegenerative disorders - adult onset v2.198 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Neurodegenerative disorders - adult onset v2.197 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Familial Meniere Disease v1.1 AQP6 Eldar Dedic reviewed gene: AQP6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Familial Meniere Disease v1.1 AQP5 Eldar Dedic reviewed gene: AQP5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Hereditary ataxia - adult onset v2.87 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Hereditary ataxia v1.243 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 23707145; 19191339
Ataxia and cerebellar anomalies - narrow panel v2.239 CLCN2 Arina Puzriakova Publications for gene: CLCN2 were set to 19191339; 23707145
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia - adult onset v2.86 CLCN2 Arina Puzriakova Tag Q4_21_MOI tag was added to gene: CLCN2.
Hereditary ataxia - adult onset v2.86 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia - adult onset v2.86 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Hereditary ataxia v1.242 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only. Ataxia is a frequent feature of CLCN2-related Leukoencephalopathy (MIM# 615651) which is caused by biallelic variants. Autosomal dominant pathogenic variants are also associated with hyperaldosteronism (MIM# 605635) and susceptibility to idiopathic epilepsy (MIM# 607628) but neither of these phenotypes include ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.238 CLCN2 Arina Puzriakova Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.237 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
Inherited white matter disorders v1.141 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema; Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukoencephalopathy with ataxia, OMIM:615651
White matter disorders - adult onset v1.31 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651 to Leukoencephalopathy with ataxia, OMIM:615651
White matter disorders and cerebral calcification - narrow panel v1.206 CLCN2 Arina Puzriakova Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Chloride Ion Channel 2(ClC-2) related leukoencephalopathy with intramyelinic oedema to Leukoencephalopathy with ataxia, OMIM:615651
Hereditary spastic paraplegia - adult onset v1.73 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Hereditary spastic paraplegia - childhood onset v2.84 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Familial Meniere Disease v1.1 AQP3 Eldar Dedic reviewed gene: AQP3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Monogenic nephrogenic diabetes insipidus v1.8 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: AVPR2.
Renal tubulopathies v2.30 AVPR2 Eleanor Williams Phenotypes for gene: AVPR2 were changed from Diabetes insipidus, nephrogenic, 304800; Nephrogenic Diabetes Insipidus; Diabetes Insipidus, Nephrogenic, X-Linked; nephrogenic diabetes insipidus (commonest cause, affected females also reported often with a milder and later presentation); Nephrogenic syndrome of inappropriate antidiuresis, 300539 to Diabetes insipidus, nephrogenic, OMIM:304800; Nephrogenic syndrome of inappropriate antidiuresis, OMIM:300539
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Added comment: Comment on mode of pathogenicity: Gain of function variants
Renal tubulopathies v2.29 AVPR2 Eleanor Williams Mode of pathogenicity for gene: AVPR2 was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Neurodegenerative disorders - adult onset v2.197 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, to Silver spastic paraplegia syndrome, OMIM:270685
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_phenotype tag was added to gene: MYMK.
Hydrocephalus v2.118 MYMK Ivone Leong commented on gene: MYMK
Mosaic skin disorders - deep sequencing v1.5 BRAF Tom Cullup changed review comment from: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list; to: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Fast track form submitted. Note from Prof Kinsler:
We have noticed that BRAF is not included on this panel. As a key player in mosaic diseases of various types this was an error somehow in the preparation of the original list. Without it's inclusion on the panel various conditions cannot be properly tested for. For example 7% of Congenital Melanocytic Naevus syndrome are caused by BRAF mosaicism and approximately 5% of Arteriovenous Malformations.
Hydrocephalus v2.118 MYMK Ivone Leong Tag Q4_21_expert_review tag was added to gene: MYMK.
Mosaic skin disorders - deep sequencing v1.5 BRAF Tom Cullup gene: BRAF was added
gene: BRAF was added to Mosaic skin disorders - deep sequencing. Sources: Expert list
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to PMID: 31111470; 31891627; 29461977
Phenotypes for gene: BRAF were set to Melanocytic naevus syndrome (MIM 137550); Vascular malformations; Noonan syndrome 7 (MIM 613706); LEOPARD syndrome 3 (MIM 613707); Cardio-facio-cutaneous syndrome 1 (MIM 115150)
Penetrance for gene: BRAF were set to Complete
Mode of pathogenicity for gene: BRAF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: BRAF was set to GREEN
Added comment: Note that the primary mosaic phenotypes are melanocytic naevus syndrome (MIM number currently not linked to BRAF) and vascular malformations (no appropriate MIM number currently) - see publications list.
Sources: Expert list
Hydrocephalus v2.118 TCIRG1 Ivone Leong Tag Q4_21_rating tag was added to gene: TCIRG1.
Hydrocephalus v2.118 TCIRG1 Ivone Leong Publications for gene: TCIRG1 were set to
Hydrocephalus v2.117 TCIRG1 Ivone Leong Classified gene: TCIRG1 as Amber List (moderate evidence)
Hydrocephalus v2.117 TCIRG1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hydrocephalus v2.117 TCIRG1 Ivone Leong Gene: tcirg1 has been classified as Amber List (Moderate Evidence).
Membranoproliferative glomerulonephritis v2.21 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained paediatric onset end-stage renal disease v1.20 CFB Eleanor Williams commented on gene: CFB: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Unexplained kidney failure in young people v1.97 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM this gene is also provisionally associated with Complement factor B deficiency based on evidence from one family with biallelic variants in CFB. However, given the phenotype/level of evidence it is not appropriate to change the mode of inheritance to Both monoallelic and biallelic on this panel.
Atypical haemolytic uraemic syndrome v2.10 CFB Eleanor Williams Mode of inheritance for gene: CFB was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Clefting v2.57 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Fetal anomalies v1.728 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184.
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Limb disorders v2.65 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh edited their review of gene: SCUBE3: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.; Changed rating: AMBER
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined.
Clefting v2.56 SCUBE3 Sarah Leigh Deleted their comment
Clefting v2.56 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Clefting v2.56 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Clefting was evident in 3/14 cases examined
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q4_21_expert_review tag was added to gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Fetal anomalies v1.727 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Prenatal growth retardation was evident in 8/11 relevant cases.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q4_21_rating tag was added to gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh Tag Q2_21_rating was removed from gene: SCUBE3.
Limb disorders v2.64 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Brachydactyly was evident in 12/15 cases examined.
Fetal anomalies v1.727 BMPR1B Arina Puzriakova changed review comment from: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.; to: Comment on mode of inheritance: Biallelic variants lead to the Demirhan type of acromesomelic dysplasia (MIM# 609441) which is pertinent to this panel. Monoallelic variants cause brachydactyly (MIM# 616849 and MIM# 112600) with dysplasia of only a single or few phalanges which would be difficult to diagnose prenatally. For this reason the MOI should remain as biallelic only on this panel.
-----
Confirmed with clinical team that this is the appropriate MOI for this panel.
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Added comment: Comment on phenotypes: Previously associated with ?Mental retardation, X-linked 91, OMIM:300577; however, OMIM has removed this
Intellectual disability v3.1364 ZDHHC15 Ivone Leong Phenotypes for gene: ZDHHC15 were changed from ?Mental retardation, X-linked 91, 300577 to cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Added comment: Comment on publications: New publication added PMID:34345675
Intellectual disability v3.1363 ZDHHC15 Ivone Leong Publications for gene: ZDHHC15 were set to 15915161
Fetal anomalies v1.727 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Fetal anomalies v1.727 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Fetal anomalies. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Clefting v2.56 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Clefting v2.56 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Clefting. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Limb disorders v2.64 SCUBE3 Sarah Leigh Entity copied from Skeletal dysplasia v2.136
Limb disorders v2.64 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Limb disorders. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Intellectual disability v3.1362 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Intellectual disability v3.1362 RAD51 Arina Puzriakova Added comment: Comment on list classification: Intellectual disability has been reported in 2/3 individuals with RAD51-associated FA (third patient with mild early DD). However, a syndromic presentation prior to this is expected. Potential for VUSs in pure ID cohort, although there is an allied chromosome breakage test. Upgrading from Red to Amber - which also reflects the rating of other FA genes associated with ID.
Intellectual disability v3.1362 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1361 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2, OMIM:614508 to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1360 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 22305526; 21242494
Intellectual disability v3.1359 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Familial Meniere Disease v1.1 AQP2 Eldar Dedic reviewed gene: AQP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Haematological malignancies cancer susceptibility v2.21 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies for rare disease v1.7 RAD51 Arina Puzriakova Publications for gene: RAD51 were set to 28297620
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova edited their review of gene: RAD51: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova reviewed gene: RAD51: Rating: AMBER; Mode of pathogenicity: None; Publications: 26681308, 26253028, 30907510; Phenotypes: Fanconi anemia, complementation group R, OMIM:617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v1.85 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Growth failure in early childhood v1.85 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).

Other FA genes have been included on this panel as Green.
Growth failure in early childhood v1.85 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Confirmed Fanconi anaemia or Bloom syndrome v1.13 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Severe microcephaly v2.264 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Severe microcephaly v2.264 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.63 RAD51 Arina Puzriakova Classified gene: RAD51 as Amber List (moderate evidence)
Limb disorders v2.63 RAD51 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 3 unrelated cases with relevant phenotype and different de novo variants. Phenotype-gene relationship listed in OMIM (MIM# 617244).
Limb disorders v2.63 RAD51 Arina Puzriakova Gene: rad51 has been classified as Amber List (Moderate Evidence).
Confirmed Fanconi anaemia or Bloom syndrome v1.12 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Confirmed Fanconi anaemia or Bloom syndrome. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Growth failure in early childhood v1.84 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Growth failure in early childhood. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Severe microcephaly v2.263 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Severe microcephaly. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Limb disorders v2.62 RAD51 Arina Puzriakova gene: RAD51 was added
gene: RAD51 was added to Limb disorders. Sources: Literature
Q4_21_rating tags were added to gene: RAD51.
Mode of inheritance for gene: RAD51 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RAD51 were set to 26681308; 26253028; 30907510
Phenotypes for gene: RAD51 were set to Fanconi anemia, complementation group R, OMIM:617244
Review for gene: RAD51 was set to GREEN
Added comment: Three unrelated patients have been identified to date (PMIDs: 26681308; 26253028; 30907510) with an atypical FA phonotype involving chromosomal instability without bone marrow failure or malignancies along with private heterozygous variants (c.877G>A; c.391A>C; c.725A>G) in the RAD51 gene. Variants occurred de novo with a dominant negative effect. All three individuals presented with thumb and radial abnormalities, microcephaly, and DD/ID (third patient showed early DD but above average IQ by age 13); and two individuals also had growth retardation (probable in third case but not reported on) and hearing impairment.
Sources: Literature
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Classified gene: ABHD16A as Green List (high evidence)
Hereditary spastic paraplegia v1.259 ABHD16A Ivone Leong Gene: abhd16a has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Tag Q4_21_rating was removed from gene: ABHD16A.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Hereditary spastic paraplegia v1.258 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Hereditary spastic paraplegia - childhood onset v2.83 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
Hereditary spastic paraplegia - childhood onset v2.83 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
White matter disorders and cerebral calcification - narrow panel v1.205 ABHD16A Ivone Leong Entity copied from Intellectual disability v3.1359
White matter disorders and cerebral calcification - narrow panel v1.205 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature,Expert Review Amber
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Haematological malignancies cancer susceptibility v2.20 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Haematological malignancies for rare disease v1.6 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Class: BM failure FA, (typ AR); Fanconi anemia; MDS; AML; Squamous cell carcinoma: oral, GI, vulvar to Fanconi anemia, complementation group R, OMIM:617244
Intellectual disability v3.1359 ABHD16A Ivone Leong Tag Q4_21_rating tag was added to gene: ABHD16A.
Intellectual disability v3.1359 ABHD16A Ivone Leong Classified gene: ABHD16A as Amber List (moderate evidence)
Intellectual disability v3.1359 ABHD16A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1359 ABHD16A Ivone Leong Gene: abhd16a has been classified as Amber List (Moderate Evidence).
COVID-19 research v1.80 RAD51 Arina Puzriakova Mode of inheritance for gene: RAD51 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1358 RAD51 Arina Puzriakova Phenotypes for gene: RAD51 were changed from Mirror movements 2,614508 to Mirror movements 2, OMIM:614508
Arthrogryposis v3.129 ERGIC1 Arina Puzriakova Publications for gene: ERGIC1 were set to 28317099; 34037256
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Classified gene: ERGIC1 as Amber List (moderate evidence)
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - three unrelated families reported to date with arthrogryposis associated with different variants in this gene (PMID: 28317099; 31230720; 34037256).
Arthrogryposis v3.128 ERGIC1 Arina Puzriakova Gene: ergic1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist was removed from gene: ERGIC1.
Tag Q3_21_rating tag was added to gene: ERGIC1.
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova reviewed gene: ERGIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230720; Phenotypes: Arthrogryposis multiplex congenita 2, neurogenic type, OMIM:208100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v2.55 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Clefting v2.55 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.726 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Fetal anomalies v1.726 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Limb disorders v2.61 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Limb disorders v2.61 BMP2 Eleanor Williams Mode of inheritance for gene: BMP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arthrogryposis v3.127 ERGIC1 Arina Puzriakova Tag watchlist tag was added to gene: ERGIC1.
Fetal anomalies v1.725 BHLHA9 Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic single nucleotide variants in this gene are associated with Syndactyly, mesoaxial synostotic, with phalangeal reduction (OMIM:609432). Monoallelic duplications of the whole gene are associated with split hand/foot malformations, but it is not clear if they are inherited in an Mendelian manner (see review on the Limb disorders panel https://panelapp.genomicsengland.co.uk/panels/384/gene/BHLHA9/)

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

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

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

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

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

Reports for 11 biallelic cases:

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

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

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

Reports for 11 biallelic cases:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Functional data in PMID 34542157

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

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

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

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

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

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

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

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

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

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

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


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

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

PMID: 25657982 - Mahdi Althaf et al 2015 - 30-year-old male was referred for persistent proteinuria. Bilateral corneal ring opacities were noted. Renal biopsy findings were consistent with LCAT deficiency.; Changed phenotypes to: Norum disease, OMIM:245900, Norum disease, MONDO:0009515, LCAT DEFICIENCY
Fetal anomalies v1.720 TMEM260 Alistair Pagnamenta reviewed gene: TMEM260: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28318500, 34612517; Phenotypes: ventricular septal defects, truncus arteriosus, elevated creatinine levels; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.191 USP48 Eleanor Williams Tag watchlist was removed from gene: USP48.
Tag Q4_21_rating tag was added to gene: USP48.
Hearing loss v2.191 USP48 Eleanor Williams Classified gene: USP48 as Amber List (moderate evidence)
Hearing loss v2.191 USP48 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber, with a recommendation for green rating following GMS review. 3 cases, 1 with segregation data (incomplete penetrance), plus supportive zebrafish model.
Hearing loss v2.191 USP48 Eleanor Williams Gene: usp48 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.190 USP48 Eleanor Williams Phenotypes for gene: USP48 were changed from non-syndromic hearing loss to non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497
Hearing loss v2.189 USP48 Eleanor Williams Publications for gene: USP48 were set to
Hearing loss v2.188 USP48 Eleanor Williams Mode of inheritance for gene: USP48 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.187 USP48 Eleanor Williams edited their review of gene: USP48: Added comment: PMID: 34059922 - Bassani et al 2021 - 3 cases reported with variants in USP48 and non syndromic hearing loss. They first analysed 4-generation Italian family with 6 individuals with hearing loss. The only rare variant segregating with the disease was a missense variant in USP48 (NM_032234.7:c.1216G > A, NP_115612.4:p.(Gly406Arg)). The variant is present in GnomAD v2.1.1 with a minor allele frequency (MAF) of 6.7 × 10−5 (17 allele out of 251 304 with no homozygotes). They also observed one hearing individual in the family who was heterozygous for the variant, suggesting incomplete penetrance.
In a Dutch family the found by exome sequencing a missense variant in USP48 (NM_032236.7:c.2215_2216delinsTT, NP_115612.4:p.(Thr739Leu)). The probands mother and uncle were also affected by no sequence data was available for analysis.
In a French family a proband is reported with right profound sensorineural hearing impairment (at 12 months), but normal left hearing (at 6 years old). The patient is heterozygote for a de novo splice variant in USP48 (NM_032236.7:c.3058 + 2 T > C, NP_115612.4:p.?;) which is not found in GnomAD and is predicted to result in a frameshift resulting in either NMD or a truncated protein.
In functional experiments they showed that the two missense variants found in the Italian and Dutch families, and a shortened protein as predicted for the variant found in the French variant, showed an impaired ability to cleave tetra-ubiquitin into tri-, di- and mono-ubiquitin. Using immunohistology, they show that the human USP48 protein is present in fetal inner ear specimens.
In addition zebrafish lacking usp48 showed a significant decrease of auditory response in acoustic startle response assays at 600 and 800 Hz wavelengths.; Changed rating: GREEN; Changed publications to: 34059922; Changed phenotypes to: nonsyndromic genetic deafness, MONDO:0019497; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.18 MARS Eleanor Williams gene: MARS was added
gene: MARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Literature
new-gene-name tags were added to gene: MARS.
Mode of inheritance for gene: MARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MARS were set to 33909043
Phenotypes for gene: MARS were set to trichothiodystrophy, MONDO:0018053
Review for gene: MARS was set to RED
Added comment: PMID: 33909043 - Botta et al 2021 - using WES/WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified a homozygous variant in one Italian patient (c.1201G > A (p.Val401Me) that is very rare (gnomAD frequency 0.00001414). Functional studies suggest that the variant affects gene product stability.
Sources: Literature
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Classified gene: AARS as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Added comment: Comment on list classification: Promoting to amber as 2 cases with plausible disease causing variants in the AARS gene reported.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.17 AARS Eleanor Williams Gene: aars has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.16 AARS Eleanor Williams gene: AARS was added
gene: AARS was added to Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome. Sources: Literature
new-gene-name tags were added to gene: AARS.
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 33909043
Phenotypes for gene: AARS were set to trichothiodystrophy, MONDO:0018053
Review for gene: AARS was set to AMBER
Added comment: PMID: 33909043 - Botta et al 2021 - using WES or WGS analysis of 34 unsolved cases with multi-system phenotypes, but with hair alterations that are typical of trichothiodystrophy but no reported photosensitivity, they identified 2 unrelated cases carrying 4 potentially pathogenic variants in the AARS1 gene (previously known as AARSB. Both patients had very rare compound heterozygous missense variants. In one family there was an older affected sibling but segregation data was not available for either family.
Sources: Literature
Growth failure in early childhood v1.83 ZNF668 Ivone Leong Entity copied from Intellectual disability v3.1332
Growth failure in early childhood v1.83 ZNF668 Ivone Leong gene: ZNF668 was added
gene: ZNF668 was added to Growth failure in early childhood. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ZNF668.
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Severe microcephaly v2.257 ZNF668 Ivone Leong Entity copied from Intellectual disability v3.1332
Severe microcephaly v2.257 ZNF668 Ivone Leong gene: ZNF668 was added
gene: ZNF668 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: ZNF668.
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Intellectual disability v3.1332 ZNF668 Ivone Leong Tag watchlist tag was added to gene: ZNF668.
Intellectual disability v3.1332 ZNF668 Ivone Leong Classified gene: ZNF668 as Amber List (moderate evidence)
Intellectual disability v3.1332 ZNF668 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently no phenotypes associated with this gene in OMIM or Gene2Phenotype. As there are only 2 cases there is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating.
Intellectual disability v3.1332 ZNF668 Ivone Leong Gene: znf668 has been classified as Amber List (Moderate Evidence).
Cataracts v2.85 UBE2U Ivone Leong Entity copied from Intellectual disability v3.1331
Cataracts v2.85 UBE2U Ivone Leong gene: UBE2U was added
gene: UBE2U was added to Cataracts. Sources: Expert Review Red,Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Intellectual disability v3.1331 UBE2U Ivone Leong Classified gene: UBE2U as Red List (low evidence)
Intellectual disability v3.1331 UBE2U Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a disease in Gene2Phenotype (there is currently no entry for this gene in OMIM). As there is currently only 1 case this gene has been given a Red rating.
Intellectual disability v3.1331 UBE2U Ivone Leong Gene: ube2u has been classified as Red List (Low Evidence).
Intellectual disability v3.1330 UBE2U Ivone Leong Phenotypes for gene: UBE2U were changed from Retinoschisis; cataracts; learning disabilities; developmental delay to Retinoschisis, MONDO:0004579; cataracts; learning disability, MONDO:0004681; developmental delay
Cardiomyopathies - including childhood onset v1.56 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Dilated cardiomyopathy,MONDO:0005021
Hearing loss v2.187 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Sensorineural hearing impairment, HP:0000407
Ataxia and cerebellar anomalies - narrow panel v2.236 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Intellectual disability, MONDO:0001071 to Ataxia, HP:0001251
Cardiomyopathies - including childhood onset v1.55 RNF220 Ivone Leong Tag Q4_21_rating tag was added to gene: RNF220.
Cardiomyopathies - including childhood onset v1.55 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

