Activity

Date Panel Item Activity
3000 actions
Limb disorders v2.49 TBX4 Ivone Leong Phenotypes for gene: TBX4 were changed from Ischiocoxopodopatellar syndrome 147891 to Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891
Pulmonary arterial hypertension v2.16 TBX4 Ivone Leong Phenotypes for gene: TBX4 were changed from Ischiocoxopodopatellar syndrome, 147891; Small patella syndrome; SPS; Idiopathic pulmonary arterial hypertension; IPAH; Heritable pulmonary arterial hypertension; HPAH; Pulmonary arterial hypertension to Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891
Fetal anomalies v1.700 TBX4 Ivone Leong Phenotypes for gene: TBX4 were changed from SMALL PATELLA SYNDROME to Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891
Skeletal dysplasia v2.113 TBX4 Ivone Leong Phenotypes for gene: TBX4 were changed from Ischiocoxopodopatellar syndrome 147891; Ischiocoxopodopatellar syndrome 147891 to Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension, OMIM:147891
Retinal disorders v2.194 TSPAN12 Ivone Leong Phenotypes for gene: TSPAN12 were changed from Eye Disorders to Eye Disorders; Exudative vitreoretinopathy 5, OMIM:613310
Lipoprotein lipase deficiency v1.16 APOB Ivone Leong Tag Q3_21_NHS_review was removed from gene: APOB.
Lipoprotein lipase deficiency v1.16 APOB Ivone Leong Tag Q3_21_NHS_review tag was added to gene: APOB.
Primary lymphoedema v2.15 TIE1 Ivone Leong Tag watchlist tag was added to gene: TIE1.
Primary lymphoedema v2.15 TIE1 Ivone Leong Classified gene: TIE1 as Amber List (moderate evidence)
Primary lymphoedema v2.15 TIE1 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. Based on the expert review this gene has been given an Amber rating until more evidence is available.
Primary lymphoedema v2.15 TIE1 Ivone Leong Gene: tie1 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v2.14 TIE1 Ivone Leong Phenotypes for gene: TIE1 were changed from Lymphatic malformation 11, MIM# 619401 to Lymphatic malformation 11, OMIM:619401
Fetal anomalies v1.699 TWIST2 Ivone Leong Added comment: Comment on phenotypes: Also associated with Focal facial dermal dysplasia 3, Setleis type, OMIM:227260
Fetal anomalies v1.699 TWIST2 Ivone Leong Phenotypes for gene: TWIST2 were changed from ABLEPHARON MACROSTOMIA SYNDROME; SETLEIS SYNDROME; Ablepharon-macrostomia syndrome, 200110; Barber-Say syndrome, 209885 to Ablepharon-macrostomia syndrome, 200110; Barber-Say syndrome, 209885
DDG2P v2.40 TWIST2 Ivone Leong Phenotypes for gene: TWIST2 were changed from ABLEPHARON MACROSTOMIA SYNDROME 200110; SETLEIS SYNDROME 227260 to ABLEPHARON MACROSTOMIA SYNDROME, OMIM:200110; Focal facial dermal dysplasia 3, Setleis type, OMIM:227260
Familial Tumours Syndromes of the central & peripheral Nervous system v1.10 VHL Ivone Leong Phenotypes for gene: VHL were changed from Von Hippel-Lindau Syndrome; von Hippel-Lindau syndrome, 193300; Renal cell carcinoma, somatic, 144700; Pheochromocytoma, 171300; Hemangioblastoma, cerebellar, somatic; Erythrocytosis, familial, 2, 263400 to von Hippel-Lindau syndrome, OMIM:193300; Pheochromocytoma, OMIM:171300; Hemangioblastoma, cerebellar, somatic
Multiple endocrine tumours v1.13 VHL Ivone Leong Phenotypes for gene: VHL were changed from Endocrine Cancer; Pheochromocytoma, OMIM:171300; von Hippel-Lindau syndrome, OMIM:193300 to Endocrine Cancer; Pheochromocytoma, OMIM:171300; von Hippel-Lindau syndrome, OMIM:193300; Paragangliomas, MONDO:0000448
Multiple endocrine tumours v1.12 VHL Ivone Leong Added comment: Comment on phenotypes: Previously:
Endocrine Cancer; Paragangliomas 1, with or without deafness, 168000; Pheochromocytoma, 171300; Carcinoid tumors, intestinal, 114900; Merkel cell carcinoma, somatic; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 3, 615106