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

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

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

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

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

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

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

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
Cardiomyopathies - including childhood onset v1.55 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Cardiomyopathies - including childhood onset v1.55 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Cardiomyopathies - including childhood onset. Sources: Literature,Expert Review Amber,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Hearing loss v2.186 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Hearing loss v2.186 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Hearing loss. Sources: Literature,Expert Review Amber,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Ataxia and cerebellar anomalies - narrow panel v2.235 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1329
Ataxia and cerebellar anomalies - narrow panel v2.235 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber,Other
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Intellectual disability, MONDO:0001071
Penetrance for gene: RNF220 were set to Complete
Intellectual disability v3.1329 RNF220 Ivone Leong Phenotypes for gene: RNF220 were changed from Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum to Intellectual disability, MONDO:0001071
White matter disorders and cerebral calcification - narrow panel v1.202 RNF220 Ivone Leong Entity copied from Intellectual disability v3.1328
White matter disorders and cerebral calcification - narrow panel v1.202 RNF220 Ivone Leong gene: RNF220 was added
gene: RNF220 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Other,Expert Review Amber,Literature
Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF220 were set to 33964137; 10881263
Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum
Penetrance for gene: RNF220 were set to Complete
Intellectual disability v3.1328 RNF220 Ivone Leong Classified gene: RNF220 as Amber List (moderate evidence)
Intellectual disability v3.1328 RNF220 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

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

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

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

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

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

While there are cases of biallelic variants causing disease there are currently no new cases reporting of this (newest report was in 2006). There is currently not enough evidence to support biallelic cause of disease, I suggest changing the MOI to Monoallelic until more evidence is available.; Changed publications to: 15668980, 12666119, 9536092, 11251997, 16730439; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb girdle muscular dystrophy v2.29 CAV3 Ivone Leong commented on gene: CAV3
Limb girdle muscular dystrophy v2.29 CAV3 Ivone Leong Deleted their review
Limb girdle muscular dystrophy v2.29 CAV3 Ivone Leong Tag Q3_21_MOI was removed from gene: CAV3.
Limb girdle muscular dystrophy v2.29 CAV3 Ivone Leong Deleted their comment
Hereditary neuropathy NOT PMP22 copy number v1.63 AIFM1 Arina Puzriakova commented on gene: AIFM1
Intellectual disability v3.1323 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6, 300816Cowchock syndrome, 310490; COWCHOCK SYNDROME to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, OMIM:300232
Hereditary neuropathy v1.416 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Cowchock syndrome; Combined oxidative phosphorylation deficiency 6 to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816
Hereditary neuropathy NOT PMP22 copy number v1.63 AIFM1 Arina Puzriakova Phenotypes for gene: AIFM1 were changed from Combined oxidative phosphorylation deficiency 6; Cowchock syndrome to Cowchock syndrome, OMIM:310490; Combined oxidative phosphorylation deficiency 6, OMIM:300816
Hereditary neuropathy NOT PMP22 copy number v1.62 ABCA1 Arina Puzriakova commented on gene: ABCA1
Adult onset movement disorder v1.123 GBA Arina Puzriakova changed review comment from: GBA included on this panel to capture association with Parkinson disease (PD). However, GBA is only a risk factor and variants do not cause highly penetrant forms of PD. For these reasons, GBA was given an Amber rating on the 'Neurodegenerative disorders - adult onset' (R58) panel (https://panelapp.genomicsengland.co.uk/panels/474/gene/GBA/). Furthermore, issues regarding interpretation a GBA variant in the context of PD have been highlighted in the 100K (see Alison Callaway review on 100K PD panel - https://panelapp.genomicsengland.co.uk/panels/39/gene/GBA/). Given the potential carrier implications, inclusion of this gene will be flagged for review at the next GMS panel update.; to: GBA included on this panel to capture association with Parkinson disease (PD). However, variants do not cause highly penetrant forms of PD and for these reasons, GBA was given an Amber rating on the 'Neurodegenerative disorders - adult onset' (R58) panel (https://panelapp.genomicsengland.co.uk/panels/474/gene/GBA/). Furthermore, issues regarding interpretation a GBA variant in the context of PD have been highlighted in the 100K (see Alison Callaway review on 100K PD panel - https://panelapp.genomicsengland.co.uk/panels/39/gene/GBA/). Given that GBA is only a PD risk factor and the potential carrier implications, inclusion of this gene will be flagged for review at the next GMS panel update.
Adult onset movement disorder v1.123 GBA Arina Puzriakova commented on gene: GBA
Adult onset movement disorder v1.123 GBA Arina Puzriakova Tag Q4_21_MOI was removed from gene: GBA.
Adult onset movement disorder v1.123 GBA Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: GBA.
Tag Q4_21_MOI tag was added to gene: GBA.
Retinal disorders v2.216 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Genetic epilepsy syndromes v2.434 MED12 Eleanor Williams Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Genetic epilepsy syndromes v2.434 MED12 Eleanor Williams changed review comment from: Review of mode of inheritance shows that although in some families only males were affected, in 5 cases females with seizures as part of the phenotype were reported who had MED12 variants therefore a mode of inheritance of X-LINKED: hemizygous mutation in males, monoallelic mutations in females appears correct.

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
Familial Meniere Disease v1.1 ADD1 Eldar Dedic reviewed gene: ADD1: Rating: RED; Mode of pathogenicity: None; Publications: PMID:30828346; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.92 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Malformations of cortical development v2.92 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Malformations of cortical development. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: VPS50.
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Growth failure in early childhood v1.82 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

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

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

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

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Genetic epilepsy syndromes v2.434 VPS50 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

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

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

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

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

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

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

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

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

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

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

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

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Growth failure in early childhood v1.82 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Growth failure in early childhood v1.82 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Growth failure in early childhood. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Cholestasis v1.88 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Cholestasis v1.88 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Cholestasis. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Severe microcephaly v2.256 VPS50 Ivone Leong Entity copied from Intellectual disability v3.1322
Severe microcephaly v2.256 VPS50 Ivone Leong gene: VPS50 was added
gene: VPS50 was added to Severe microcephaly. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: VPS50.
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Penetrance for gene: VPS50 were set to Complete
Genetic epilepsy syndromes v2.434 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag watchlist tag was added to gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating was removed from gene: VPS50.
Intellectual disability v3.1322 VPS50 Ivone Leong Tag Q3_21_rating tag was added to gene: VPS50.
Genetic epilepsy syndromes v2.434 VPS50 Ivone Leong Classified gene: VPS50 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.434 VPS50 Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

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

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

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

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

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

Reports with females affected:

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

PMID: 34079076 - Riccardi et al 2021 - report an additional 4 female patients that carry de novo missense variants in MED12. All four patients had an intellectual disability, though it was severe only in one case. No seizures were noted.
Inborn errors of metabolism v2.183 ACAT2 Arina Puzriakova Publications for gene: ACAT2 were set to PMID:33340416
Inborn errors of metabolism v2.182 ACAT2 Arina Puzriakova Phenotypes for gene: ACAT2 were changed from Developmental delay to ?ACAT2 deficiency, OMIM:614055; Increased serum lactate and pyruvate; High levels of ketones; Low levels of cytosolic acetoacetyl-CoA thiolase; Hypotonia; Severe developmental delay
Mitochondrial disorders v2.54 ACAT2 Arina Puzriakova Phenotypes for gene: ACAT2 were changed from Increased serum lactate and pyruvate; high levels of ketones to ?ACAT2 deficiency, OMIM:614055; Increased serum lactate and pyruvate; High levels of ketones; Low levels of cytosolic acetoacetyl-CoA thiolase; Hypotonia; Severe developmental delay
Mitochondrial disorders v2.53 ACAT2 Arina Puzriakova Mode of inheritance for gene: ACAT2 was changed from Other to Unknown
Inborn errors of metabolism v2.181 ACAT2 Arina Puzriakova Classified gene: ACAT2 as Red List (low evidence)
Inborn errors of metabolism v2.181 ACAT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Andžela Lazdāne. Currently associated with a provisional phenotype in OMIM (?ACAT2 deficiency, OMIM:614055) and not yet listed in G2P. In the 2 cases reported to date (PMIDs: 20597, 6150136), diagnoses were made based on molecular rather than genetic findings. Rating Red as at present there is no published evidence of deleterious variants in the ACAT2 gene leading to this phenotype.
Inborn errors of metabolism v2.181 ACAT2 Arina Puzriakova Gene: acat2 has been classified as Red List (Low Evidence).
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Classified gene: ACAT2 as Red List (low evidence)
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Andžela Lazdāne. Currently associated with a provisional phenotype in OMIM (?ACAT2 deficiency, OMIM:614055) and not yet listed in G2P. In the 2 cases reported to date (PMIDs: 20597, 6150136), diagnoses were made based on molecular rather than genetic findings. Rating Red as at present there is no published evidence of deleterious variants in the ACAT2 gene leading to this phenotype.
Mitochondrial disorders v2.52 ACAT2 Arina Puzriakova Gene: acat2 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v2.431 MED12 Eleanor Williams commented on gene: MED12
Growth failure in early childhood v1.81 BTK Ivone Leong Phenotypes for gene: BTK were changed from to Isolated growth hormone deficiency, type III, with agammaglobulinaemia, OMIM:307200
Growth failure in early childhood v1.80 BTK Ivone Leong Publications for gene: BTK were set to
Growth failure in early childhood v1.79 MRAS Ivone Leong Publications for gene: MRAS were set to 28289718; 31173466; 31108500
Growth failure in early childhood v1.78 MRAS Ivone Leong Classified gene: MRAS as Amber List (moderate evidence)
Growth failure in early childhood v1.78 MRAS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (confirmed).

PMID: 28289718. 2 patients with a clinical diagnosis of Noonan syndrome were reported. Case 1: 15 yo girl with biventricular HCM that presented in infancy. She had short stature, facial dysmorphisms, global DD and cognitive disability. Parents are unaffected.
Case 2: 6 yo girl with cardiac hypertrophy, pulmonary valve stenosis, atrial septal defect, facial dysmorphisms, ptosis and DD. Both patients had de novo missense variants.

PMID: 31173466. 3 yo Japanese boy. Diagnosed with HCM during neonatal period, bilateral sensoineural hearing impairment, difficulty feeding at 4 months (poor weight gain), short stature, relative macrocephaly, height at 1 year 3 months was -3.0 SD, facial dysmorphisms. Patient had de novo missense variant.

PMID: 31108500. Case 1: North African Jewish descent. Birth length -1.1 SD, birth weight -1.1 SD. 14 months LV HCM. 15 months growth delay (height and weight -2.0 SD). Moderate hearing loss, mild global DD, GH deficiency. 2 years 3 months, height and weight was -2.0 SD and OCF +1.0 SD, facial dysmorphisms (suggestive of NS). Case 2: Germany. HCM, facial dysmorphisms and short neck.

PMID: 34080768. HCM at birth and facial dysmorphisms.

While there are >3 unrelated cases the patients in the article did not meet the criteria set out for this panel. This gene has been given an Amber rating for now.
Growth failure in early childhood v1.78 MRAS Ivone Leong Gene: mras has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Classified gene: RNF113A as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 300953) and as possible Gen2Phen gene for X-linked trichothiodystrophy. At least 3 terminating variants reported in unrelated cases. Supportive functional studies also reported. Upgraded from Red to Amber but this gene should be promoted to Green at the next review.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.15 RNF113A Arina Puzriakova Gene: rnf113a has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.431 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive, 300953 to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.14 RNF113A Arina Puzriakova Publications for gene: RNF113A were set to 25612912
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.13 RNF113A Arina Puzriakova Tag Q3_21_rating tag was added to gene: RNF113A.
White matter disorders and cerebral calcification - narrow panel v1.201 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Intellectual disability v3.1319 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from X-linked trichothiodystrophy; Trichothiodystrophy 5, nonphotosensitive, 300953; Intellectual disability to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.13 RNF113A Arina Puzriakova Phenotypes for gene: RNF113A were changed from ?Trichothiodystrophy 5, nonphotosensitive to Trichothiodystrophy 5, nonphotosensitive, OMIM:300953
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - two distinct homozygous variants identified in 5 individuals from 4 families who all had microcephaly among other features. Supportive in vitro studies that demonstrate functional impairment.
Severe microcephaly v2.253 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - two distinct homozygous variants identified in 5 individuals from 4 families who all had ichthyosis among other features. Supportive in vitro studies that demonstrate functional impairment.
Ichthyosis and erythrokeratoderma v1.68 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Ichthyosis and erythrokeratoderma v1.67 GTF2E2 Arina Puzriakova gene: GTF2E2 was added
gene: GTF2E2 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Q3_21_rating tags were added to gene: GTF2E2.
Mode of inheritance for gene: GTF2E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2E2 were set to 26996949; 28973399
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Review for gene: GTF2E2 was set to GREEN
Added comment: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified, as well as an additional patient from Asian origin with a distinct homozygous variant (c.448G>C). Predominant phenotype was that of trichothiodystrophy; however, all 5 individuals also had ID/DD, microcephaly and ichthyosis - and therefore adding GTF2E2 to these relevant panel.
Sources: Literature
Severe microcephaly v2.252 GTF2E2 Arina Puzriakova gene: GTF2E2 was added
gene: GTF2E2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: GTF2E2.
Mode of inheritance for gene: GTF2E2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF2E2 were set to 26996949; 28973399
Phenotypes for gene: GTF2E2 were set to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Review for gene: GTF2E2 was set to GREEN
Added comment: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified, as well as an additional patient from Asian origin with a distinct homozygous variant (c.448G>C). Predominant phenotype was that of trichothiodystrophy; however, all 5 individuals also had ID/DD, microcephaly and ichthyosis - and therefore adding GTF2E2 to these relevant panel.
Sources: Literature
Growth failure in early childhood v1.77 MRAS Ivone Leong Phenotypes for gene: MRAS were changed from Noonan syndrome 11, MIM#618499 to Noonan syndrome 11, OMIM:618499
Intellectual disability v3.1318 GTF2E2 Arina Puzriakova changed review comment from: Comment on list classification: Two distinct homozygous variants identified in 5 individuals from 4 families who all presented with DD/ID. Despite indication that one of these represents a founder variants, discovery of a distinct homozygous variant in a patient with an overlapping phenotype corroborates pertinence of GTF2E2. Furthermore, there are some supportive functional studies.

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

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

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

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

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

X-linked hemizygous mutation in males, monoallelic mutations in females is the appropriate mode of inheritance for Hardikar syndrome but there are carrier implications for the predominantly male-only phenotypes associated with this gene (e.g. Lujan-Fryns syndrome, Ohdo syndrome, X-linked and Opitz-Kaveggia syndrome) in female cases.
Growth failure in early childhood v1.76 MRAS Ivone Leong Publications for gene: MRAS were set to 28289718; 31173466; 31108500; 31173466
White matter disorders and cerebral calcification - narrow panel v1.200 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Red List (low evidence)
White matter disorders and cerebral calcification - narrow panel v1.200 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only a single individual has been described to date with white matter alternations in the context of variants in this gene.
White matter disorders and cerebral calcification - narrow panel v1.200 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.199 GTF2E2 Arina Puzriakova reviewed gene: GTF2E2: Rating: ; Mode of pathogenicity: None; Publications: 26996949, 28973399; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1316 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive, 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
White matter disorders and cerebral calcification - narrow panel v1.199 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive; 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.12 GTF2E2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: GTF2E2.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.12 GTF2E2 Arina Puzriakova Publications for gene: GTF2E2 were set to 26996949
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.11 GTF2E2 Arina Puzriakova Phenotypes for gene: GTF2E2 were changed from Trichothiodystrophy 6, nonphotosensitive; 616943 to Trichothiodystrophy 6, nonphotosensitive, OMIM:616943
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Classified gene: GTF2E2 as Amber List (moderate evidence)
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Added comment: Comment on list classification: Four individuals from 3 different Moroccan families with the same homozygous variant (c.C559T) in the GTF2E2 gene have been identified who all presented with non-photosensitive trichothiodystrophy. Even though this likely represents a founder effect in this population, an additional patient from Asian origin has been identified with a distinct homozygous variant (c.448G>C), corroborating pertinence of GTF2E2 variants in trichothiodystrophy. Furthermore, studies on primary fibroblasts of patients harbouring the founder variant demonstrated a reduction in the cellular levels of both subunits of the transcription initiation factor TFIIE.

Overall this is sufficient evidence to promote this gene to Green at the next GMS panel update.
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.10 GTF2E2 Arina Puzriakova Gene: gtf2e2 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v1.75 MAPK1 Ivone Leong Classified gene: MAPK1 as Amber List (moderate evidence)
Growth failure in early childhood v1.75 MAPK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association; however, the patients in the article did not meet the criteria set out for this panel. However, will check with the Genomics England Clinical Team. Therefore, this gene has been given an Amber rating until further confirmation.
Growth failure in early childhood v1.75 MAPK1 Ivone Leong Gene: mapk1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1315 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Tag Q3_21_MOI tag was added to gene: MED12.
Tag Q3_21_expert_review tag was added to gene: MED12.
Intellectual disability v3.1315 MED12 Eleanor Williams changed review comment from: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.; to: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+) female cases reported now with de novo variants in MED12 and an intellectual disability phenotype so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as XL hemizigous in males, biallelic in females for now, but there are several (10+ female cases reported now with de novo variants in MED12 and an intellectual disability phenotype) so consideration should be given to changing the mode of inheritance to monoallelic in females.
Intellectual disability v3.1315 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.1314 MED12 Eleanor Williams Publications for gene: MED12 were set to 6711603
Intellectual disability v3.1313 MED12 Eleanor Williams edited their review of gene: MED12: Changed publications to: 33244165, 34079076, 33244166
Intellectual disability v3.1313 MED12 Eleanor Williams reviewed gene: MED12: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Classified gene: MYO18B as Amber List (moderate evidence)
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting with a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Skeletal dysplasia v2.134 MYO18B Arina Puzriakova Gene: myo18b has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.133 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to PMID: 32637634
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova Tag Q3_21_rating tag was added to gene: MYO18B.
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova reviewed gene: MYO18B: Rating: GREEN; Mode of pathogenicity: None; Publications: 25748484, 31195167, 32184166, 32637634, 33179433; Phenotypes: Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure in early childhood v1.74 MAPK1 Ivone Leong Phenotypes for gene: MAPK1 were changed from Noonan syndrome 13, MIM#619087 to Noonan syndrome 13, OMIM:619087
Growth failure in early childhood v1.73 RRAS2 Ivone Leong Phenotypes for gene: RRAS2 were changed from Noonan syndrome 12, MIM #618624 to Noonan syndrome 12, OMIM:618624
Growth failure in early childhood v1.72 RRAS2 Ivone Leong Classified gene: RRAS2 as Amber List (moderate evidence)
Growth failure in early childhood v1.72 RRAS2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (confirmed). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Growth failure in early childhood v1.72 RRAS2 Ivone Leong Gene: rras2 has been classified as Amber List (Moderate Evidence).
Growth failure in early childhood v1.71 RRAS2 Ivone Leong Tag Q3_21_rating tag was added to gene: RRAS2.
Congenital myopathy v2.59 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to 27879346; 27858739; 25748484; 32637634
Congenital myopathy v2.59 MYO18B Arina Puzriakova Publications for gene: MYO18B were set to 27879346; 27858739; 25748484
Intellectual disability v3.1313 CDH15 Zornitza Stark reviewed gene: CDH15: Rating: RED; Mode of pathogenicity: None; Publications: 19012874, 12052883, 28422132, 26506440; Phenotypes: Mental retardation, autosomal dominant 3, MIM#612580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.132 MYO18B Arina Puzriakova Phenotypes for gene: MYO18B were changed from Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549
Skeletal dysplasia v2.131 ARCN1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ARCN1.
Skeletal dysplasia v2.131 ARCN1 Arina Puzriakova Publications for gene: ARCN1 were set to PMID: 27476655
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Classified gene: ARCN1 as Amber List (moderate evidence)
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Andžela Lazdāne. ARCN1 is associated with a relevant phenotype in OMIM (MIM# 617164) which is characterised by rhizomelic short stature. At least 6 individuals from 5 unrelated families reported in literature (PMIDs: 27476655; 31075182; 33154040), which is sufficient to rate this gene as Green at the next GMS panel update.
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.129 ARCN1 Arina Puzriakova Phenotypes for gene: ARCN1 were changed from Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, OMIM:617164
Brain cancer pertinent cancer susceptibility v1.1 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.0 has been signed off on 2021-09-29
Breast cancer pertinent cancer susceptibility v1.2 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.1 has been signed off on 2021-09-29
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Classified gene: PTEN as Red List (low evidence)
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Added comment: Comment on list classification: Rating red following review by C Turnball (ICR) of predisposition panels for GMS phase 2 indications.
Breast cancer pertinent cancer susceptibility v1.1 PTEN Catherine Snow Gene: pten has been classified as Red List (Low Evidence).
Ovarian cancer pertinent cancer susceptibility v1.4 Catherine Snow Panel types changed to Cancer Germline 100K; GMS Cancer Germline Virtual; GMS signed-off
Panel version 1.3 has been signed off on 2021-09-29
Ovarian cancer pertinent cancer susceptibility v1.3 BRIP1 Catherine Snow Classified gene: BRIP1 as Green List (high evidence)
Ovarian cancer pertinent cancer susceptibility v1.3 BRIP1 Catherine Snow Gene: brip1 has been classified as Green List (High Evidence).
Ovarian cancer pertinent cancer susceptibility v1.2 BRIP1 Catherine Snow gene: BRIP1 was added
gene: BRIP1 was added to Ovarian cancer pertinent cancer susceptibility. Sources: Expert list
Mode of inheritance for gene: BRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Review for gene: BRIP1 was set to GREEN
Added comment: Rating Green, following review by C Turnball (ICR), of predisposition panels for GMS phase 2 indications.
Sources: Expert list
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Classified gene: PMS2 as Red List (low evidence)
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Added comment: Comment on list classification: Rating red, following review by C Turnball (ICR), of predisposition panels for GMS phase 2 indications.
Ovarian cancer pertinent cancer susceptibility v1.1 PMS2 Catherine Snow Gene: pms2 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.476 KDM6A Arina Puzriakova Publications for gene: KDM6A were set to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834; 31363182
Primary immunodeficiency v2.475 KMT2A Arina Puzriakova Classified gene: KMT2A as Amber List (moderate evidence)
Primary immunodeficiency v2.475 KMT2A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is enough evidence to promote to Green at the next GMS panel update.