Multiple endocrine tumours v1.12 VHL Ivone Leong Phenotypes for gene: VHL were changed from Endocrine Cancer; Paragangliomas 1, with or without deafness, 168000; Pheochromocytoma, 171300; Carcinoid tumors, intestinal, 114900; Merkel cell carcinoma, somatic; Paraganglioma and gastric stromal sarcoma, 606864; Cowden syndrome 3, 615106 to Endocrine Cancer; Pheochromocytoma, OMIM:171300; von Hippel-Lindau syndrome, OMIM:193300
Inherited phaeochromocytoma and paraganglioma v1.9 VHL Ivone Leong Phenotypes for gene: VHL were changed from Pheochromocytoma, OMIM:171300 to Pheochromocytoma, OMIM:171300; von Hippel-Lindau syndrome, OMIM:193300
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.19 VHL Ivone Leong Phenotypes for gene: VHL were changed from Pheochromocytoma, OMIM:171300 to Pheochromocytoma, OMIM:171300; von Hippel-Lindau syndrome, OMIM:193300
Inherited phaeochromocytoma and paraganglioma v1.8 VHL Ivone Leong Publications for gene: VHL were set to
Inherited phaeochromocytoma and paraganglioma v1.7 VHL Ivone Leong Phenotypes for gene: VHL were changed from von Hippel-Lindau syndrome, 193300Renal cell carcinoma, somatic, 144700Pheochromocytoma, 171300Hemangioblastoma, cerebellar, somaticErythrocytosis, familial, 2, 263400 to Pheochromocytoma, OMIM:171300
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.18 VHL Ivone Leong Phenotypes for gene: VHL were changed from von Hippel-Lindau syndrome, 193300Renal cell carcinoma, somatic, 144700Pheochromocytoma, 171300Hemangioblastoma, cerebellar, somaticErythrocytosis, familial, 2, 263400 to Pheochromocytoma, OMIM:171300
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.17 VHL Ivone Leong Publications for gene: VHL were set to
Inborn errors of metabolism v2.155 VKORC1 Ivone Leong Phenotypes for gene: VKORC1 were changed from Vitamin K epoxide reductase deficiency (Other disorders of vitamins and cofactors); Inherited bleeding disorders to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473
Undiagnosed metabolic disorders v1.470 VKORC1 Ivone Leong Phenotypes for gene: VKORC1 were changed from Vitamin K epoxide reductase deficiency (Other disorders of vitamins and cofactors); Inherited bleeding disorders to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473
Inherited bleeding disorders v1.164 VKORC1 Ivone Leong Phenotypes for gene: VKORC1 were changed from Multiple coagulation factor deficiency type 2 to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473
Bleeding and platelet disorders v1.31 VKORC1 Ivone Leong Phenotypes for gene: VKORC1 were changed from 607473 Vitamin K-dependent clotting factors, combined deficiency of, 2; 122700 Warfarin resistance to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473; Warfarin resistance, OMIM:122700
Hereditary spastic paraplegia v1.229 WASHC5 Ivone Leong Publications for gene: WASHC5 were set to Valdmanis et al. (2007)
Hereditary spastic paraplegia v1.228 WASHC5 Ivone Leong Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant to Spastic paraplegia 8, autosomal dominant, OMIM:603563
Hereditary spastic paraplegia - childhood onset v2.47 WASHC5 Ivone Leong Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563 to Spastic paraplegia 8, autosomal dominant, OMIM:603563
Hereditary spastic paraplegia - adult onset v1.25 WASHC5 Ivone Leong Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563 to Spastic paraplegia 8, autosomal dominant, OMIM:603563
Gastrointestinal neuromuscular disorders v1.15 RAD21 Zornitza Stark gene: RAD21 was added
gene: RAD21 was added to Gastrointestinal neuromuscular disorders. Sources: Expert Review
Mode of inheritance for gene: RAD21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD21 were set to 14638363; 32193685; 25575569
Phenotypes for gene: RAD21 were set to Mungan syndrome, MIM# 611376
Review for gene: RAD21 was set to GREEN
Added comment: Mono-allelic variants are associated with CdL but bi-allelic variants are associated with Mungan syndrome, which includes pseudo-obstruction.