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

Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism idiopathic v1.46 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 32936766
Hypogonadotropic hypogonadism idiopathic v1.45 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Hypogonadotropic hypogonadism idiopathic v1.45 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Hypogonadotropic hypogonadism idiopathic v1.45 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Hypogonadotropic hypogonadism idiopathic v1.44 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1310 CPE Arina Puzriakova Publications for gene: CPE were set to 26120850; 32936766
Hypogonadotropic hypogonadism idiopathic v1.44 CPE Arina Puzriakova Tag watchlist was removed from gene: CPE.
Tag Q3_21_rating tag was added to gene: CPE.
Intellectual disability v3.1309 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability v3.1309 CPE Arina Puzriakova Added comment: Comment on list classification: There are now sufficient unrelated families (5) reported in literature presenting a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1309 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1308 CPE Arina Puzriakova Tag watchlist was removed from gene: CPE.
Tag Q3_21_rating tag was added to gene: CPE.
Intellectual disability v3.1308 CPE Arina Puzriakova edited their review of gene: CPE: Added comment: Bosch et al. 2021 (PMID: 34383079) reported on 4 individuals from 3 additional families harbouring 2 different homozygous truncating variants in this gene. Clinical presentation was prominent for obesity and intellectual disability. Hypogonadotropic hypogonadism was confirmed in one individual and was suspected but not tested for in another two subjects.; Changed rating: GREEN; Changed publications to: 26120850, 32936766, 34383079; Changed phenotypes to: Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.62 PIGB Arina Puzriakova Classified gene: PIGB as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.62 PIGB Arina Puzriakova Added comment: Comment on list classification: Axonal degenerative polyneuropathy and demyelinating sensorimotor polyneuropathy are observed in the more severely affected individuals with biallelic variants in this gene. There are sufficient cases with a relevant phenotype (5 individuals from 3 families) to rate as Green at the next GMS panel update.
Hereditary neuropathy NOT PMP22 copy number v1.62 PIGB Arina Puzriakova Gene: pigb has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.61 PIGB Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIGB.
Retinal disorders v2.216 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Clefting v2.50 MED12 Eleanor Williams Tag Skewed X-inactivation tag was added to gene: MED12.
Fetal anomalies v1.719 GREB1L Ivone Leong Publications for gene: GREB1L were set to 29261186; 29100091; 31424080; 32378186
Retinal disorders v2.216 IRX6 Eleanor Williams Tag Q3_21_rating tag was added to gene: IRX6.
Tag Q3_21_expert_review tag was added to gene: IRX6.
Retinal disorders v2.216 IRX6 Eleanor Williams edited their review of gene: IRX6: Added comment: Ideally, a region representing the IRX5/IRX6 duplication should be added to PanelApp with a monallelic mode of inheritance. There is a lack of single nucleotide variants reported in this gene with relevance to retinal disorders and and therefore adding this gene as green risks reporting irrelevant SNVs.; Changed rating: AMBER
Retinal disorders v2.216 IRX5 Eleanor Williams changed review comment from: Associated with Hamamy syndrome #611174 (AR) in OMIM. Hamamy syndrome is characterised by craniofacial dysmorphism, hearing loss, skeletal anomalies, microcytic hypochromic anemia and congenital heart defects. Severe myopia has also been reported. Homozygous missense variants in IRX5 were reported in 2 families with this condition (PMID: 22581230;17230486)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The gene is also included in Inborn errors of immunity classification: PMID 31953710
Thyroid cancer pertinent cancer susceptibility v1.3 CDKN1B Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'biallelic to 'monoallelic'. Literature review did not indicate presence of biallelic variants pertaining to thyroid or parathyroid tumours. The MOI for this gene is also monoallelic in OMIM and other PanelApp panels.
Thyroid cancer pertinent cancer susceptibility v1.3 CDKN1B Arina Puzriakova Mode of inheritance for gene: CDKN1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1305 ATP1A3 Zornitza Stark Deleted their comment
Osteogenesis imperfecta v2.36 COPB2 Eleanor Williams Tag watchlist_moi tag was added to gene: COPB2.
DDG2P v2.46 ALG8 Sarah Leigh Added comment: Comment on mode of inheritance: Monoallelic variants are associated with Polycystic liver disease 3 with or without kidney cysts OMIM:617874, which is not relevant to this panel. Therefore biallelic moi is relevant to this panel.
DDG2P v2.46 ALG8 Sarah Leigh Mode of inheritance for gene: ALG8 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
DDG2P v2.45 ALG8 Sarah Leigh Phenotypes for gene: ALG8 were changed from ALG8-CDG 237145 to Congenital disorder of glycosylation, type Ih OMIM:608104; ALG8-CDG MONDO:0011969
Primary immunodeficiency v2.468 B2M Eleanor Williams Added comment: Comment on mode of inheritance: Biallelic mode of inheritance is correct for Immunodeficiency 43. OMIM also has an entry for ?Amyloidosis, familial visceral, OMIM:105200 - Autosomal dominant but this phenotype is not relevant to this panel.
Primary immunodeficiency v2.468 B2M Eleanor Williams Mode of inheritance for gene: B2M was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Severe Paediatric Disorders v1.84 ATXN7 Dmitrijs Rots reviewed gene: ATXN7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia or chorea or related movement disorder v1.156 ATXN7 Dmitrijs Rots reviewed gene: ATXN7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.84 ATXN3 Dmitrijs Rots reviewed gene: ATXN3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.84 ATXN2 Dmitrijs Rots reviewed gene: ATXN2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.84 ATXN10 Dmitrijs Rots reviewed gene: ATXN10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe Paediatric Disorders v1.84 ATXN1 Dmitrijs Rots reviewed gene: ATXN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.156 ATXN1 Dmitrijs Rots reviewed gene: ATXN1: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Severe microcephaly v2.250 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.429 TNPO2 Arina Puzriakova Classified gene: TNPO2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.429 TNPO2 Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases presenting were a relevant phenotype associated with variants in this gene to rate as Green at the next GMS panel update.
Genetic epilepsy syndromes v2.429 TNPO2 Arina Puzriakova Gene: tnpo2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.249 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Severe microcephaly. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID: 33154040
Severe microcephaly v2.247 ARCN1 Ivone Leong Publications for gene: ARCN1 were set to 27476655
Severe microcephaly v2.246 ARCN1 Ivone Leong Tag Q3_21_rating was removed from gene: ARCN1.
Tag watchlist tag was added to gene: ARCN1.
Severe microcephaly v2.246 ARCN1 Ivone Leong Classified gene: ARCN1 as Amber List (moderate evidence)
Severe microcephaly v2.246 ARCN1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). Patients 1, 3 and 4 (patients 3 and 4 are from the same family) from PMID:27476655 have a head circumference <-3 SD. Patient 2 has head circumference of -1.53 SD, which is not severe enough for this panel. Therefore, there is currently not enough evidence for a gene-disease association. This gene has been given an Amber rating.
Severe microcephaly v2.246 ARCN1 Ivone Leong Gene: arcn1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.245 ARCN1 Ivone Leong Tag Q3_21_rating tag was added to gene: ARCN1.
Childhood onset dystonia or chorea or related movement disorder v1.156 IMPDH2 Arina Puzriakova Publications for gene: IMPDH2 were set to 33098801
Childhood onset dystonia or chorea or related movement disorder v1.155 IMPDH2 Arina Puzriakova Classified gene: IMPDH2 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.155 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: This gene is not yet associated with a relevant phenotype in OMIM or G2P, but there are sufficient unrelated cases (3) presenting with signs of dystonia to rate as Green at the next GMS review. Other cases reported with motor dysfunction, and it is plausible that this may develop into dystonia later in life.
Childhood onset dystonia or chorea or related movement disorder v1.155 IMPDH2 Arina Puzriakova Gene: impdh2 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.154 IMPDH2 Arina Puzriakova Deleted their comment
Childhood onset dystonia or chorea or related movement disorder v1.154 IMPDH2 Arina Puzriakova edited their review of gene: IMPDH2: Added comment: Kuukasjärvi et al., 2021 (PMID: 34305140) report on an additional large Finnish family (6 affected members) with a heterozygous truncating variant co-segregating with a dominantly inherited dystonia-tremor phenotype. Patient fibroblasts showed reduced IMPDH2 expression. IMPDH2 is the rate-limiting enzyme in the biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders.; Changed publications to: 33098801, 34305140
Childhood onset dystonia or chorea or related movement disorder v1.154 IMPDH2 Arina Puzriakova Entity copied from Intellectual disability v3.1300
Childhood onset dystonia or chorea or related movement disorder v1.154 IMPDH2 Arina Puzriakova gene: IMPDH2 was added
gene: IMPDH2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: IMPDH2.
Mode of inheritance for gene: IMPDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IMPDH2 were set to 33098801
Phenotypes for gene: IMPDH2 were set to Neurodevelopmental disorder with dystonia
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Classified gene: IMPDH2 as Amber List (moderate evidence)
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not yet associated with a relevant phenotype in OMIM or G2P, but sufficient unrelated cases with relevant phenotype to rate Green at the next GMS review. Neurodevelopmental delay is an early feature that may be evident prior to other manifestations (plausible that other cases may develop dystonic signs later in life) and so inclusion on this panel is warranted.
Intellectual disability v3.1300 IMPDH2 Arina Puzriakova Gene: impdh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: IMPDH2.
Intellectual disability v3.1299 IMPDH2 Arina Puzriakova reviewed gene: IMPDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33098801; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v2.427 CLCN3 Arina Puzriakova Entity copied from Intellectual disability v3.1299
Genetic epilepsy syndromes v2.427 CLCN3 Arina Puzriakova gene: CLCN3 was added
gene: CLCN3 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: CLCN3.
Mode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CLCN3 were set to 34186028
Phenotypes for gene: CLCN3 were set to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Mode of pathogenicity for gene: CLCN3 was set to Other
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CLCN3.
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Classified gene: CLCN3 as Amber List (moderate evidence)
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update. Sufficient number of unrelated cases with relevant phenotype to add to the ID and epilepsy panels. Functional studies and animal model support pathogenicity. CLCN3 is also associated with a relevant phenotype in OMIM (MIM# 619512 and 619517)
Intellectual disability v3.1299 CLCN3 Arina Puzriakova Gene: clcn3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1298 CLCN3 Arina Puzriakova Mode of inheritance for gene: CLCN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability v3.1297 CLCN3 Arina Puzriakova Phenotypes for gene: CLCN3 were changed from Neurodevelopmental disorder to Neurodevelopmental disorder with hypotonia and brain abnormalities, OMIM:619512; Neurodevelopmental disorder with seizures and brain abnormalities, OMIM:619517
Fetal anomalies v1.717 GREB1L Rhiannon Mellis edited their review of gene: GREB1L: Added comment: A further prenatal case reported in PMID 31974414 (Vora et al 2020) - c.4881_4882del; [p.H1627fs] inherited from parent, 2 affected pregnancies with bilateral renal agenesis plus a living child with single kidney.; Changed rating: GREEN; Changed publications to: PMID: 31424080, 32378186, 31974414
Intellectual disability v3.1296 ANK2 Arina Puzriakova Classified gene: ANK2 as Amber List (moderate evidence)
Intellectual disability v3.1296 ANK2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel review - sufficient unrelated cases with relevant phenotype and de novo PTVs in this gene. Definitive gene-disease association is supported by the ClinGen ID and Autism Expert Panel.
Intellectual disability v3.1296 ANK2 Arina Puzriakova Gene: ank2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1295 ANK2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ANK2.
Primary immunodeficiency v2.467 KDM6A Arina Puzriakova Phenotypes for gene: KDM6A were changed from Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Kabuki Syndrome 2 due to KDM6A deficiency; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 2, OMIM:300867; Recurrent infections (otitis media, pneumonia); Autoimmunity; Combined immunodeficiencies with associated or syndromic features
Primary immunodeficiency v2.466 KDM6A Arina Puzriakova Publications for gene: KDM6A were set to 25142838; 15523604; 32048120; 25546742; 15887282; 32086639; 26411453; 22197486; 23076834
Primary immunodeficiency v2.465 KDM6A Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: KDM6A.
Primary immunodeficiency v2.465 KDM6A Arina Puzriakova commented on gene: KDM6A
Malformations of cortical development v2.91 TP73 Arina Puzriakova Entity copied from Intellectual disability v3.1295
Malformations of cortical development v2.91 TP73 Arina Puzriakova gene: TP73 was added
gene: TP73 was added to Malformations of cortical development. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: TP73.
Mode of inheritance for gene: TP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP73 were set to 31130284; 34077761
Phenotypes for gene: TP73 were set to Ciliary dyskinesia, primary, 47, and lissencephaly, OMIM:619466
Intellectual disability v3.1295 TP73 Arina Puzriakova Publications for gene: TP73 were set to 31130284
Intellectual disability v3.1295 TP73 Arina Puzriakova Classified gene: TP73 as Amber List (moderate evidence)
Intellectual disability v3.1295 TP73 Arina Puzriakova Added comment: Comment on list classification: There is now sufficient evidence to promote this gene to Green at the next GMS panel review - at least 7 unrelated families with distinct variants and relevant phenotypes. Supported by some functional data.

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

There is sufficient evidence to promote this gene to Green at the next GMS panel update, with 'monoallelic' MOI. Biallelic cases would still be picked up by the Genomics England pipeline - but this may be reviewed if additional cases are discovered.
Intellectual disability v3.1292 AP1G1 Arina Puzriakova Gene: ap1g1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1291 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to
Severe microcephaly v2.245 ATP9A Arina Puzriakova Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Intellectual disability v3.1290 ATP9A Arina Puzriakova Classified gene: ATP9A as Amber List (moderate evidence)
Intellectual disability v3.1290 ATP9A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.
Intellectual disability v3.1290 ATP9A Arina Puzriakova Gene: atp9a has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.153 CAMK4 Arina Puzriakova Entity copied from Intellectual disability v3.1289
Childhood onset dystonia or chorea or related movement disorder v1.153 CAMK4 Arina Puzriakova gene: CAMK4 was added
gene: CAMK4 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Other,Expert Review Amber,Literature
Q3_21_rating tags were added to gene: CAMK4.
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Penetrance for gene: CAMK4 were set to Complete
Mode of pathogenicity for gene: CAMK4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Classified gene: CAMK4 as Amber List (moderate evidence)
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. There are sufficient unrelated cases (3) presenting with a relevant phenotype in association with different variants in the CAMK4 gene.
Intellectual disability v3.1289 CAMK4 Arina Puzriakova Gene: camk4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CAMK4.
Intellectual disability v3.1288 CAMK4 Arina Puzriakova Mode of pathogenicity for gene: CAMK4 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Genetic epilepsy syndromes v2.425 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.425 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as only two individuals with seizures have been reported to date (MAE type)
Genetic epilepsy syndromes v2.425 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1287 SYNCRIP Arina Puzriakova Phenotypes for gene: SYNCRIP were changed from to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Intellectual disability v3.1286 SYNCRIP Arina Puzriakova Publications for gene: SYNCRIP were set to 27479843; 26350204
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Tag watchlist was removed from gene: SYNCRIP.
Tag Q3_21_rating tag was added to gene: SYNCRIP.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Classified gene: SYNCRIP as Amber List (moderate evidence)
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there are sufficient unrelated cases to rate as Green at the next GMS review. All individuals reported to date have presented with ID of various severity as the predominant feature.
Intellectual disability v3.1285 SYNCRIP Arina Puzriakova Gene: syncrip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1284 SYNCRIP Arina Puzriakova Mode of inheritance for gene: SYNCRIP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.244 EIF2S3 Ivone Leong Tag Q3_21_rating tag was added to gene: EIF2S3.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Classified gene: EIF2S3 as Amber List (moderate evidence)
Severe microcephaly v2.244 EIF2S3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.244 EIF2S3 Ivone Leong Gene: eif2s3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.243 EIF2S3 Ivone Leong Phenotypes for gene: EIF2S3 were changed from MEHMO syndrome, MIM# 300148 to MEHMO syndrome, OMIM:300148
Intellectual disability v3.1283 HIST1H4C Ivone Leong Tag watchlist was removed from gene: HIST1H4C.
Tag Q3_21_rating tag was added to gene: HIST1H4C.
Intellectual disability v3.1283 HIST1H4C Ivone Leong reviewed gene: HIST1H4C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.242 HIST1H4C Ivone Leong Tag Q3_21_rating tag was added to gene: HIST1H4C.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Classified gene: HIST1H4C as Amber List (moderate evidence)
Severe microcephaly v2.242 HIST1H4C Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.242 HIST1H4C Ivone Leong Gene: hist1h4c has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.241 HIST1H4C Ivone Leong commented on gene: HIST1H4C
Severe microcephaly v2.241 HIST1H4C Ivone Leong Tag new-gene-name tag was added to gene: HIST1H4C.
Severe microcephaly v2.241 LAGE3 Ivone Leong Tag Q3_21_rating tag was added to gene: LAGE3.
Severe microcephaly v2.241 LAGE3 Ivone Leong Classified gene: LAGE3 as Amber List (moderate evidence)
Severe microcephaly v2.241 LAGE3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype (possible). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.241 LAGE3 Ivone Leong Gene: lage3 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.240 LAGE3 Ivone Leong Phenotypes for gene: LAGE3 were changed from Galloway-Mowat syndrome 2, X-linked, MIM# 301006 to Galloway-Mowat syndrome 2, X-linked, OMIM:301006
Intellectual disability v3.1283 ATP1A3 Arina Puzriakova Publications for gene: ATP1A3 were set to 22842232; 29396171; 29291920; 22842232; 28969699; 32802951
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: ATP1A3.
Intellectual disability v3.1282 ATP1A3 Arina Puzriakova commented on gene: ATP1A3: Gene was reassessed following a further Green review by Zornitza Stark (8 Jul 2021). Vetro et al. (PMID: 33880529) identified several individuals with variants in this gene who presented with DD/ID as the predominant feature. Therefore, ATP1A3 will be flagged for GMS expert review as inclusion on this panel may be of value in some patients but previous comments regarding association with several phenotypes should be considered.
Genetic epilepsy syndromes v2.424 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Genetic epilepsy syndromes v2.424 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Genetic epilepsy syndromes v2.423 MED17 Ivone Leong Publications for gene: MED17 were set to 26004231; 20950787
Genetic epilepsy syndromes v2.422 MED17 Ivone Leong reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.239 MED17 Ivone Leong Classified gene: MED17 as Amber List (moderate evidence)
Severe microcephaly v2.239 MED17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene as been given an Amber rating as 2 out of 3 cases (PMID:20950787 is caused by founder effect) have severe microcephaly. Until further evidence is available this gene will remain as Amber.
Severe microcephaly v2.239 MED17 Ivone Leong Gene: med17 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.238 MED17 Ivone Leong Tag watchlist tag was added to gene: MED17.
Severe microcephaly v2.238 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Severe microcephaly v2.237 MED17 Ivone Leong Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Intellectual disability v3.1282 CPE Dmitrijs Rots reviewed gene: CPE: Rating: GREEN; Mode of pathogenicity: None; Publications: 34383079; Phenotypes: Obesity, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1282 RFX3 Arina Puzriakova Phenotypes for gene: RFX3 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1282 RFX7 Arina Puzriakova Phenotypes for gene: RFX7 were changed from Intellectual disability, MONDO:0001071, autism spectrum disorder, MONDO:0005258, attention deficit-hyperactivity disorder, MONDO:0007743 to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258; Attention deficit-hyperactivity disorder, MONDO:0007743
Intellectual disability v3.1281 RFX4 Arina Puzriakova Phenotypes for gene: RFX4 were changed from ID, ASD, ADHD to Intellectual disability, MONDO:0001071; Autism spectrum disorder, MONDO:0005258
Intellectual disability v3.1280 RFX7 Arina Puzriakova Classified gene: RFX7 as Amber List (moderate evidence)
Intellectual disability v3.1280 RFX7 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). 14 unrelated individuals were identified with different variants in the RFX7 gene (13 de novo, 1 unknown). Presenting phenotypes were predominantly of ID/GDD (13/14) and dysmorphism (12/14).