Sources: Expert Review
Gastrointestinal neuromuscular disorders v1.15 L1CAM Zornitza Stark reviewed gene: L1CAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 9279760, 11857550, 15148591, 15368500, 22354677; Phenotypes: Hydrocephalus with Hirschsprung disease or congenital idiopathic intestinal pseudoobstruction MIM#307000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency v2.452 RGS10 Boaz Palterer gene: RGS10 was added
gene: RGS10 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: RGS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS10 were set to 34315806
Phenotypes for gene: RGS10 were set to short stature; GH deficiency; immunodeficiency; hypergammaglobulinemia; reduced lymphocyte chemotaxis
Penetrance for gene: RGS10 were set to unknown
Review for gene: RGS10 was set to AMBER
Added comment: Chinn et al. a kindred with three affected siblings presenting with short stature and immunodeficiency and segregating with biallelic variants in RGS10 (c.489_491del:p.E163del and c.G511T:p.A171S). The affected individuals exhibited systemic abnormalities directly related to the RGS10 mutations, including recurrent infections, hypergammaglobulinemia, profoundly reduced lymphocyte chemotaxis, abnormal lymph node architecture, and short stature due to growth hormone deficiency. Some functional data is presented.
Sources: Literature
Primary immunodeficiency v2.452 ELF4 Boaz Palterer reviewed gene: ELF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Inflammatory bowel disease, IBD, mucosal inflammation, fever, ulcers, Behcet-like disease; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Malformations of cortical development v2.46 DPYSL5 Ivone Leong Entity copied from Intellectual disability v3.1214
Malformations of cortical development v2.46 DPYSL5 Ivone Leong gene: DPYSL5 was added
gene: DPYSL5 was added to Malformations of cortical development. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: DPYSL5.
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Ataxia and cerebellar anomalies - narrow panel v2.223 DPYSL5 Ivone Leong Entity copied from Intellectual disability v3.1214
Ataxia and cerebellar anomalies - narrow panel v2.223 DPYSL5 Ivone Leong gene: DPYSL5 was added
gene: DPYSL5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: DPYSL5.
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Gastrointestinal neuromuscular disorders v1.15 ACTA2 Zornitza Stark gene: ACTA2 was added
gene: ACTA2 was added to Gastrointestinal neuromuscular disorders. Sources: Expert Review
Mode of inheritance for gene: ACTA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTA2 were set to 20734336; 29300374
Phenotypes for gene: ACTA2 were set to Multisystemic smooth muscle dysfunction syndrome, MIM# 613834
Review for gene: ACTA2 was set to GREEN
gene: ACTA2 was marked as current diagnostic
Added comment: Multisystemic smooth muscle dysfunction syndrome (MSMDS) presents with a recognizable pattern of complications, including congenital mydriasis, patent ductus arteriosus (PDA), pulmonary artery hypertension, aortic and other arterial aneurysms, moyamoya-like cerebrovascular disease, intestinal hypoperistalsis and malrotation, and hypotonic bladder.

More than 40 unrelated individuals reported, missense at p.Arg179 position.
Sources: Expert Review
Intellectual disability v3.1214 COG4 Arina Puzriakova Publications for gene: COG4 were set to 25529582
Intellectual disability v3.1213 COG4 Arina Puzriakova Added comment: Comment on mode of inheritance: Early developmental delay (speech and motor) can be a feature of Saul-Wilson syndrome (monoallelic inheritance), however cognition is normal. Therefore, the monoallelic form is not pertinent to this panel and the MOI should remain as biallelic only which is associated with CDG-IIj, including psychomotor retardation.
Intellectual disability v3.1213 COG4 Arina Puzriakova Mode of inheritance for gene: COG4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1212 COG4 Arina Puzriakova Tag for-review was removed from gene: COG4.
Genetic epilepsy syndromes v2.400 COG4 Arina Puzriakova Phenotypes for gene: COG4 were changed from to Congenital disorder of glycosylation, type IIj, OMIM:613489
Genetic epilepsy syndromes v2.399 COG4 Arina Puzriakova Mode of inheritance for gene: COG4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.112 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, 615220 to {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, OMIM:615220
Osteogenesis imperfecta v2.18 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, 615220; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221 to Osteogenesis imperfecta, type XV, OMIM:615220; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221
Osteogenesis imperfecta v2.17 WNT1 Ivone Leong Publications for gene: WNT1 were set to 23434763; 2349931
Osteogenesis imperfecta v2.16 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from Osteogenesis imperfecta, type XV, 615220; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221; osteogenesis imperfecta to Osteogenesis imperfecta, type XV, 615220; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221
Osteogenesis imperfecta v2.15 WNT1 Ivone Leong Publications for gene: WNT1 were set to PMID: 23434763; 2349931
Skeletal dysplasia v2.111 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from osteogenesis imperfecta; OI/osteoporosis; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221; Osteogenesis imperfecta, type XV, 615220 to {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, 615220
Fetal anomalies v1.698 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from OSTEOGENESIS IMPERFECTA to Osteogenesis imperfecta, type XV, OMIM:615220
Intellectual disability v3.1212 MYCN Ivone Leong Publications for gene: MYCN were set to 21224895; 8470948
Intellectual disability v3.1211 MYCN Ivone Leong Phenotypes for gene: MYCN were changed from Feingold syndrome, 164280; FEINGOLD SYNDROME TYPE 1 to Feingold syndrome 1, OMIM:164280
Intellectual disability v3.1210 MYCN Ivone Leong Publications for gene: MYCN were set to
Intellectual disability v3.1209 PTPN4 Ivone Leong Classified gene: PTPN4 as Amber List (moderate evidence)
Intellectual disability v3.1209 PTPN4 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. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1209 PTPN4 Ivone Leong Gene: ptpn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1209 PTPN4 Ivone Leong Classified gene: PTPN4 as Amber List (moderate evidence)
Intellectual disability v3.1209 PTPN4 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. Based on the expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1209 PTPN4 Ivone Leong Gene: ptpn4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1208 PTPN4 Ivone Leong Tag Q3_21_rating tag was added to gene: PTPN4.
Ectodermal dysplasia v1.26 CDSN Arina Puzriakova Phenotypes for gene: CDSN were changed from hypotrichosis simplex of the scalp; HYPT2; Hypotrichosis 2, 146520 to Hypotrichosis 2, OMIM:146520
Non-syndromic hypotrichosis v1.9 CDSN Arina Puzriakova Phenotypes for gene: CDSN were changed from hypotrichosis simplex of the scalp; Hypotrichosis 2, 146520; HYPT2 to Hypotrichosis 2, OMIM:146520
Adult solid tumours cancer susceptibility v2.14 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Thyroid cancer; Pituitary adenoma to Multiple endocrine neoplasia, type IV, OMIM:610755; Thyroid cancer; Pituitary adenoma
Endocrine neoplasms v1.23 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Endocrine Cancer; Multiple Endocrine Neoplasia; Multiple endocrine neoplasia, type IV, 610755 to Multiple endocrine neoplasia, type IV, OMIM:610755
Multiple endocrine tumours v1.11 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Multiple endocrine neoplasia, type IV, 610755; Multiple Endocrine Neoplasia; Endocrine Cancer to Multiple endocrine neoplasia, type IV, OMIM:610755
Familial hyperparathyroidism v2.14 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Multiple endocrine neoplasia, type IV (610755) to Multiple endocrine neoplasia, type IV, OMIM:610755