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

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

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

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

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

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

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

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

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

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

A search of PubMed finds no further cases.
Osteogenesis imperfecta v2.24 MBTPS2 Eleanor Williams Phenotypes for gene: MBTPS2 were changed from Osteogenesis imperfecta, type XIX, MIM# 301014 to Osteogenesis imperfecta, type XIX, OMIM:301014; osteogenesis imperfecta, type 19, MONDO:0049223
Osteogenesis imperfecta v2.23 MBTPS2 Eleanor Williams Tag Q3_21_rating tag was added to gene: MBTPS2.
Tag Q3_21_expert_review tag was added to gene: MBTPS2.
Osteogenesis imperfecta v2.23 MBTPS2 Eleanor Williams reviewed gene: MBTPS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27380894; Phenotypes: Osteogenesis imperfecta, type XIX, OMIM:301014; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v2.7 HID1 Arina Puzriakova Entity copied from Intellectual disability v3.1274
Pituitary hormone deficiency v2.7 HID1 Arina Puzriakova gene: HID1 was added
gene: HID1 was added to Pituitary hormone deficiency. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: HID1.
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Genetic epilepsy syndromes v2.422 HID1 Arina Puzriakova Entity copied from Intellectual disability v3.1274
Genetic epilepsy syndromes v2.422 HID1 Arina Puzriakova gene: HID1 was added
gene: HID1 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: HID1.
Mode of inheritance for gene: HID1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HID1 were set to 33999436
Phenotypes for gene: HID1 were set to Syndromic infantile encephalopathy; Hypopituitarism
Intellectual disability v3.1274 HID1 Arina Puzriakova Tag Q3_21_rating tag was added to HID1.
Intellectual disability v3.1273 HID1 Arina Puzriakova Classified gene: HID1 as Amber List (moderate evidence)
Intellectual disability v3.1273 HID1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1273 HID1 Arina Puzriakova Gene: hid1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1272 HID1 Arina Puzriakova reviewed gene: HID1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33999436; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.717 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Fetal anomalies v1.717 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Childhood onset dystonia or chorea or related movement disorder v1.152 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Childhood onset dystonia or chorea or related movement disorder v1.152 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from None to Other
Intellectual disability v3.1272 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Intellectual disability v3.1272 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to None
Genetic epilepsy syndromes v2.421 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Genetic epilepsy syndromes v2.421 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from None to Other
Clefting v2.49 GNB1 Sarah Leigh Added comment: Comment on mode of pathogenicity: Gen2Phen entry for GNB1 (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=2121) lists the mutation consequence summary as Activating
Clefting v2.49 GNB1 Sarah Leigh Mode of pathogenicity for gene: GNB1 was changed from to Other
Childhood onset dystonia or chorea or related movement disorder v1.151 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen, although there is a confirmed association with epileptic encephalopathy in Gen2Phen. At least 20 variants have been associated with Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254 and three have been associated with Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820.; Changed rating: GREEN
Intellectual disability v3.1271 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; Mental retardation, autosomal dominant 8, 614254; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Genetic epilepsy syndromes v2.420 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, 617820; NDHMSR; Mental retardation, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, 614254; NDHMSD; early onset epileptic encephalopathies; involuntary movements; severe developmental delay; intellectual disability; EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Fetal anomalies v1.716 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: The MOI monoallelic is listed for this panel, as the phenotype was initially listed as epileptic encephalopathy and only one biallelic case has been reported with this phenotype. However, other fetal phenotypes are associated with both monoallelic and biallelic GRIN1 variants in Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254 and Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820.; Changed rating: GREEN
Fetal anomalies v1.716 GRIN1 Sarah Leigh changed review comment from: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.; to: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Fetal anomalies v1.716 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Malformations of cortical development v2.90 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: Although the MOI could be listed as "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, this was not done on this panel, as the phenotypes of malformation of cortical development have not been reported with biallelic variants.
Malformations of cortical development v2.90 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.44 GRIN1 Sarah Leigh changed review comment from: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy, and only one biallelic case has been reported with this phenotype.; to: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=1357), and only one biallelic case has been reported with this phenotype.
DDG2P v2.44 GRIN1 Sarah Leigh Deleted their comment
DDG2P v2.44 GRIN1 Sarah Leigh Added comment: Comment on phenotypes: EPILEPTIC ENCEPHALOPATHY
DDG2P v2.44 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from EPILEPTIC ENCEPHALOPATHY to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655
DDG2P v2.43 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: The MOI could be changed to "both mono and biallelic" in order to agree with the MOI listed in OMIM:138249, however, this was not done on this panel, as the phenotype that is confirmed on Gen2Phen is epileptic encephalopathy, and only one biallelic case has been reported with this phenotype.
DDG2P v2.43 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.715 GRIN1 Sarah Leigh Added comment: Comment on mode of inheritance: The Q3_21_MOI tag has been added to this gene as the MOI should be changed to - BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Fetal anomalies v1.715 GRIN1 Sarah Leigh Mode of inheritance for gene: GRIN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.714 GRIN1 Sarah Leigh Tag Q3_21_MOI tag was added to gene: GRIN1.
Malformations of cortical development v2.89 GRIN1 Sarah Leigh edited their review of gene: GRIN1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen, although there is a confirmed association with epileptic encephalopathy in Gen2Phen. Nine de novo GRIN1 variants in eleven cases of bilateral polymicrogyria have been reported by Fry et al (PMID: 29365063), analysis of available samples from parents confirmed the de novo occurance of these GRIN1 variants.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.89 GRIN1 Sarah Leigh Tag Q3_21_rating tag was added to gene: GRIN1.
Malformations of cortical development v2.89 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, OMIM:614254 to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655
Malformations of cortical development v2.88 GRIN1 Sarah Leigh Publications for gene: GRIN1 were set to 29365063
Childhood onset dystonia or chorea or related movement disorder v1.151 GRIN1 Sarah Leigh Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072
Childhood onset dystonia or chorea or related movement disorder v1.150 GRIN1 Sarah Leigh Tag Q3_21_rating tag was added to gene: GRIN1.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Tag Q3_21_rating tag was added to gene: RAD21.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Classified gene: RAD21 as Amber List (moderate evidence)
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). At least 3 unrelated individuals reported in literature with different heterozygous KMT2D variants and holoprosencephaly, which may be observed with or without overt features of CdLS. Sufficient to rate this gene as Green at the next GMS panel update.
Holoprosencephaly v2.23 RAD21 Arina Puzriakova Gene: rad21 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.22 RAD21 Arina Puzriakova Added comment: Comment on publications: PMID: 32696056 (2020) - fourth unrelated individual reported presenting holoprosencephaly associated with a heterozygous RAD21 LoF variant
Holoprosencephaly v2.22 RAD21 Arina Puzriakova Publications for gene: RAD21 were set to 31334757
Holoprosencephaly v2.21 RAD21 Arina Puzriakova Phenotypes for gene: RAD21 were changed from Holoprosencephaly; Septo-optic dysplasia to Cornelia de Lange syndrome 4, OMIM:614701; Holoprosencephaly with or without CdLS features; Septo-optic dysplasia
Fetal hydrops v1.35 KMT2D Arina Puzriakova Classified gene: KMT2D as Green List (high evidence)
Fetal hydrops v1.35 KMT2D Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There are sufficient unrelated cases with prenatal hydrops and variants in this gene to rate as Green on this panel. KMT2D is also already Green on the GMS Fetal anomalies (R21) panel.
Fetal hydrops v1.35 KMT2D Arina Puzriakova Gene: kmt2d has been classified as Green List (High Evidence).
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Tag Q3_21_rating tag was added to gene: KMT2D.
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Classified gene: KMT2D as Amber List (moderate evidence)
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). At least 3 unrelated individuals reported in literature with different heterozygous KMT2D variants and holoprosencephaly, which may be observed in the absence of overtly obvious features of Kabuki syndrome. Sufficient to rate this gene as Green at the next GMS panel update.
Holoprosencephaly v2.20 KMT2D Arina Puzriakova Gene: kmt2d has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.228 OSGEP Ivone Leong Tag Q3_21_rating tag was added to gene: OSGEP.
Severe microcephaly v2.228 OSGEP Ivone Leong Classified gene: OSGEP as Amber List (moderate evidence)
Severe microcephaly v2.228 OSGEP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.228 OSGEP Ivone Leong Gene: osgep has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.227 OSGEP Ivone Leong Phenotypes for gene: OSGEP were changed from Galloway-Mowat syndrome 3, MIM# 617729 to Galloway-Mowat syndrome 3, OMIM:617729
Craniosynostosis v2.53 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 147920; 147920 to Kabuki syndrome 1, OMIM:147920
Intellectual disability v3.1270 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome to Kabuki syndrome 1, OMIM:147920
Severe microcephaly v2.226 VRK1 Ivone Leong Tag Q3_21_rating tag was added to gene: VRK1.
Severe microcephaly v2.226 VRK1 Ivone Leong Classified gene: VRK1 as Amber List (moderate evidence)
Severe microcephaly v2.226 VRK1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.226 VRK1 Ivone Leong Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.225 VRK1 Ivone Leong Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A MIM#607596 to Pontocerebellar hypoplasia type 1A, OMIM:607596
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Classified gene: GRIN1 as Amber List (moderate evidence)
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Malformations of cortical development v2.87 GRIN1 Sarah Leigh Gene: grin1 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.19 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, OMIM:147920
Childhood onset dystonia or chorea or related movement disorder v1.150 GRIN1 Sarah Leigh Classified gene: GRIN1 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.150 GRIN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia or chorea or related movement disorder v1.150 GRIN1 Sarah Leigh Gene: grin1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.149 GRIN1 Sarah Leigh Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820 to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant OMIM:614254; intellectual disability, autosomal dominant 8 MONDO:0013655; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive OMIM:617820; neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive MONDO:0060629
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Intellectual disability v3.1269 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, OMIM:616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Genetic epilepsy syndromes v2.419 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973; seizures to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Severe Paediatric Disorders v1.84 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Clefting v2.48 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, 616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
DDG2P v2.42 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Severe Neurodevelopmental Disability, Hypotonia, and Seizures to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Fetal anomalies v1.714 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Severe Neurodevelopmental Disability, Hypotonia, and Seizures to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Childhood onset dystonia or chorea or related movement disorder v1.148 GNB1 Sarah Leigh Phenotypes for gene: GNB1 were changed from Mental retardation, autosomal dominant 42, MIM# 616973 to Mental retardation, autosomal dominant 42 OMIM:616973; intellectual disability, autosomal dominant 42 MONDO:0014855
Childhood onset dystonia or chorea or related movement disorder v1.147 GNB1 Sarah Leigh Tag Q3_21_rating tag was added to gene: GNB1.
Childhood onset dystonia or chorea or related movement disorder v1.147 GNB1 Sarah Leigh edited their review of gene: GNB1: Added comment: Hemati et al (2018)(PMID: 30194818) reviewed 46 pathognic GNB1 variants in cases with Mental retardation, autosomal dominant 42 (OMIM:616973). They reported early hypotonia leading to hypertonia and spasticity in >75% of cases.; Changed rating: GREEN
Primary immunodeficiency v2.465 KMT2D Arina Puzriakova Tag Q3_21_rating tag was added to gene: KMT2D.
Primary immunodeficiency v2.465 KMT2D Arina Puzriakova Publications for gene: KMT2D were set to 25142838; 15523604; 21671394; 32048120; 15887282; 21607748; 32086639; 23913813; 26411453
Primary immunodeficiency v2.464 KMT2D Arina Puzriakova Classified gene: KMT2D as Amber List (moderate evidence)
Primary immunodeficiency v2.464 KMT2D Arina Puzriakova Added comment: Comment on list classification: Immunopathological manifestations are seen in ~50% of cases with KMT2D-related Kabuki syndrome. There is sufficient evidence to support this gene-disease association and therefore this gene should be promoted to Green status at the next GMS panel update.
Primary immunodeficiency v2.464 KMT2D Arina Puzriakova Gene: kmt2d has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.463 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, 147920; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 1, OMIM:147920; Hypogammaglobulinemia; Recurrent infections (otitis media, pneumonia); Autoimmunity
Structural eye disease v1.81 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1 (can include coloboma), 147920 to Kabuki syndrome 1, OMIM:147920; Coloboma; Microphthalmia
IUGR and IGF abnormalities v1.36 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki to Kabuki syndrome 1, OMIM:147920
Kabuki syndrome v1.5 KMT2D Arina Puzriakova Phenotypes for gene: KMT2D were changed from Kabuki Syndrome; Kabuki Syndrome Type 1 to Kabuki syndrome 1, OMIM:147920
Primary immunodeficiency v2.462 DCLRE1B Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: DCLRE1B.
Primary immunodeficiency v2.462 DCLRE1B Arina Puzriakova reviewed gene: DCLRE1B: Rating: ; Mode of pathogenicity: None; Publications: 20479256; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia or chorea or related movement disorder v1.147 GNB1 Sarah Leigh Classified gene: GNB1 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.147 GNB1 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 or chorea or related movement disorder v1.147 GNB1 Sarah Leigh Gene: gnb1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.86 GRIN1 Ivone Leong Phenotypes for gene: GRIN1 were changed from Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254 to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, OMIM:614254
Hearing loss v2.185 HARS2 Ivone Leong Phenotypes for gene: HARS2 were changed from #614926:?Perrault syndrome 2 to Perrault syndrome 2, OMIM:614926
Hearing loss v2.184 HARS2 Ivone Leong Publications for gene: HARS2 were set to 12056811; 15779907; 21464306; 517579; 7755634; 27650058
Primary ovarian insufficiency v1.47 HARS2 Ivone Leong Classified gene: HARS2 as Green List (high evidence)
Primary ovarian insufficiency v1.47 HARS2 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is now enough evidence to support a gene-disease association. Therefore this gene has been promoted to Green.
Primary ovarian insufficiency v1.47 HARS2 Ivone Leong Gene: hars2 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.46 HARS2 Ivone Leong Phenotypes for gene: HARS2 were changed from Perrault syndrome 2, 614926 to Perrault syndrome 2, OMIM:614926
Skeletal dysplasia v2.119 MYO1H Sarah Leigh Entity copied from Familial dysautonomia v1.15
Skeletal dysplasia v2.119 MYO1H Sarah Leigh gene: MYO1H was added
gene: MYO1H was added to Skeletal dysplasia. Sources: Expert Review Red,Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Genetic epilepsy syndromes v2.418 MYO1H Sarah Leigh Entity copied from Familial dysautonomia v1.15
Genetic epilepsy syndromes v2.418 MYO1H Sarah Leigh gene: MYO1H was added
gene: MYO1H was added to Genetic epilepsy syndromes. Sources: Expert Review Red,Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Intellectual disability v3.1268 MYO1H Sarah Leigh Entity copied from Familial dysautonomia v1.15
Intellectual disability v3.1268 MYO1H Sarah Leigh gene: MYO1H was added
gene: MYO1H was added to Intellectual disability. Sources: Expert Review Red,Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Familial dysautonomia v1.15 MYO1H Sarah Leigh reviewed gene: MYO1H: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency v2.462 ELF4 Arina Puzriakova Phenotypes for gene: ELF4 were changed from X-linked hypogammaglobulinemia with isolated growth hormone deficiency to Inflammatory bowel disease; Mucosal inflammation; Fever; Ulcers; Behcet-like disease; X-linked hypogammaglobulinemia with isolated growth hormone deficiency
Primary immunodeficiency v2.461 ELF4 Arina Puzriakova Classified gene: ELF4 as Amber List (moderate evidence)
Primary immunodeficiency v2.461 ELF4 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is enough evidence to rate this gene as Green at the next GMS panel update. At least two variants identified in three unrelated individuals with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model.
Primary immunodeficiency v2.461 ELF4 Arina Puzriakova Gene: elf4 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.58 CNTN1 Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: CNTN1.
Arthrogryposis v3.122 CNTN1 Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: CNTN1.
Primary immunodeficiency v2.460 ELF4 Arina Puzriakova Tag Q3_21_rating tag was added to gene: ELF4.
Primary immunodeficiency v2.460 ELF4 Arina Puzriakova Publications for gene: ELF4 were set to 16264330
Familial dysautonomia v1.15 MYO1H Sarah Leigh Phenotypes for gene: MYO1H were changed from Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction, MIM#619482 to ?Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction OMIM:619482
Familial dysautonomia v1.14 MYO1H Sarah Leigh Classified gene: MYO1H as Red List (low evidence)
Familial dysautonomia v1.14 MYO1H Sarah Leigh Gene: myo1h has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.459 ELF4 Arina Puzriakova Mode of inheritance for gene: ELF4 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary ovarian insufficiency v1.45 HARS2 Ivone Leong Publications for gene: HARS2 were set to 21464306
Thoracic aortic aneurysm or dissection v1.123 ARIH1 Ivone Leong Classified gene: ARIH1 as Green List (high evidence)
Thoracic aortic aneurysm or dissection v1.123 ARIH1 Ivone Leong Added comment: Comment on list classification: Promoted this gene to Green based on reviews.
Thoracic aortic aneurysm or dissection v1.123 ARIH1 Ivone Leong Gene: arih1 has been classified as Green List (High Evidence).
Thoracic aortic aneurysm or dissection v1.122 ARIH1 Ivone Leong Tag Q3_21_rating was removed from gene: ARIH1.
Thoracic aortic aneurysm or dissection v1.122 ARIH1 Ivone Leong Entity copied from Thoracic aortic aneurysm and dissection v1.18
Thoracic aortic aneurysm or dissection v1.122 ARIH1 Ivone Leong gene: ARIH1 was added
gene: ARIH1 was added to Thoracic aortic aneurysm or dissection. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: ARIH1.
Mode of inheritance for gene: ARIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm, MONDO:0005396
Thoracic aortic aneurysm and dissection v1.18 ARIH1 Ivone Leong Classified gene: ARIH1 as Amber List (moderate evidence)
Thoracic aortic aneurysm and dissection v1.18 ARIH1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Thoracic aortic aneurysm and dissection v1.18 ARIH1 Ivone Leong Gene: arih1 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm and dissection v1.17 ARIH1 Ivone Leong Tag Q3_21_rating tag was added to gene: ARIH1.
Rare anaemia v1.26 GSR Arina Puzriakova Phenotypes for gene: GSR were changed from NA Enzyme Disorder; Hemolytic anemia due to glutathione reductase deficiency; Enzyme Disorder to Hemolytic anemia due to glutathione reductase deficiency, OMIM:618660
Thoracic aortic aneurysm and dissection v1.17 ARIH1 Ivone Leong Phenotypes for gene: ARIH1 were changed from Thoracic aortic aneurysm to Thoracic aortic aneurysm, MONDO:0005396
Rare anaemia v1.25 GSR Arina Puzriakova Publications for gene: GSR were set to 8533822
Rare anaemia v1.24 GSR Arina Puzriakova commented on gene: GSR
Fetal anomalies v1.713 CNTN1 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber as two families with homozygous variants and a relevant phenotype have now been reported in literature.; to: Comment on list classification: Rating Amber as two families with homozygous variants have now been reported in literature. Both display fetally-relevant phenotypes such as fetal akinesia, polyhydramnios, and contractures.
Fetal anomalies v1.713 CNTN1 Arina Puzriakova Entity copied from Arthrogryposis v3.122
Fetal anomalies v1.713 CNTN1 Arina Puzriakova gene: CNTN1 was added
gene: CNTN1 was added to Fetal anomalies. Sources: Expert list,Radboud University Medical Center, Nijmegen,Expert Review Amber
Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN1 were set to 19026398; 32779773
Phenotypes for gene: CNTN1 were set to Myopathy, congenital, Compton-North, OMIM:612540
Penetrance for gene: CNTN1 were set to Complete
Congenital myopathy v2.58 CNTN1 Arina Puzriakova Publications for gene: CNTN1 were set to 19026398
Congenital myopathy v2.57 CNTN1 Arina Puzriakova Phenotypes for gene: CNTN1 were changed from ?Myopathy, congenital, Compton-North, 612540 to Myopathy, congenital, Compton-North, OMIM:612540
Arthrogryposis v3.122 CNTN1 Arina Puzriakova Phenotypes for gene: CNTN1 were changed from Myopathy, congenital, Compton-North, 612540 to Myopathy, congenital, Compton-North, OMIM:612540
Arthrogryposis v3.121 CNTN1 Arina Puzriakova Publications for gene: CNTN1 were set to
Arthrogryposis v3.120 CNTN1 Arina Puzriakova Classified gene: CNTN1 as Amber List (moderate evidence)
Arthrogryposis v3.120 CNTN1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as two families with homozygous variants and a relevant phenotype have now been reported in literature.
Arthrogryposis v3.120 CNTN1 Arina Puzriakova Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.87 SLC51A Ivone Leong Classified gene: SLC51A as Red List (low evidence)
Cholestasis v1.87 SLC51A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. As there is only 1 case there is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Cholestasis v1.87 SLC51A Ivone Leong Gene: slc51a has been classified as Red List (Low Evidence).
Cholestasis v1.86 SLC51A Ivone Leong Phenotypes for gene: SLC51A were changed from Cholestasis, progressive familial intrahepatic, 6, MIM# 619484 to ?Cholestasis, progressive familial intrahepatic, 6, OMIM:619484
Retinal disorders v2.209 LRP1 Ivone Leong Classified gene: LRP1 as Red List (low evidence)
Retinal disorders v2.209 LRP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Retinal disorders v2.209 LRP1 Ivone Leong Gene: lrp1 has been classified as Red List (Low Evidence).
Intellectual disability v3.1267 PGRMC1 Ivone Leong Publications for gene: PGRMC1 were set to
Intellectual disability v3.1266 PGRMC1 Ivone Leong reviewed gene: PGRMC1: Rating: ; Mode of pathogenicity: None; Publications: 33867527; Phenotypes: ; Mode of inheritance: None
Cataracts v2.84 PGRMC1 Ivone Leong Tag watchlist tag was added to gene: PGRMC1.
Cataracts v2.84 PGRMC1 Ivone Leong Phenotypes for gene: PGRMC1 were changed from Isolated paediatric cataract to Isolated paediatric cataract; cataract, MONDO:0005129
Cataracts v2.83 PGRMC1 Ivone Leong Classified gene: PGRMC1 as Amber List (moderate evidence)
Cataracts v2.83 PGRMC1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Cataracts v2.83 PGRMC1 Ivone Leong Gene: pgrmc1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.224 NUF2 Ivone Leong Classified gene: NUF2 as Red List (low evidence)
Severe microcephaly v2.224 NUF2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As there is only 1 case there is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Severe microcephaly v2.224 NUF2 Ivone Leong Gene: nuf2 has been classified as Red List (Low Evidence).
Intellectual disability v3.1266 TRAPPC10 Ivone Leong Phenotypes for gene: TRAPPC10 were changed from microcephaly (disease), MONDO:0001149 to Intellectual disability, MONDO:0001071
Intellectual disability v3.1265 TRAPPC10 Ivone Leong Entity copied from Severe microcephaly v2.223
Intellectual disability v3.1265 TRAPPC10 Ivone Leong gene: TRAPPC10 was added
gene: TRAPPC10 was added to Intellectual disability. Sources: Expert Review Red,Other
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to 30167849
Phenotypes for gene: TRAPPC10 were set to microcephaly (disease), MONDO:0001149
Penetrance for gene: TRAPPC10 were set to Complete
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Classified gene: TRAPPC10 as Red List (low evidence)
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Added comment: Comment on list classification: New gene added by Aleš Maver (Clinical Institute of Medical Genetics). This gene is not associated with a phenotype in OMIM, but is possibly associated with a disease in Gene2Phenotype. The affected individuals in PMID:30167849 (2 individuals from the same family) had severe ID. As I do not have access to the ESHG2021 talk, this gene has been given a Red rating until further evidence is available.
Severe microcephaly v2.223 TRAPPC10 Ivone Leong Gene: trappc10 has been classified as Red List (Low Evidence).
Severe microcephaly v2.222 TRAPPC10 Ivone Leong Phenotypes for gene: TRAPPC10 were changed from to microcephaly (disease), MONDO:0001149
Intellectual disability v3.1264 ATP1A2 Arina Puzriakova Publications for gene: ATP1A2 were set to 15159495; 29610157
Severe microcephaly v2.221 TRAPPC10 Ivone Leong Publications for gene: TRAPPC10 were set to PMID: 30167849
Genetic epilepsy syndromes v2.417 PARP6 Arina Puzriakova Entity copied from Intellectual disability v3.1263
Genetic epilepsy syndromes v2.417 PARP6 Arina Puzriakova gene: PARP6 was added
gene: PARP6 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: PARP6.
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Malformations of cortical development v2.85 FAT4 Ivone Leong Tag watchlist tag was added to gene: FAT4.
Malformations of cortical development v2.85 FAT4 Ivone Leong Classified gene: FAT4 as Amber List (moderate evidence)
Malformations of cortical development v2.85 FAT4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Malformations of cortical development v2.85 FAT4 Ivone Leong Gene: fat4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1263 PARP6 Arina Puzriakova Classified gene: PARP6 as Amber List (moderate evidence)
Intellectual disability v3.1263 PARP6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. At least 3 individuals with heterozygous PARP6 variants and a relevant phenotype have been reported (PMID: 34067418) - however, segregation analysis has only been complete for one of these cases. Furthermore, identification of two sibs with biallelic variants and unaffected parents who were heterozygous carriers arises possibility of incomplete penetrance or role of variants in other genes.

Overall there is not enough evidence to add this gene as diagnostic grade, so rating Amber with watchlist tag.
Intellectual disability v3.1263 PARP6 Arina Puzriakova Gene: parp6 has been classified as Amber List (Moderate Evidence).
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.9 GTF2E2 Michael Yau reviewed gene: GTF2E2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26996949): (PMID:28973399):; Phenotypes: Trichothiodystrophy 6, nonphotosensitive:; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.84 FAT4 Ivone Leong Phenotypes for gene: FAT4 were changed from Van Maldergem syndrome 2, MIM# 615546 to Van Maldergem syndrome 2, OMIM:615546
Intellectual disability v3.1262 PARP6 Arina Puzriakova Tag watchlist tag was added to gene: PARP6.
Intellectual disability v3.1262 PARP6 Arina Puzriakova reviewed gene: PARP6: Rating: ; Mode of pathogenicity: None; Publications: 34067418; Phenotypes: ; Mode of inheritance: None
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.9 RNF113A Michael Yau reviewed gene: RNF113A: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 19377476): (PMID: 25612912): (PMID:31793730): (PMID 31880405): (PMID:32152280); Phenotypes: X-linked nonphotosensitive trichothiodystrophy, intellectual disability, partial corpus callosum agenesis, microcephaly, microphallus, hypergonadotropic hypogonadism; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Paroxysmal central nervous system disorders v1.17 RHOBTB2 Zornitza Stark gene: RHOBTB2 was added
gene: RHOBTB2 was added to Paroxysmal central nervous system disorders. Sources: Literature
Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RHOBTB2 were set to 33504645
Phenotypes for gene: RHOBTB2 were set to Developmental and epileptic encephalopathy 64 618004; Alternating hemiplegia
Review for gene: RHOBTB2 was set to GREEN
Added comment: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in ATP1A3, these events were reported later only in RHOBTB2 mutation-positive patients from 20 months of age. All had ID, and many had seizures, so this represents an expansion of the phenotype rather than a distinct disorder.
Sources: Literature
Genetic epilepsy syndromes v2.416 SLC32A1 Zornitza Stark gene: SLC32A1 was added
gene: SLC32A1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC32A1 were set to 34038384
Phenotypes for gene: SLC32A1 were set to Genetic epilepsy with febrile seizures plus
Review for gene: SLC32A1 was set to GREEN
Added comment: 8 unrelated families reported, including segregation evidence in two large pedigrees. Variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition.
Sources: Literature
Intellectual disability v3.1262 ZNF668 Zornitza Stark gene: ZNF668 was added
gene: ZNF668 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF668 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF668 were set to 34313816; 26633546
Phenotypes for gene: ZNF668 were set to DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism
Review for gene: ZNF668 was set to AMBER
Added comment: 2 consanguineous families reported with different biallelic truncating (not NMD) variants in ZNF668. Phenotypes included microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism.

Immunofluorescence indicated ZNF668 deficiency. An increased DNA damage phenotype was demonstrated in patient fibroblasts.
Sources: Literature
Infantile enterocolitis & monogenic inflammatory bowel disease v1.22 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFIH1 were set to 34185153
Phenotypes for gene: IFIH1 were set to Inflammatory Bowel Disease
Review for gene: IFIH1 was set to GREEN
Added comment: IFIH1 encodes MDA5, a key cystolic sensor for viral nucleic acids. Rare, likely loss-of-functions IFIH1 variants identified in eight independent probands with Very Early Onset Inflammatory Bowel Disease (VEOIBD) from a combined cohort of 42 children. IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p=0.007).
In one case of neonatal-onset IBD, a homozygous truncating variant was identified. There were seven carriers of LoF variants identified (range of onset 6 months to 6 years of age). In three of these cases, a second hypomorphic missense variant was identified.
Luciferase reporter assays were employed to assess MDA5 activity. In some cases, the second missense variant was either proven to not affect protein function or was in cis with the LoF variant.
Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
Sources: Literature
Intellectual disability v3.1262 PRICKLE2 Zornitza Stark reviewed gene: PRICKLE2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34092786; Phenotypes: Neurodevelopmental disorder, global developmental delay, behavioural difficulties ± epilepsy, autistic features, attention deficit hyperactive disorder, psychiatric symptoms; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cataracts v2.82 PGRMC1 Zornitza Stark gene: PGRMC1 was added
gene: PGRMC1 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: PGRMC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PGRMC1 were set to 33867527; 23783460
Phenotypes for gene: PGRMC1 were set to Isolated paediatric cataract
Review for gene: PGRMC1 was set to AMBER
Added comment: A single large family with X-linked isolated paediatric cataract in males segregating a large 127 kb deletion truncating PGRMC1. A supporting knockout zebrafish model with cataract. Also, two unrelated male probands with non-syndromic ID and cataract with a large deletion encompassing PGRMC1 and SLC25A5.
Sources: Literature
Intellectual disability v3.1262 UBE2U Zornitza Stark gene: UBE2U was added
gene: UBE2U was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE2U was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBE2U were set to 33776059
Phenotypes for gene: UBE2U were set to Retinoschisis; cataracts; learning disabilities; developmental delay
Review for gene: UBE2U was set to RED
Added comment: Single family with 5 individuals reported.
Sources: Literature
Retinal disorders v2.208 LRP1 Zornitza Stark gene: LRP1 was added
gene: LRP1 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: LRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRP1 were set to 33776059
Phenotypes for gene: LRP1 were set to Macular drusen
Review for gene: LRP1 was set to RED
Added comment: PMID: 33776059 - 2x unrelated individuals with compound heterozygous missense variants and inherited retinal disorder/macular drusen. No functional data.
Sources: Literature
Intellectual disability v3.1262 CACNA1I Zornitza Stark gene: CACNA1I was added
gene: CACNA1I was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CACNA1I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1I were set to 33704440
Phenotypes for gene: CACNA1I were set to Neurodevelopmental disorder
Mode of pathogenicity for gene: CACNA1I was set to Other
Review for gene: CACNA1I was set to GREEN
gene: CACNA1I was marked as current diagnostic
Added comment: 4 different missense variants identified and shown to result in a gain of function.

2 individuals with de novo variants (a 3rd also suspected de novo but their father was unavailable for testing) - these patients all had severe neurodevelopmental disorders, involving severe global developmental delay, absence of speech, gross motor delay, muscular hypotonia, early-onset seizures, cortical visual impairment, and feeding difficulties. Variable clinical features include various brain malformations, startle response or seizures, postnatal growth retardation, gastroesophageal reflux, and gastrostomy.

1 family had three affected individuals - variable cognitive impairment in all, involving borderline intellectual functioning or mild or moderate intellectual disability as main clinical feature, with late-onset seizures in the mother and speech retardation in one of the children. This variant had a milder functional effect than the variants in sporadic cases.
Sources: Literature
Fetal anomalies v1.712 FGF8 Zornitza Stark reviewed gene: FGF8: Rating: AMBER; Mode of pathogenicity: None; Publications: 34433009; Phenotypes: Femoral hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Osteogenesis imperfecta v2.23 COPB2 Zornitza Stark reviewed gene: COPB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34450031; Phenotypes: Osteoporosis, recurrent fractures and developmental delay; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency v2.458 ELF4 Dmitrijs Rots reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34326534; Phenotypes: Ulcers, fever, inflammatory bowel disease, autoinflammatory condition; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency v2.458 KDM6A Dmitrijs Rots Deleted their comment
Primary immunodeficiency v2.458 KDM6A Dmitrijs Rots edited their review of gene: KDM6A: Added comment: Immunodeficiency is a well-known and common feature of KS. Recent study shows:
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively"; Changed publications to: PMID: 31363182; Changed phenotypes to: Hypogammaglobulinemia, intellectual disability, short stature
Primary immunodeficiency v2.458 KDM6A Dmitrijs Rots reviewed gene: KDM6A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34326534; Phenotypes: Autoinflammatory, inflammatory bowel disease, ulcers; 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 v2.458 KMT2D Dmitrijs Rots reviewed gene: KMT2D: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31363182; Phenotypes: Hypogammaglobulinemia, intellectual disability, short stature; Mode of inheritance: None
Intellectual disability v3.1262 GRIK2 Zornitza Stark reviewed gene: GRIK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34375587, 17847003, 25039795; Phenotypes: Mental retardation, autosomal recessive, 6 MIM# 611092, Non-syndromic neurodevelopmental disorder (NDD), autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital muscular dystrophy v2.16 GOSR2 Zornitza Stark reviewed gene: GOSR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34167170, 33639315, 33639315, 29855340, DOI:https://doi.org/10.1016/j.nmd.2013.06.404; Phenotypes: Epilepsy, progressive myoclonic 6 MIM#614018, congenital muscluar dystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1262 CHRM1 Zornitza Stark gene: CHRM1 was added
gene: CHRM1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218
Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism
Review for gene: CHRM1 was set to AMBER
Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways.
PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu)
PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction.
Sources: Literature
Osteogenesis imperfecta v2.23 SUCO Zornitza Stark gene: SUCO was added
gene: SUCO was added to Osteogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: SUCO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUCO were set to 29620724; 20440000
Phenotypes for gene: SUCO were set to Osteogenesis imperfecta
Review for gene: SUCO was set to AMBER
Added comment: A single case with diffuse osteopenia, multiple fractures with limb deformities, and short long bones, with biallelic variants (a missense and a splice site variant). Also, a null mouse model with acute onset skeletal defects that include impaired bone formation and spontaneous fractures.
Sources: Literature
Familial dysautonomia v1.13 MYO1H Zornitza Stark gene: MYO1H was added
gene: MYO1H was added to Familial dysautonomia. Sources: Literature
Mode of inheritance for gene: MYO1H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO1H were set to 28779001
Phenotypes for gene: MYO1H were set to Central hypoventilation syndrome, congenital, 2, and autonomic dysfunction, MIM#619482
Review for gene: MYO1H was set to RED
Added comment: Single family reported with three affected children, homozygous LoF variant.
Sources: Literature
Intellectual disability v3.1262 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Cholestasis v1.85 SLC51A Zornitza Stark gene: SLC51A was added
gene: SLC51A was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: SLC51A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC51A were set to 31863603
Phenotypes for gene: SLC51A were set to Cholestasis, progressive familial intrahepatic, 6, MIM# 619484
Review for gene: SLC51A was set to RED
Added comment: Single individual reported with homozygous LoF variant, who presented with chronic malabsorptive diarrhoea, easy bruising, episodes of prolonged bleeding that required blood transfusions, and failure to thrive. Laboratory testing at age 2.5 years showed elevated liver transaminases and alkaline phosphatase. Liver biopsy demonstrated portal and periportal fibrosis and hepatocytes with foci of hepatocytic cholestasis. Analysis of bile acids in a blood spot were normal. Treatment with ursodiol and cholestyramine was started at 5 years of age. The coagulopathy resolved and his growth was adequate, but his liver transaminases, direct bilirubin, and GGT levels remained elevated.
Sources: Literature
Arthrogryposis v3.119 CNTN1 Rhiannon Mellis reviewed gene: CNTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32779773; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.56 CNTN1 Rhiannon Mellis reviewed gene: CNTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 32779773; Phenotypes: Fetal akinesia deformation sequence; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.80 FOXE3 Eleanor Williams changed review comment from: Review of mode of inheritance:
There are many reported cases of biallelic variants in FOXE3 associated with an eye phenotype, particularly cataracts, aphakia, microphthalmia and sclerocornea (PMID: 27218149 Khan et al 2016, PMID: 16826526 Valleix et al 2006, PMID: 19708017 Iseri et al 2009, PMID: 20140963 Reis et al 2010, PMID: 20664696 Ali et al 2010, PMID: 20361012 Anjum et al 2010, PMID: 24019743 Pantoja-Melendez et al 2013, PMID: 27669367 Saboo et al 2017, PMID: 29878917 Quiroz-Casian et al 2018, PMID: 32436650 Taha Najim et al 2020, PMID: 34046667 Reis et al 2021). Glaucoma is also noted in some individuals. Heterozygous carriers are largely unaffected in these cases.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID: 34046667 - Reis et al 2021 - 2 families reported with dominant pathogenic extension alleles which modify the stop codon but keep the amino acids in frame, adding a 72–amino acid nonsense peptide. Cataracts were found in all cases where the lens could be evaluated. Eye size was normal in all individuals, but mild anterior segment anomalies affecting the cornea and/or iris were noted in some individuals. Sclerocornea was observed in two family members (15C and 16B).
Fetal anomalies v1.712 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968; {Aortic aneurysm, familial thoracic 11, susceptibility to}, OMIM:617349 CONGENITAL PRIMARY APHAKIA to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968; {Aortic aneurysm, familial thoracic 11, susceptibility to}, OMIM:617349 CONGENITAL PRIMARY APHAKIA; ANTERIOR SEGMENT MESENCHYMAL DYSGENESIS
Fetal anomalies v1.711 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Monoallleic cases related to Aortic aneurysm, familial thoracic 11, susceptibility to and to some cases with an eye phenotype. Biallelic cases associated with an eye phenotype.
Fetal anomalies v1.711 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.710 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from ANTERIOR SEGMENT MESENCHYMAL DYSGENESIS; CONGENITAL PRIMARY APHAKIA to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Cataract 34, multiple types, OMIM:612968; {Aortic aneurysm, familial thoracic 11, susceptibility to}, OMIM:617349 CONGENITAL PRIMARY APHAKIA
Anophthalmia or microphthalmia v1.42 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from to Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256; Ocular anterior segment dysgenesis, HP:0007700
Anophthalmia or microphthalmia v1.41 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Only 1 monoallelic case reported with microphthalmia so leaving the mode of inheritance as biallelic for now (PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia,coloboma, and cerulean type (blue dot) cataracts). See full review on on the Structural eye disease panel for all monoallelic cases https://panelapp.genomicsengland.co.uk/panels/509/gene/FOXE3/.
Anophthalmia or microphthalmia v1.41 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1262 TCF7L2 Zornitza Stark edited their review of gene: TCF7L2: Added comment: Additional 11 cases reported.; Changed rating: GREEN; Changed publications to: 33057194, 34003604
White matter disorders and cerebral calcification - narrow panel v1.198 COLGALT1 Zornitza Stark gene: COLGALT1 was added
gene: COLGALT1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: COLGALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COLGALT1 were set to 30412317; 33709034; 31759980
Phenotypes for gene: COLGALT1 were set to Brain small vessel disease 3 MIM#618360
Review for gene: COLGALT1 was set to GREEN
Added comment: 3 unrelated cases with biallelic variants, and supporting functional assays. The main features of the cases were porencephalic cysts, leukoencephalopathy, lacunar infarcts, cerebral microbleeds/haemorrhages and calcifications. A null mouse model was embryonic lethal, but had defects in the vascular networks of the embryos.
Sources: Literature
Intellectual disability v3.1262 JAKMIP1 Zornitza Stark gene: JAKMIP1 was added
gene: JAKMIP1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JAKMIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAKMIP1 were set to 29158550; 26627310; 27799067
Phenotypes for gene: JAKMIP1 were set to Intellectual disability; seizures
Review for gene: JAKMIP1 was set to AMBER
Added comment: Identified in two independent patients in the literature with a mouse model. Patient 1 (27799067) with developmental delay, speech delay, and cognitive impairment; self-injurious and aggressive behaviour, seizures, dysmorphic features. De-novo missense JAKMIP1 (p.D586H). Patient 2 (29158550) with feeding difficulties, hypotonia, epilepsy, severe ID, no active speech, kyphoscoliosis, constipation, autism, short stature. Splice variant c.1432-2A>G, no segregation or RNA data available. KO mouse model (27799067) displays social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors.
Sources: Literature
Thoracic aortic aneurysm and dissection v1.16 ARIH1 Zornitza Stark gene: ARIH1 was added
gene: ARIH1 was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: ARIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a Drosophila model.
Sources: Literature
Ocular coloboma v1.44 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Review of mode of inheritance - two reports of coloboma in monoallelic cases from one publication but leaving inheritance as biallelic for now until a 3rd case is reported (PMID: 19708017 - Iseri et al 2009 - identified 2 pedigrees with dominant mutations in the FOXE3 gene by screening a large cohort of 236 anophthalmia-microphthalmia subjects; one with anterior segment anomalies, including Peters’ anomaly, early onset cataract, and coloboma, and another with microphthalmia, coloboma, and cerulean type (blue dot) cataracts.).
Ocular coloboma v1.44 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.82 FOXE3 Eleanor Williams Publications for gene: FOXE3 were set to Iseri et al (2009) Hum Mutat 30:1378-1386; Semina et al (2001) Hum Mol Genet 10:231-236; Br mond-Gignac et al (2010) Mol Vis 16:1705-1711.
Cataracts v2.81 FOXE3 Eleanor Williams Phenotypes for gene: FOXE3 were changed from Autosomal dominant cataracts; Peter's anomaly, microphthalmia. to Cataract 34, multiple types, OMIM:612968; cataract 34 multiple types, MONDO:0013067; Peter's anomaly; microphthalmia.
Glaucoma (developmental) v1.39 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Only one report on a monoallelic case where glaucoma specified as part of the phenotype (PMID: 11980846 - Ormestad et al 2002 - one individual with Peters anomaly (with eccentric corneal opacities and glaucoma but not cataract) was found to be heterozygous for a nonconservative missense mutation in FOXE3) and so leaving the mode of inheritance as biallelic only for now.
Glaucoma (developmental) v1.39 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.80 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: Review of mode of inheritance confirms that there are both biallelic and monoallelic cases with FOXE3 variants where cataracts are reported. See full review of MOI on the Structural eye disease panel https://panelapp.genomicsengland.co.uk/panels/509/gene/FOXE3/
Cataracts v2.80 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Structural eye disease v1.80 FOXE3 Eleanor Williams reviewed gene: FOXE3: Rating: ; Mode of pathogenicity: None; Publications: 27218149, 16826526, 19708017, 20140963, 20664696, 20361012, 24019743, 27669367, 29878917, 32436650, 34046667, 11159941, 19708017, 20806047, 21150893, 11980846, 34046667; Phenotypes: Anterior segment dysgenesis 2, multiple subtypes, OMIM:610256, Cataract 34, multiple types, OMIM:612968; Mode of inheritance: None
Hereditary neuropathy v1.415 C1orf194 Sarah Leigh Classified gene: C1orf194 as Green List (high evidence)
Hereditary neuropathy v1.415 C1orf194 Sarah Leigh Gene: c1orf194 has been classified as Green List (High Evidence).
Hereditary neuropathy v1.414 C1orf194 Sarah Leigh Entity copied from Hereditary neuropathy NOT PMP22 copy number v1.61
Hereditary neuropathy v1.414 C1orf194 Sarah Leigh gene: C1orf194 was added
gene: C1orf194 was added to Hereditary neuropathy. Sources: Expert Review Amber,Literature
Q3_21_NHS_review tags were added to gene: C1orf194.
Mode of inheritance for gene: C1orf194 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C1orf194 were set to 31199454; 32592472
Phenotypes for gene: C1orf194 were set to Charcot-Marie-Tooth disease, intermediate or demyelinating
Hereditary neuropathy NOT PMP22 copy number v1.61 C1orf194 Sarah Leigh Tag Q3_21_rating was removed from C1orf194.
Hereditary neuropathy NOT PMP22 copy number v1.60 C1orf194 Sarah Leigh edited their review of gene: C1orf194: Added comment: This green review is based on the review of Alexander Rossor (UCL Institute of Neurology), 8 Mar 2021, which was entered in error on the entry for C1orf94. The review is as follows: Two unrelated families, knock in mouse with relevant phenotype. Functional evidence for one variant only. Sources: Expert list.; Changed rating: GREEN
Hereditary neuropathy NOT PMP22 copy number v1.60 C1orf194 Sarah Leigh Tag Q3_21_rating tag was added to gene: C1orf194.
Tag Q3_21_NHS_review tag was added to gene: C1orf194.
Hereditary neuropathy NOT PMP22 copy number v1.60 C1orf194 Sarah Leigh Classified gene: C1orf194 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.60 C1orf194 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy NOT PMP22 copy number v1.60 C1orf194 Sarah Leigh Gene: c1orf194 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy v1.413 C1orf94 Sarah Leigh Tag curated_removed tag was added to gene: C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.59 C1orf94 Sarah Leigh Tag Q3_21_NHS_review was removed from gene: C1orf94.
Tag curated_removed tag was added to gene: C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.59 C1orf94 Sarah Leigh Tag Q3_21_rating was removed from gene: C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.59 C1orf94 Sarah Leigh Classified gene: C1orf94 as No list
Hereditary neuropathy NOT PMP22 copy number v1.59 C1orf94 Sarah Leigh Added comment: Comment on list classification: Curator deletion of this gene from this panel.
This gene has been added to this panel in error. The publications, phenotype and reviews are appropriate for C1orf194 and not for C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.59 C1orf94 Sarah Leigh Gene: c1orf94 has been removed from the panel.
Hereditary neuropathy v1.413 C1orf94 Sarah Leigh Classified gene: C1orf94 as No list
Hereditary neuropathy v1.413 C1orf94 Sarah Leigh Added comment: Comment on list classification: Curator deletion of this gene from this panel.
This gene has been added to this panel in error. The publications, phenotype and reviews are appropriate for C1orf194 and not for C1orf94.
Hereditary neuropathy v1.413 C1orf94 Sarah Leigh Gene: c1orf94 has been removed from the panel.
Malformations of cortical development v2.83 EML1 Arina Puzriakova Publications for gene: EML1 were set to 31710781
Malformations of cortical development v2.82 EML1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: EML1.
Malformations of cortical development v2.82 EML1 Arina Puzriakova Classified gene: EML1 as Amber List (moderate evidence)
Malformations of cortical development v2.82 EML1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). EML1 is associated with a relevant phenotype in OMIM (MIM# 600348) but is not yet listed in G2P. Animal models and sufficient number of unrelated cases (>3) with relevant phenotype (periventricular and ribbon-like subcortical heterotopia with polymicrogyria) and variants in this gene to rate as Green at the next GMS panel update.
Malformations of cortical development v2.82 EML1 Arina Puzriakova Gene: eml1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.81 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from Band heterotopia (MIM# 600348) to Band heterotopia, OMIM:600348
Fetal anomalies v1.709 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from Band heterotopia, 600348 to Band heterotopia, OMIM:600348
Intellectual disability v3.1262 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from congenital hydrocephalus, profound global developmental delay and intractable epilepsy; Band heterotopia, 600348 (includes severe intellectual disability) to Band heterotopia, OMIM:600348
Genetic epilepsy syndromes v2.416 EML1 Arina Puzriakova Phenotypes for gene: EML1 were changed from Band heterotopia, 600348 to Band heterotopia, OMIM:600348
Malformations of cortical development v2.80 DEPDC5 Arina Puzriakova Publications for gene: DEPDC5 were set to 31444548
Malformations of cortical development v2.79 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, OMIM:604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364; Focal cortical dysplasia
Malformations of cortical development v2.78 DEPDC5 Arina Puzriakova Tag Q3_21_rating tag was added to gene: DEPDC5.
Malformations of cortical development v2.78 DEPDC5 Arina Puzriakova Classified gene: DEPDC5 as Amber List (moderate evidence)
Malformations of cortical development v2.78 DEPDC5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DEPDC5 is associated with a relevant phenotype in OMIM (MIM# 604364) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases (>3) with relevant phenotype (focal cortical dysplasia of variable severity) and variants in this gene to rate as Green at the next GMS panel update.
Malformations of cortical development v2.78 DEPDC5 Arina Puzriakova Gene: depdc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1261 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from FAMILIAL FOCAL EPILEPSY WITH VARIABLE FOCI (FFEVF) to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Genetic epilepsy syndromes v2.415 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1 604364 to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Malformations of cortical development v2.77 DEPDC5 Arina Puzriakova Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1 (MIM#604364) to Epilepsy, familial focal, with variable foci 1, OMIM:604364
Malformations of cortical development v2.76 DCHS1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases with relevant phenotype and variants in this gene to rate as Green.

Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases (4 patients from 3 families) with relevant phenotype and confirmed variants in this gene to rate as Green.

Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect.
Malformations of cortical development v2.76 DCHS1 Arina Puzriakova Publications for gene: DCHS1 were set to 27262615; 22473091
Malformations of cortical development v2.75 DCHS1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: DCHS1.
Malformations of cortical development v2.75 DCHS1 Arina Puzriakova Classified gene: DCHS1 as Amber List (moderate evidence)
Malformations of cortical development v2.75 DCHS1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). DCHS1 is associated with a relevant phenotype in OMIM (MIM# 601390) and G2P ('confirmed' disease confidence rating). Sufficient number of unrelated cases with relevant phenotype and variants in this gene to rate as Green.

Brain MRI typically shows periventricular nodular heterotopia, often with a dysmorphic corpus callosum or simplified gyral pattern, consistent with a neuronal migration defect.
Malformations of cortical development v2.75 DCHS1 Arina Puzriakova Gene: dchs1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.74 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from Van Maldergem syndrome 1, OMIM:601390 to Van Maldergem syndrome 1, OMIM:601390; Periventricular nodular heterotopia
Malformations of cortical development v2.73 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from Van Maldergem syndrome 1 (MIM#601390) to Van Maldergem syndrome 1, OMIM:601390
Primary lymphoedema v2.18 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from Van Maldergem syndrome 1, 601390 to Van Maldergem syndrome 1, OMIM:601390
Intellectual disability v3.1260 DCHS1 Arina Puzriakova Phenotypes for gene: DCHS1 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA; Van Maldergem syndrome 1, 601390 to Van Maldergem syndrome 1, OMIM:601390
Malformations of cortical development v2.72 CTNNA2 Arina Puzriakova Tag Q3_21_rating tag was added to gene: CTNNA2.
Malformations of cortical development v2.72 CTNNA2 Arina Puzriakova Classified gene: CTNNA2 as Amber List (moderate evidence)
Malformations of cortical development v2.72 CTNNA2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). CTNNA2 is associated with a relevant phenotype in OMIM (MIM# 618174) and G2P ('probable' disease confidence rating). There is sufficient evidence to rate this gene as Green at the next GMS panel update - 13 patients from 3 unrelated families, pachygyria without posterior-anterior gradient or focal dysplasias was common to all.
Malformations of cortical development v2.72 CTNNA2 Arina Puzriakova Gene: ctnna2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1259 CTNNA2 Arina Puzriakova Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9, 618174; intellectual disability; global developmental delay to Cortical dysplasia, complex, with other brain malformations 9, OMIM:618174
Genetic epilepsy syndromes v2.414 CTNNA2 Arina Puzriakova Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 4, 618174, seizures to Cortical dysplasia, complex, with other brain malformations 9, OMIM:618174
Malformations of cortical development v2.71 CTNNA2 Arina Puzriakova Phenotypes for gene: CTNNA2 were changed from Cortical dysplasia, complex, with other brain malformations 9, MIM#618174 to Cortical dysplasia, complex, with other brain malformations 9, OMIM:618174
Malformations of cortical development v2.70 CSNK2A1 Arina Puzriakova Classified gene: CSNK2A1 as Green List (high evidence)
Malformations of cortical development v2.70 CSNK2A1 Arina Puzriakova Added comment: Comment on list classification: Three individuals reported by Okur et al., 2016 (PMID: 27048600) displayed cortical abnormalities which meets the threshold for a Green rating. However it should be noted that this is not a common finding and has not been described since the initial report.
Malformations of cortical development v2.70 CSNK2A1 Arina Puzriakova Gene: csnk2a1 has been classified as Green List (High Evidence).
Malformations of cortical development v2.69 CSNK2A1 Arina Puzriakova Publications for gene: CSNK2A1 were set to 27048600
Osteogenesis imperfecta v2.23 KDELR2 Meena Balasubramanian reviewed gene: KDELR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33964184, 33053334; Phenotypes: Ostoegenesis Imperfecta, Fractures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis imperfecta v2.23 MESD Meena Balasubramanian reviewed gene: MESD: Rating: GREEN; Mode of pathogenicity: None; Publications: 33596325, 31564437; Phenotypes: Ostoegenesis Imperfecta, Fractures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1258 CSNK2A1 Arina Puzriakova Phenotypes for gene: CSNK2A1 were changed from Okur-Chung neurodevelopmental syndrome to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Genetic epilepsy syndromes v2.413 CSNK2A1 Arina Puzriakova Phenotypes for gene: CSNK2A1 were changed from Neurodevelopmental abnormalities and dysmorphic features; seizures; Okur-Chung neurodevelopmental syndrome, 617062; CSNK2A1 syndrome to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Osteogenesis imperfecta v2.23 FAM46A Meena Balasubramanian reviewed gene: FAM46A: Rating: GREEN; Mode of pathogenicity: None; Publications: 29358272; Phenotypes: Ostoegenesis Imperfecta, Fractures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.68 CSNK2A1 Arina Puzriakova Phenotypes for gene: CSNK2A1 were changed from 617062 to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Osteogenesis imperfecta v2.23 MBTPS2 Meena Balasubramanian reviewed gene: MBTPS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27380894; Phenotypes: Ostoegenesis Imperfecta, Fractures; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare anaemia v1.24 GSR Zornitza Stark reviewed gene: GSR: Rating: AMBER; Mode of pathogenicity: None; Publications: 17185460, 31122244; Phenotypes: Haemolytic anaemia due to glutathione reductase deficiency, MIM# 618660; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.67 PEX7 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PEX7.
Tag Q3_21_expert_review tag was added to gene: PEX7.
Malformations of cortical development v2.67 PEX7 Arina Puzriakova commented on gene: PEX7
Cataracts v2.79 PEX7 Arina Puzriakova Phenotypes for gene: PEX7 were changed from Rhizomelic chondrodysplasia punctata type 1; Confirmed DD gene for Rhizomelic chondrodysplasia punctata type 1; Refsum disease; Peroxisome biogenesis disorder to Peroxisome biogenesis disorder 9B, OMIM:614879; Rhizomelic chondrodysplasia punctata, type 1, OMIM:215100
Peroxisomal disorders v1.16 PEX7 Arina Puzriakova Phenotypes for gene: PEX7 were changed from Peroxisome biogenesis disorder 9B 614879; Rhizomelic chondrodysplasia punctata, type 1 215100 to Peroxisome biogenesis disorder 9B, OMIM:614879; Rhizomelic chondrodysplasia punctata, type 1, OMIM:215100
Chondrodysplasia punctata v1.5 PEX7 Arina Puzriakova Phenotypes for gene: PEX7 were changed from Rhizomelic chondrodysplasia punctata, type 1, 215100 to Peroxisome biogenesis disorder 9B, OMIM:614879; Rhizomelic chondrodysplasia punctata, type 1, OMIM:215100
Genetic epilepsy syndromes v2.412 PIDD1 Arina Puzriakova Classified gene: PIDD1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.412 PIDD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Overall there are sufficient unrelated cases (>3) with a relevant phenotype and biallelic variants in this gene to rate as Green at the next GMS panel update.
Genetic epilepsy syndromes v2.412 PIDD1 Arina Puzriakova Gene: pidd1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.411 PIDD1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIDD1.
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Classified gene: PIDD1 as Amber List (moderate evidence)
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Overall there are sufficient unrelated cases (>3) with a relevant phenotype and biallelic variants in this gene to rate as Green at the next GMS panel update.
Intellectual disability v3.1257 PIDD1 Arina Puzriakova Gene: pidd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1256 PIDD1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: PIDD1.
Malformations of cortical development v2.67 PIDD1 Arina Puzriakova Classified gene: PIDD1 as Amber List (moderate evidence)
Malformations of cortical development v2.67 PIDD1 Arina Puzriakova Gene: pidd1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.66 PIDD1 Arina Puzriakova gene: PIDD1 was added
gene: PIDD1 was added to Malformations of cortical development. Sources: Literature
Q3_21_rating tags were added to gene: PIDD1.
Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIDD1 were set to 33414379; 34163010
Phenotypes for gene: PIDD1 were set to Intellectual disability; Pachygyria; Lissencephaly; Seizures
Review for gene: PIDD1 was set to GREEN
Added comment: At least 9 distinct biallelic variants have been identified in 26 individuals from 11 families. All affected individuals had DD and variable degree of ID (mild to severe) and all those that had brain imaging exhibited cortical abnormalities, particularly pachygyria/lissencephaly and corpus callosum anomalies. Seizures were recorded in 9 patients (6 families).

Overall there is are sufficient unrelated cases with relevant phenotype and biallelic variants in this gene to rate as Green on this panel.
Sources: Literature
Hereditary neuropathy v1.412 C1orf94 Sarah Leigh Classified gene: C1orf94 as Green List (high evidence)
Hereditary neuropathy v1.412 C1orf94 Sarah Leigh Added comment: Comment on list classification: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants reported, together with a supportive mouse knock-out model (PMID: 31199454; 32592472).
Hereditary neuropathy v1.412 C1orf94 Sarah Leigh Gene: c1orf94 has been classified as Green List (High Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.58 C1orf94 Sarah Leigh Classified gene: C1orf94 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.58 C1orf94 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy NOT PMP22 copy number v1.58 C1orf94 Sarah Leigh Gene: c1orf94 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh Tag Q3_21_rating tag was added to gene: C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh Tag Q3_21_NHS_review tag was added to gene: C1orf94.
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants reported, together with a supportive mouse knock-out model.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants reported, together with a supportive mouse knock-out model (PMID: 31199454; 32592472).
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh reviewed gene: C1orf94: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh Entity copied from Hereditary neuropathy v1.411
Hereditary neuropathy NOT PMP22 copy number v1.57 C1orf94 Sarah Leigh gene: C1orf94 was added
gene: C1orf94 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert list
Mode of inheritance for gene: C1orf94 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: C1orf94 were set to 31199454; 32592472
Phenotypes for gene: C1orf94 were set to Intermediate Charcot-Marie-Tooth disease
Penetrance for gene: C1orf94 were set to Complete
Mode of pathogenicity for gene: C1orf94 was set to Other
Hereditary neuropathy v1.411 C1orf94 Sarah Leigh Phenotypes for gene: C1orf94 were changed from Intermediate CMT to Intermediate Charcot-Marie-Tooth disease
Hereditary neuropathy v1.410 C1orf94 Sarah Leigh Publications for gene: C1orf94 were set to 31199454
Hereditary neuropathy v1.409 C1orf94 Sarah Leigh Publications for gene: C1orf94 were set to PMID: 31199454
Intellectual disability v3.1256 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Mental retardation, autosomal recessive 34, with variant lissencephaly 614499 to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Malformations of cortical development v2.65 CRADD Arina Puzriakova Phenotypes for gene: CRADD were changed from Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499 to Mental retardation, autosomal recessive 34, with variant lissencephaly, OMIM:614499
Intellectual disability v3.1255 CRADD Arina Puzriakova Publications for gene: CRADD were set to 22279524; 27773430
Malformations of cortical development v2.64 CRADD Arina Puzriakova Publications for gene: CRADD were set to 27773430
Malformations of cortical development v2.63 CRADD Arina Puzriakova Classified gene: CRADD as Amber List (moderate evidence)
Malformations of cortical development v2.63 CRADD Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Brain phenotypes include megalencephaly with variable lissencephaly/pachygyria. Sufficient number of unrelated cases (>3) to rate as Green on this panel.
Malformations of cortical development v2.63 CRADD Arina Puzriakova Gene: cradd has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.62 CRADD Arina Puzriakova Tag Q3_21_rating tag was added to gene: CRADD.
Malformations of cortical development v2.62 CDK13 Arina Puzriakova reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 29021403; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360; Mode of inheritance: None
Neurological ciliopathies v1.18 LAMA1 Arina Puzriakova Classified gene: LAMA1 as Amber List (moderate evidence)
Neurological ciliopathies v1.18 LAMA1 Arina Puzriakova Added comment: Comment on list classification: Clinical features of Poretti-Boltshauser syndrome resemble Joubert syndrome which can lead to misdiagnosis. Although not a ciliopathy per se, inclusion on ciliopathy panels may be warranted to enable differential diagnosis. The LAMA1 gene will be flagged for GMS specialist review to determine whether it is appropriate to include this gene on this panel.
Neurological ciliopathies v1.18 LAMA1 Arina Puzriakova Gene: lama1 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v1.19 LAMA1 Arina Puzriakova Classified gene: LAMA1 as Amber List (moderate evidence)
Ophthalmological ciliopathies v1.19 LAMA1 Arina Puzriakova Added comment: Comment on list classification: Clinical features of Poretti-Boltshauser syndrome resemble Joubert syndrome which can lead to misdiagnosis. Although not a ciliopathy per se, inclusion on ciliopathy panels may be warranted to enable differential diagnosis. The LAMA1 gene will be flagged for GMS specialist review to determine whether it is appropriate to include this gene on this panel.
Ophthalmological ciliopathies v1.19 LAMA1 Arina Puzriakova Gene: lama1 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.17 LAMA1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: LAMA1.
Tag Q3_21_expert_review tag was added to gene: LAMA1.
Ophthalmological ciliopathies v1.18 LAMA1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: LAMA1.
Tag Q3_21_expert_review tag was added to gene: LAMA1.
Neurological ciliopathies v1.17 LAMA1 Arina Puzriakova Entity copied from Rare multisystem ciliopathy disorders v1.146
Neurological ciliopathies v1.17 LAMA1 Arina Puzriakova gene: LAMA1 was added
gene: LAMA1 was added to Neurological ciliopathies. Sources: Expert Review,Expert Review Green
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227; 34423300
Phenotypes for gene: LAMA1 were set to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Penetrance for gene: LAMA1 were set to Complete
Ophthalmological ciliopathies v1.18 LAMA1 Arina Puzriakova Entity copied from Rare multisystem ciliopathy disorders v1.146
Ophthalmological ciliopathies v1.18 LAMA1 Arina Puzriakova gene: LAMA1 was added
gene: LAMA1 was added to Ophthalmological ciliopathies. Sources: Expert Review,Expert Review Green
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227; 34423300
Phenotypes for gene: LAMA1 were set to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Penetrance for gene: LAMA1 were set to Complete
Rare multisystem ciliopathy disorders v1.146 LAMA1 Arina Puzriakova Publications for gene: LAMA1 were set to 25105227
Hereditary neuropathy v1.408 JAG1 Arina Puzriakova Tag watchlist tag was added to gene: JAG1.
Hereditary neuropathy NOT PMP22 copy number v1.56 JAG1 Arina Puzriakova Tag watchlist tag was added to gene: JAG1.
Hereditary neuropathy v1.408 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Vocal cord palsy to Vocal cord palsy; Peripheral neuropathy
Hereditary neuropathy NOT PMP22 copy number v1.56 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Peripheral neuropathy to Vocal cord palsy; Peripheral neuropathy
Hereditary neuropathy v1.407 JAG1 Arina Puzriakova Classified gene: JAG1 as Amber List (moderate evidence)
Hereditary neuropathy v1.407 JAG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Alexander Rossor (UCL). Sullivan et al., 2020 (PMID:32065591) report two unrelated families with segregation, presenting vocal fold paresis. Knock in mouse model showed slight but nonsignificant reduction in compound muscle action potential and morphological assessments of the recurrent laryngeal nerve were normal. Mice did however display an increased frequency of axons with focally folded myelin. Notably, variants in JAG1 are associated with several phenotypes that have not included neuropathy and there was no history of cardiac, kidney, or liver disease in affected individuals in either of the two families discussed here (possibly different mechanisms of pathogenesis but further investigation may be warranted).

At this point there is not enough evidence to add this gene as diagnostic-grade; however, additional cases would corroborate this gene-disease association - rating Amber with 'watchlist' tag.
Hereditary neuropathy v1.407 JAG1 Arina Puzriakova Gene: jag1 has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.55 JAG1 Arina Puzriakova Classified gene: JAG1 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.55 JAG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Sullivan et al., 2020 (PMID:32065591) report two unrelated families with segregation, presenting vocal fold paresis. Knock in mouse model showed slight but nonsignificant reduction in compound muscle action potential and morphological assessments of the recurrent laryngeal nerve were normal. Mice did however display an increased frequency of axons with focally folded myelin. Notably, variants in JAG1 are associated with several phenotypes that have not included neuropathy and there was no history of cardiac, kidney, or liver disease in affected individuals in either of the two families discussed here (possibly different mechanisms of pathogenesis but further investigation may be warranted).

At this point there is not enough evidence to add this gene as diagnostic-grade; however, additional cases would corroborate this gene-disease association - rating Amber with 'watchlist' tag.
Hereditary neuropathy NOT PMP22 copy number v1.55 JAG1 Arina Puzriakova Gene: jag1 has been classified as Amber List (Moderate Evidence).
Severe Paediatric Disorders v1.83 JAG1 Arina Puzriakova Mode of inheritance for gene: JAG1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.208 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from to Alagille syndrome 1, OMIM:118450
Retinal disorders v2.207 JAG1 Arina Puzriakova Mode of inheritance for gene: JAG1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hearing loss v2.183 JAG1 Arina Puzriakova Mode of inheritance for gene: JAG1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hearing loss v2.182 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome, 118450Deafness, congenital heart defects and posterior embryotoxonTetralogy of Fallot, 187500; Alagillesyndrome,118450TetralogyofFallot,187500Deafness,congenitalheartdefects,andposteriorembryotoxon to ?Deafness, congenital heart defects, and posterior embryotoxon, OMIM:617992
Intellectual disability v3.1254 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome, 118450; Tetralogy of Fallot, 187500; Deafness, congenital heart defects, and posterior embryotoxon to Alagille syndrome 1, OMIM:118450
Craniosynostosis v2.52 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome to Alagille syndrome 1, OMIM:118450
Familial non syndromic congenital heart disease v1.65 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Tetralogy of Fallot; Alagille syndrome to Alagille syndrome 1, OMIM:118450; Tetralogy of Fallot, OMIM:187500; Deafness, congenital heart defects, and posterior embryotoxon, OMIM:617992
CAKUT v1.164 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome 1 118450 to Alagille syndrome 1, OMIM:118450
Ductal plate malformation v1.18 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome 1 (118450) to Alagille syndrome 1, OMIM:118450
Cerebral vascular malformations v2.58 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Moyamoya disease; Alagille syndrome 1, 118450 to Alagille syndrome 1, OMIM:118450; Moyamoya disease
Intellectual disability v3.1253 JAG1 Arina Puzriakova Mode of inheritance for gene: JAG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cholestasis v1.85 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome; Neonatal and Adult Cholestasis; Alagille syndrome 1, 118450 to Alagille syndrome 1, OMIM:118450; Neonatal and Adult Cholestasis
Neonatal cholestasis v1.20 JAG1 Arina Puzriakova Phenotypes for gene: JAG1 were changed from Alagille syndrome; Neonatal and Adult Cholestasis; Alagille syndrome 1, 118450 to Alagille syndrome 1, OMIM:118450; Neonatal and Adult Cholestasis
Skeletal dysplasia v2.118 SPARC Arina Puzriakova Phenotypes for gene: SPARC were changed from Osteogenesis imperfecta, type XVII 616507 to Osteogenesis imperfecta, type XVII, OMIM:616507
Osteogenesis imperfecta v2.23 SPARC Arina Puzriakova Phenotypes for gene: SPARC were changed from Osteogenesis Imperfecta, Type XVII; Osteogenesis Imperfecta to Osteogenesis imperfecta, type XVII, OMIM:616507
Skeletal dysplasia v2.117 SPARC Arina Puzriakova Publications for gene: SPARC were set to 26027498
Osteogenesis imperfecta v2.22 SPARC Arina Puzriakova Publications for gene: SPARC were set to 26027498
Genetic epilepsy syndromes v2.411 ARF1 Arina Puzriakova edited their review of gene: ARF1: Added comment: Added to this panel as seizures have been reported in 3/5 cases. Epilepsy is likely to arise in these cases prior to detection of cortical malformations and may prompt earlier genetic investigation. Inclusion on this panel could increase the likelihood of detecting cases and therefore a Green rating is warranted.; Changed rating: GREEN; Changed publications to: 28868155, 34353862; Changed phenotypes to: Periventricular nodular heterotopia 8, OMIM:618185; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v2.411 ARF1 Arina Puzriakova Entity copied from Malformations of cortical development v2.62
Genetic epilepsy syndromes v2.411 ARF1 Arina Puzriakova gene: ARF1 was added
gene: ARF1 was added to Genetic epilepsy syndromes. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: ARF1.
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, OMIM:618185
Intellectual disability v3.1252 ARF1 Arina Puzriakova edited their review of gene: ARF1: Added comment: Added to ID panel as developmental delay (especially in speech) is a reported feature in all cases (except for one individuals for which only limited clinical information was available). Although only one patient has been reported with a moderate ID diagnosis, developmental delay is likely to be noticed earlier in the course of disease than cortical malformations and may prompt genetic investigation. Inclusion on this panel could increase the likelihood of detecting cases and therefore a Green rating is warranted.; Changed rating: GREEN; Changed publications to: 28868155, 34353862; Changed phenotypes to: Periventricular nodular heterotopia 8, OMIM:618185; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1252 ARF1 Arina Puzriakova Entity copied from Malformations of cortical development v2.62
Intellectual disability v3.1252 ARF1 Arina Puzriakova gene: ARF1 was added
gene: ARF1 was added to Intellectual disability. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: ARF1.
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155; 34353862
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, OMIM:618185
Malformations of cortical development v2.62 ARF1 Arina Puzriakova Added comment: Comment on publications: Gana et al., 2021 (PMID: 34353862) - additional family identified with a 5-year-old girl who inherited a heterozygous nonsense variant in the ARF1 gene (c.234G>A; p.Trp78Ter) from her father. Both displayed periventricular nodular heterotopia on brain MRI but with milder clinical expression in the father.
Malformations of cortical development v2.62 ARF1 Arina Puzriakova Publications for gene: ARF1 were set to 28868155
Craniosynostosis v2.51 GINS2 Arina Puzriakova gene: GINS2 was added
gene: GINS2 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: GINS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GINS2 were set to 34353863
Phenotypes for gene: GINS2 were set to Meier-Gorlin syndrome with craniosynostosis
Review for gene: GINS2 was set to RED
Added comment: Sa et al., 2021 (PMID: 34353863) identified a patient presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. A homozygous missense variant (c.341G>T, p.Arg114Leu) in GINS2 was identified that was heterozygous in both unaffected parents. Some supportive functional data included.

GINS2 is not currently not associated with any phenotype in OMIM or G2P and no additional cases have been identified to date. Rating Red, awaiting further evidence.
Sources: Literature
Arthrogryposis v3.119 FLNC Arina Puzriakova Added comment: Comment on publications: PMID: 33060286 - additional patient presenting at birth with mild arthrogryposis including hip dislocation, clenched hands, adducted thumbs.
Arthrogryposis v3.119 FLNC Arina Puzriakova Publications for gene: FLNC were set to 29858533
Congenital myaesthenic syndrome v2.38 GMPPB Sarah Leigh Added comment: Comment on phenotypes: This phenotype includes features of congenital myasthenic syndrome (in some patients) according to OMIM:615352.
Congenital myaesthenic syndrome v2.38 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Congenital Myasthenic Syndrome, MONDO:0018940 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Intellectual disability v3.1251 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Inborn errors of metabolism v2.180 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Undiagnosed metabolic disorders v1.486 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Congenital muscular dystrophy v2.16 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Congenital disorders of glycosylation v2.76 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 OMIM:615351; muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 MONDO:0014141; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Ataxia and cerebellar anomalies - narrow panel v2.234 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 OMIM:615350; muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 MONDO:0014140
Rhabdomyolysis and metabolic muscle disorders v1.56 GMPPB Sarah Leigh Tag Q3_21_rating tag was added to gene: GMPPB.
Limb girdle muscular dystrophy v2.25 GMPPB Sarah Leigh reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rhabdomyolysis and metabolic muscle disorders v1.56 GMPPB Sarah Leigh edited their review of gene: GMPPB: Added comment: Associated with relevant phenotype in OMIM, but not associated with the phenotype in Gen2Phen (although it has a confirmed association with OMIM:615350). At least nine variants reported in at least eight cases, supportive functional studies were also presented (PMID 23768512;26133662).; Changed rating: GREEN
Rhabdomyolysis and metabolic muscle disorders v1.56 GMPPB Sarah Leigh Classified gene: GMPPB as Amber List (moderate evidence)
Rhabdomyolysis and metabolic muscle disorders v1.56 GMPPB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Rhabdomyolysis and metabolic muscle disorders v1.56 GMPPB Sarah Leigh Gene: gmppb has been classified as Amber List (Moderate Evidence).
Limb girdle muscular dystrophy v2.25 GMPPB Sarah Leigh Publications for gene: GMPPB were set to 28456886; 27874200; 25681410; 26133662; 23768512
Limb girdle muscular dystrophy v2.24 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Rhabdomyolysis and metabolic muscle disorders v1.55 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142 to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Rhabdomyolysis and metabolic muscle disorders v1.54 GMPPB Sarah Leigh Publications for gene: GMPPB were set to 28456886; 27874200; 25681410; 26133662; 23768512
Congenital disorders of glycosylation v2.75 GMPPB Sarah Leigh Publications for gene: GMPPB were set to 23768512
Limb girdle muscular dystrophy v2.23 GMPPB Sarah Leigh Publications for gene: GMPPB were set to
Limb girdle muscular dystrophy v2.22 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Rhabdomyolysis and metabolic muscle disorders v1.53 GMPPB Sarah Leigh Publications for gene: GMPPB were set to 28456886; 27874200; 25681410
Rhabdomyolysis and metabolic muscle disorders v1.52 GMPPB Sarah Leigh Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 MIM#615352; Limb myalgia; exercise intolerance; myoglobinuria to Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 OMIM:615352; autosomal recessive limb-girdle muscular dystrophy type 2T MONDO:0014142
Intellectual disability v3.1250 KMT2E Arina Puzriakova Added comment: Comment on publications: PMID: 34321323 - 18 additional patients from 17 families with genetically confirmed ODLURO
Intellectual disability v3.1250 KMT2E Arina Puzriakova Publications for gene: KMT2E were set to 31079897
Genetic epilepsy syndromes v2.410 KMT2E Arina Puzriakova Publications for gene: KMT2E were set to 31079897
Intellectual disability v3.1249 MAP1B Arina Puzriakova Tag Q3_21_rating tag was added to gene: MAP1B.
Intellectual disability v3.1249 MAP1B Arina Puzriakova edited their review of gene: MAP1B: Added comment: MAP1B was flagged by a GLH following identification of some potential cases relating to variants in this gene and predominantly ID phenotypes within 100K data. Although these are pending confirmations (will request update once cases are validated), upon reassessment of MAP1B it was highlighted that inclusion on this panels may still be warranted to increase the likelihood of detecting cases, particularly given that DD/ID is more likely to be observed earlier in the course of disease albeit at varying severities.

For this reason, MAP1B should be promoted to Green status at the next GMS panel review (tagged Q3_21_rating); Changed rating: GREEN
Thoracic aortic aneurysm and dissection v1.16 FOXE3 Eleanor Williams Added comment: Comment on mode of inheritance: All cases reported in PMID: 26854927 (Kuang et al 2016) are heterozygous so the MONOALLELIC mode of inheritance is appropriate for the Thoracic aortic aneurysms and acute aortic dissection phenotype.
Thoracic aortic aneurysm and dissection v1.16 FOXE3 Eleanor Williams Mode of inheritance for gene: FOXE3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited white matter disorders v1.138 PI4KA Ivone Leong Classified gene: PI4KA as Green List (high evidence)
Inherited white matter disorders v1.138 PI4KA Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.138 PI4KA Ivone Leong Gene: pi4ka has been classified as Green List (High Evidence).
Inherited white matter disorders v1.137 PI4KA Ivone Leong Tag Q3_21_rating was removed from gene: PI4KA.
Intellectual disability v3.1249 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.233
Intellectual disability v3.1249 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Intellectual disability. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Inherited white matter disorders v1.137 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.233
Inherited white matter disorders v1.137 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Inherited white matter disorders. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
White matter disorders and cerebral calcification - narrow panel v1.198 PI4KA Ivone Leong Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.233
White matter disorders and cerebral calcification - narrow panel v1.198 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Ataxia and cerebellar anomalies - narrow panel v2.233 PI4KA Ivone Leong Tag Q3_21_rating tag was added to gene: PI4KA.
Ataxia and cerebellar anomalies - narrow panel v2.233 PI4KA Ivone Leong Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis , 616531 to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Ataxia and cerebellar anomalies - narrow panel v2.232 PI4KA Ivone Leong Publications for gene: PI4KA were set to 25855803
Ataxia and cerebellar anomalies - narrow panel v2.231 PI4KA Ivone Leong Classified gene: PI4KA as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.231 PI4KA Ivone Leong Gene: pi4ka has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.230 PI4KA Ivone Leong reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25855803, 34415322, 34415310; Phenotypes: ; Mode of inheritance: None
Cerebellar hypoplasia v1.59 PI4KA Ivone Leong Added comment: Comment on publications: PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Cerebellar hypoplasia v1.59 PI4KA Ivone Leong Publications for gene: PI4KA were set to 25855803
Hereditary spastic paraplegia - adult onset v1.72 L1CAM Arina Puzriakova Tag Q3_21_phenotype tag was added to gene: L1CAM.
Hereditary spastic paraplegia - adult onset v1.72 L1CAM Arina Puzriakova commented on gene: L1CAM
Arthrogryposis v3.118 L1CAM Arina Puzriakova Mode of inheritance for gene: L1CAM was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cerebellar hypoplasia v1.58 PI4KA Ivone Leong Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis , 616531 to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Malformations of cortical development v2.61 PI4KA Ivone Leong Tag watchlist tag was added to gene: PI4KA.
Malformations of cortical development v2.61 PI4KA Ivone Leong Classified gene: PI4KA as Amber List (moderate evidence)
Malformations of cortical development v2.61 PI4KA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Malformations of cortical development v2.61 PI4KA Ivone Leong Gene: pi4ka has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.60 PI4KA Ivone Leong Phenotypes for gene: PI4KA were changed from Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531 to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Hereditary spastic paraplegia - adult onset v1.72 GJA1 Arina Puzriakova changed review comment from: Progressive neurological symptoms are occasionally seen in ODDD due to degeneration of the white matter tracts and can include spastic paraplegia. Gait disturbances due to spasticity can be a presenting feature for which patients initially seek medical attention. Typically signs of spasticity arise in adulthood (PMID: 18660473; 22214631; 29927410; 31023660; 33190326; 33612672); however, several adolescent onset cases (PMID: 18660473; 31023660) have also been described and I could only find a single childhood-onset case with spasticity arising at age 8 (PMID: 29927410).

Overall there is enough evidence to rate as Green on both the adult and childhood-onset HSP panels to ensure identification of all cases. >10 unrelated families reported in literature.; to: Progressive neurological symptoms are occasionally seen in ODDD due to degeneration of the white matter tracts and can include spastic paraplegia. Gait disturbances due to spasticity can be a presenting feature for which patients initially seek medical attention. Typically signs of spasticity arise in adulthood (PMID: 18660473; 22214631; 29927410; 31023660; 33190326; 33612672); however, several adolescent onset cases (PMID: 18660473; 31023660) have also been described and I could only find a single childhood-onset case with spasticity arising at age 8 (PMID: 29927410).

Overall there is enough evidence to rate as Green on the adult-onset HSP panel (>10 unrelated families reported in literature). I will seek further clinical opinion with regard to inclusion on the childhood-onset panel given the implications of carrier status being found incidentally for this primarily adult-onset condition.
Hereditary spastic paraplegia - adult onset v1.72 GJA1 Arina Puzriakova Classified gene: GJA1 as Amber List (moderate evidence)
Hereditary spastic paraplegia - adult onset v1.72 GJA1 Arina Puzriakova Gene: gja1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - adult onset v1.71 GJA1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: GJA1.
Hereditary spastic paraplegia - adult onset v1.71 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia - adult onset v1.70 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Hereditary spastic paraplegia; Oculodentodigital dysplasia, MIM#164200 to Oculodentodigital dysplasia, OMIM:164200; Spastic paraplegia
Hereditary spastic paraplegia - adult onset v1.69 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 31023660
Hereditary spastic paraplegia - adult onset v1.68 GJA1 Arina Puzriakova reviewed gene: GJA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18660473, 22214631, 29927410, 31023660, 33190326, 33612672; Phenotypes: Oculodentodigital dysplasia, OMIM:164200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders - adult onset v2.196 SOD1 Ivone Leong Publications for gene: SOD1 were set to 23687121; 24501761; 25439728
Neurodegenerative disorders - adult onset v2.195 SOD1 Ivone Leong Tag Q3_21_MOI tag was added to gene: SOD1.
Neurodegenerative disorders - adult onset v2.195 SOD1 Ivone Leong reviewed gene: SOD1: Rating: ; Mode of pathogenicity: None; Publications: 7647793, 9817920, 7647793, 18608106, 10809943, 12442272, 11284995, 11127534, 23062701, 11220750; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Amyotrophic lateral sclerosis/motor neuron disease v1.39 SOD1 Ivone Leong Phenotypes for gene: SOD1 were changed from Amyotrophic Lateral Sclerosis, Dominant; Amyotrophic lateral sclerosis 1, 105400; amyotrophic lateral sclerosis to Amyotrophic lateral sclerosis 1, OMIM:105400
Amyotrophic lateral sclerosis/motor neuron disease v1.38 SOD1 Ivone Leong Publications for gene: SOD1 were set to 23687121
Amyotrophic lateral sclerosis/motor neuron disease v1.37 SOD1 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal".

PMID: 7647793 identified homozygous variants in SOD1 in 14 affected people from 4 unrelated families (some were consanguineous) from Sweden or Finland with ALS. All affected individuals are homozgyous for the the same variant (D90A). Heterozygous carriers were not affected.

PMID: 9817920 studied 28 pedigrees with D90A from around the world. The authors found that 20 recessive familes have the same founder haplotype as PMID:7647793, regardless of location, and that heterozygous carriers in these families were also unaffected. In the dominant families, 5 were sporadic (no family history of ALS) and 3 were familial and several founders existed for these families. This study shows that D90A can cause disease in a dominant fashion just like all other SOD1 variants.

Recessive inheritance of ALS caused by D90A has also been reported in families from Russia, Germany, Iran, Italy, France, Australia, Canada, and US (PMID: 18608106, 10809943, 12442272, 11284995, 11127534, 23062701).

PMID: 11220750 identified a French family with ALS, where the affected individuals were compound heterozygous for D90A and D96N in SOD1.
Amyotrophic lateral sclerosis/motor neuron disease v1.37 SOD1 Ivone Leong Mode of inheritance for gene: SOD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1248 ASXL3 Arina Puzriakova Publications for gene: ASXL3 were set to 23383720
Intellectual disability v3.1247 ASXL3 Arina Puzriakova Phenotypes for gene: ASXL3 were changed from BAINBRIDGE-ROPERS SYNDROME; BRPS to Bainbridge-Ropers syndrome, OMIM:615485
Palmoplantar keratoderma and erythrokeratodermas v1.20 GJA1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 4 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 20597923, 29902798) none have reported dermal abnormalities. It is possible that these may have been overlooked in the context of other more prominent features of the disorder - but this further emphasises the limited value of this panel for this particular phenotype.

MOI for GJA1 on the GMS Palmoplantar keratodermas (R166) panel was set to 'monoallelic' only in 2019, and so the MOI was updated on this panel to reflect this.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100); to: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 4 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 20597923, 29902798) none have reported dermal abnormalities. It is possible that these may have been overlooked in the context of other more prominent features of the disorder - but this further emphasises the limited value of this panel for this particular phenotype.

MOI for GJA1 on the GMS Palmoplantar keratodermas (R166) panel was set to 'monoallelic' in 2019, and so the MOI was also updated to 'monoallelic' on this panel to reflect this.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)
Palmoplantar keratoderma and erythrokeratodermas v1.20 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratoderma and erythrokeratodermas v1.19 GJA1 Arina Puzriakova Tag Q3_21_MOI was removed from gene: GJA1.
Tag Q3_21_expert_review was removed from gene: GJA1.
Palmoplantar keratoderma and erythrokeratodermas v1.19 GJA1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 3 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 29902798) none have reported dermal abnormalities. However, it is possible that these may have been overlooked in the context of other more prominent features of the disorder.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)

GJA1 will be flagged for GMS expert review to determine whether the MOI should be changed on this panel (tagged).; to: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 4 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 20597923, 29902798) none have reported dermal abnormalities. It is possible that these may have been overlooked in the context of other more prominent features of the disorder - but this further emphasises the limited value of this panel for this particular phenotype.

MOI for GJA1 on the GMS Palmoplantar keratodermas (R166) panel was set to 'monoallelic' only in 2019, and so the MOI was updated on this panel to reflect this.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)
Ichthyosis and erythrokeratoderma v1.66 GJA1 Arina Puzriakova Tag Q3_21_expert_review was removed from gene: GJA1.
Ichthyosis and erythrokeratoderma v1.66 GJA1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 3 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 29902798) none have reported dermal abnormalities. However, it is possible that these may have been overlooked in the context of other more prominent features of the disorder.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)

GJA1 will be flagged for GMS expert review to determine whether the MOI should be changed on this panel (tagged).; to: Comment on mode of inheritance: MOI should be changed from 'both mono- and biallelic' to 'monoallelic' only at the next GMS panel update.

GJA1 was imported to this panel from the 'Palmoplantar keratoderma and erythrokeratodermas' 100K panel and the MOI reflects the mixed inheritance pattern associated with GJA1 oculodentodigital dysplasia (ODDD) (dominant - MIM:164200; recessive - MIM:257850) which can manifest with PPK. Following the uncoupling of PPK and erythrokeratodermas into two separate GMS panels (R165 & R166), only monoallelic variants remain relevant to this particular panel.

Monoallelic variants can cause erythrokeratodermia variabilis et progressiva 3 (MIM: 617525). Erythematous palms and soles have also been described in cases of GJA1-related palmoplantar keratoderma (MIM:104100), also associated with heterozygous variants.
Clefting v2.47 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia,164200; ODDD to Oculodentodigital dysplasia, OMIM:164200
Skeletal dysplasia v2.116 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia 164200; Syndactyly, type III 186100; Erythrokeratodermia variabilis et progressiva 133200; Palmoplantar keratoderma with congenital alopecia 104100; Oculodentodigital dysplasia, autosomal recessive 257850; Craniometaphyseal dysplasia, autosomal recessive 218400; Hypoplastic left heart syndrome 1 241550 to Craniometaphyseal dysplasia, autosomal recessive, OMIM:218400; Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850; Syndactyly, type III, OMIM:186100
Limb disorders v2.57 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Craniometaphyseal dysplasia, autosomal recessive 218400; Erythrokeratodermia variabilis et progressiva 133200; Hypoplastic left heart syndrome 1 241550; Oculodentodigital dysplasia 164200; Oculodentodigital dysplasia, autosomal recessive 257850; Palmoplantar keratoderma with congenital alopecia 104100; Syndactyly, type III 186100 to Craniometaphyseal dysplasia, autosomal recessive, OMIM:218400; Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850; Syndactyly, type III, OMIM:186100
Primary lymphoedema v2.17 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 23550541
Primary lymphoedema v2.16 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia 164200 to Oculodentodigital dysplasia, OMIM:164200
White matter disorders - adult onset v1.30 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia, 164200, Oculodentodigital dysplasia, autosomal recessive, 257850 to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
White matter disorders and cerebral calcification - narrow panel v1.197 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia, autosomal recessive 257850; Oculodentodigital dysplasia (AD) 164200 to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
Inherited white matter disorders v1.136 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia (AD) 164200; Oculodentodigital dysplasia, autosomal recessive 257850 to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
Corneal abnormalities v1.9 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia 164200; Oculodentodigital dysplasia, autosomal recessive 257850 to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
Hearing loss v2.181 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from to Craniometaphyseal dysplasia, autosomal recessive, OMIM:218400
Structural eye disease v1.80 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 15637728; 25976645; 21273537; 30628995; 24508941; 16816024; 29902798
Glaucoma (developmental) v1.38 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 25976645; 21273537
Glaucoma (developmental) v1.37 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital dysplasia; open angle glaucoma (OAG) and microcornea to Oculodentodigital dysplasia, OMIM:164200
Structural eye disease v1.79 GJA1 Arina Puzriakova Publications for gene: GJA1 were set to 15637728; 25976645; 21273537; 30628995; 24508941
Structural eye disease v1.78 GJA1 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: GJA1.
Structural eye disease v1.78 GJA1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'monoallelic' only to 'both mono- and biallelic' at the next GMS panel update.

Ocular abnormalities including microphthalmia and microcornea are reported in GJA1-related oculodentodigital dysplasia, which can be dominantly (MIM:164200) or recessively (MIM:257850) inherited.
Structural eye disease v1.78 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v1.77 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from open angle glaucoma (OAG) and microcornea; Oculodentodigital dysplasia to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
Cataracts v2.78 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Oculodentodigital Dysplasia to Oculodentodigital dysplasia, OMIM:164200; Oculodentodigital dysplasia, autosomal recessive, OMIM:257850
Rare genetic inflammatory skin disorders v1.40 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Palmoplantar keratoderma with congenital alopecia, OMIM:104100; ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 3, OMIM:617525 to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525
Rare genetic inflammatory skin disorders v1.39 GJA1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'both mono- and biallelic' to 'monoallelic' only at the next GMS panel update.

EKVP3 (MIM: 617525) which manifests in transient erythematous patches is associated with monoallelic variants only. Biallelic variants are not pertinent to this panel.
Rare genetic inflammatory skin disorders v1.39 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rare genetic inflammatory skin disorders v1.38 GJA1 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: GJA1.
Pigmentary skin disorders v1.15 GJA1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'both mono- and biallelic' to 'monoallelic' only at the next GMS panel update.

Monoallelic variants can cause EKVP3 (MIM: 617525) which manifests in hyperpigmentation. Erythematous palms and soles have also been described in cases of GJA1-related palmoplantar keratoderma (MIM: 104100), also associated with heterozygous variants. Biallelic variants are not pertinent to this panel.
Pigmentary skin disorders v1.15 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pigmentary skin disorders v1.14 GJA1 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: GJA1.
Ichthyosis and erythrokeratoderma v1.66 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Palmoplantar keratoderma with congenital alopecia, OMIM:104100; Erythrokeratodermia variabilis et progressiva 3, OMIM:617525 to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525; Palmoplantar keratoderma with congenital alopecia, OMIM:104100
Pigmentary skin disorders v1.14 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 3, 617525 to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525; Palmoplantar keratoderma with congenital alopecia, OMIM:104100
Ichthyosis and erythrokeratoderma v1.65 GJA1 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: GJA1.
Tag Q3_21_expert_review tag was added to gene: GJA1.
Ichthyosis and erythrokeratoderma v1.65 GJA1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 3 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 29902798) none have reported dermal abnormalities. However, it is possible that these may have been overlooked in the context of other more prominent features of the disorder.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)

GJA1 will be flagged for GMS expert review to determine whether the MOI should be changed on this panel (tagged).
Ichthyosis and erythrokeratoderma v1.65 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.19 GJA1 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: GJA1.
Tag Q3_21_expert_review tag was added to gene: GJA1.
Palmoplantar keratoderma and erythrokeratodermas v1.19 GJA1 Arina Puzriakova Added comment: Comment on mode of inheritance: MOI was set to 'both mono- and biallelic' in 2017 as PPK has been observed in some patients with oculodentodigital dysplasia (ODDD). Although GJA1-related ODDD can be dominantly (MIM:164200) or recessively (MIM:257850) inherited, of the 3 unrelated families published to date with confirmed recessive ODDD (PMID: 14981729, 16816024, 29902798) none have reported dermal abnormalities. However, it is possible that these may have been overlooked in the context of other more prominent features of the disorder.

Notably, heterozygous variants are also associated with other relevant phenotypes (MIM: 617525 & 104100)

GJA1 will be flagged for GMS expert review to determine whether the MOI should be changed on this panel (tagged).
Palmoplantar keratoderma and erythrokeratodermas v1.19 GJA1 Arina Puzriakova Mode of inheritance for gene: GJA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Palmoplantar keratoderma and erythrokeratodermas v1.18 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Palmoplantar keratoderma with congenital alopecia, 104100; Erythrokeratodermia variabilis et progressiva 3, 617525; Erythrokeratoderma; Palmoplantar keratoderma; Oculodentodigital dysplasia (ODDD) with palmoplantar keratoderma; keratoderma, hypotrichosis and leukonychia to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525; Palmoplantar keratoderma with congenital alopecia, OMIM:104100; Oculodentodigital dysplasia, OMIM:164200
Palmoplantar keratodermas v1.9 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Palmoplantar keratoderma to Erythrokeratodermia variabilis et progressiva 3, OMIM:617525; Palmoplantar keratoderma with congenital alopecia, OMIM:104100; Oculodentodigital dysplasia, OMIM:164200
Hearing loss v2.180 HARS2 Bill Newman reviewed gene: HARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID:34406847, 34338890); Phenotypes: sensorineural hearing loss, primary ovarian insufficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary ovarian insufficiency v1.44 HARS2 Bill Newman reviewed gene: HARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID:34406847, 34338890); Phenotypes: sensorineural hearing loss, primary ovarian insufficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial non syndromic congenital heart disease v1.64 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Hypoplastic left heart syndrome 1; Hypoplastic Left Heart Syndrome to Hypoplastic left heart syndrome 1, OMIM:241550; Atrioventricular septal defect 3, OMIM:600309
Familial cicatricial alopecia v1.3 GJA1 Arina Puzriakova Phenotypes for gene: GJA1 were changed from Palmoplantar keratoderma with congenital alopecia, 104100 to Palmoplantar keratoderma with congenital alopecia, OMIM:104100
Hereditary spastic paraplegia - childhood onset v2.82 SLC25A15 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. Spasticity can be a predominant presenting feature, and inclusion on the adult onset panel would ensure later onset, as well as edge cases are identified. SLC25A15 should be promoted to Green at the next GMS panel update.; to: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. Spasticity can be a predominant presenting feature, particularly in early-onset cases. SLC25A15 should be promoted to Green at the next GMS panel update.
Hereditary spastic paraplegia - childhood onset v2.82 SLC25A15 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - adult onset v1.68
Hereditary spastic paraplegia - childhood onset v2.82 SLC25A15 Arina Puzriakova gene: SLC25A15 was added
gene: SLC25A15 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: SLC25A15.
Mode of inheritance for gene: SLC25A15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A15 were set to 11355015; 16376511; 18978333; 22465082; 28592010; 33314525
Phenotypes for gene: SLC25A15 were set to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Hereditary spastic paraplegia - adult onset v1.68 SLC25A15 Arina Puzriakova Classified gene: SLC25A15 as Amber List (moderate evidence)
Hereditary spastic paraplegia - adult onset v1.68 SLC25A15 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. Spasticity can be a predominant presenting feature, and inclusion on the adult onset panel would ensure later onset, as well as edge cases are identified. SLC25A15 should be promoted to Green at the next GMS panel update.
Hereditary spastic paraplegia - adult onset v1.68 SLC25A15 Arina Puzriakova Gene: slc25a15 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - adult onset v1.67 SLC25A15 Arina Puzriakova Publications for gene: SLC25A15 were set to 16376511; 22465082; 28592010
Hereditary spastic paraplegia - adult onset v1.66 SLC25A15 Arina Puzriakova Tag Q3_21_rating tag was added to gene: SLC25A15.
Hereditary spastic paraplegia - adult onset v1.66 SLC25A15 Arina Puzriakova reviewed gene: SLC25A15: Rating: GREEN; Mode of pathogenicity: None; Publications: 11355015, 16376511, 18978333, 22465082, 33314525; Phenotypes: Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.179 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970; HHH syndrome (Urea cycle disorders and inherited hyperammonaemias) to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970; HHH syndrome (Urea cycle disorders and inherited hyperammonaemias)
Hereditary spastic paraplegia - adult onset v1.66 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome MIM#238970 to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Intellectual disability v3.1246 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 -3; HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME (HHH SYNDROME) to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Undiagnosed metabolic disorders v1.485 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from HHH syndrome (Urea cycle disorders and inherited hyperammonaemias); Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970; HHH syndrome (Urea cycle disorders and inherited hyperammonaemias)
Hyperammonaemia v1.12 SLC25A15 Arina Puzriakova Phenotypes for gene: SLC25A15 were changed from Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, 238970 to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Severe microcephaly v2.220 TRAPPC10 Aleš Maver gene: TRAPPC10 was added
gene: TRAPPC10 was added to Severe microcephaly. Sources: Other
Mode of inheritance for gene: TRAPPC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC10 were set to PMID: 30167849
Penetrance for gene: TRAPPC10 were set to Complete
Review for gene: TRAPPC10 was set to RED
Added comment: This gene was originally reported in association with microcephalic NDD in PMID:30167849 (biallelic missense variant) and was replicated in a large family consanguineous family with a biallelic frameshift variant - reported at the ESHG2021 conference, talk C16.4 by Rawlins).
Sources: Other
Peroxisomal disorders v1.15 PEX6 Ivone Leong Phenotypes for gene: PEX6 were changed from Peroxisome biogenesis disorder 4A (Zellweger) 614862; Peroxisome biogenesis disorder 4B 614863 to Peroxisome biogenesis disorder 4A (Zellweger), OMIM:614862; Peroxisome biogenesis disorder 4B, OMIM:614863
Peroxisomal disorders v1.14 PEX6 Ivone Leong Publications for gene: PEX6 were set to
Unexplained kidney failure in young people v1.96 TRIM8 Ivone Leong Publications for gene: TRIM8 were set to 33508234
Unexplained kidney failure in young people v1.95 TRIM8 Ivone Leong Classified gene: TRIM8 as Green List (high evidence)
Unexplained kidney failure in young people v1.95 TRIM8 Ivone Leong Added comment: Comment on list classification: New gene added by Julia Baptista (Royal Devon and Exeter NHS Foundation Trust). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Unexplained kidney failure in young people v1.95 TRIM8 Ivone Leong Gene: trim8 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.94 TRIM8 Ivone Leong Phenotypes for gene: TRIM8 were changed from nephrotic syndrome; epilepsy to nephrotic syndrome; epilepsy; Fo