Adult solid tumours for rare disease v1.25 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Thyroid cancer; Pituitary adenoma to Multiple endocrine neoplasia, type IV, OMIM:610755; Thyroid cancer; Pituitary adenoma
Neuroendocrine cancer pertinent cancer susceptibility v1.2 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Neuroendocrine cancer to Multiple endocrine neoplasia, type IV, OMIM:610755
Parathyroid Cancer v1.4 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Pituitary Cancer, Parathyroid and Hypercalcemia to Multiple endocrine neoplasia, type IV, OMIM:610755; Pituitary Cancer, Parathyroid and Hypercalcemia
Thyroid cancer pertinent cancer susceptibility v1.2 CDKN1B Arina Puzriakova Phenotypes for gene: CDKN1B were changed from Thyroid cancer; Pituitary adenoma to Multiple endocrine neoplasia, type IV, OMIM:610755; Thyroid cancer; Pituitary adenoma
Thyroid cancer pertinent cancer susceptibility v1.1 CDKN1B Arina Puzriakova Mode of inheritance for gene: CDKN1B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy NOT PMP22 copy number v1.34 GSN Ivone Leong Tag Q3_21_rating tag was added to gene: GSN.
Hereditary neuropathy NOT PMP22 copy number v1.34 GSN Ivone Leong Classified gene: GSN as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.34 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. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hereditary neuropathy NOT PMP22 copy number v1.34 GSN Ivone Leong Gene: gsn has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.33 GSN Ivone Leong Phenotypes for gene: GSN were changed from Amyloidosis; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy; arrhytmia to Amyloidosis, Finnish type, OMIM:105120; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy, MONDO:0004994; arrhythmia
Hereditary neuropathy NOT PMP22 copy number v1.32 GSN Ivone Leong Publications for gene: GSN were set to PMID: 33499149; 26339870
Hereditary neuropathy NOT PMP22 copy number v1.31 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Encephalopathy, progressive, with or without lipodystrophy, 615924; Silver spastic paraplegia syndrome 270685 to Neuropathy, distal hereditary motor, type VC, OMIM:619112
Hereditary neuropathy v1.389 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Neuropathy, distal hereditary motor, type VA 600794; Encephalopathy, progressive, with or without lipodystrophy, 615924; Lipodystrophy, congenital generalized, type 2 269700; Silver spastic paraplegia syndrome 270685 to Neuropathy, distal hereditary motor, type VC, OMIM:619112
Hereditary spastic paraplegia - adult onset v1.24 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, 270685 to Silver spastic paraplegia syndrome, OMIM:270685
Hereditary spastic paraplegia - childhood onset v2.46 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, 270685 to Silver spastic paraplegia syndrome, OMIM:270685
Hereditary spastic paraplegia v1.227 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, to Silver spastic paraplegia syndrome, OMIM:270685
Intellectual disability v3.1208 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924; Lipodystrophy, congenital generalized, type 2, OMIM:269700
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: BSCL2.
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Added comment: Comment on mode of inheritance: Monoallelic variants lead to a motor neuropathy (MIM# 619112) or spastic paraplegia (MIM# 270685) presentation, both characterised by motor symptoms, but neither are associated with any cognitive deficits. On the other hand, biallelic variants cause encephalopathy (MIM# 615924) or generalised lipodystrophy (MIM# 269700) which do include cognitive decline and intellectual impairment, respectively.

Therefore, the MOI should be changed from 'Both mono- and biallelic' to 'Biallelic' only at the next GMS panel review.
Intellectual disability v3.1207 BSCL2 Arina Puzriakova Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Craniosynostosis v2.50 RNU12 Eleanor Williams Classified gene: RNU12 as Amber List (moderate evidence)
Craniosynostosis v2.50 RNU12 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. It could be promoted to green after GMS review as there are 3 unrelated cases with a craniosynostosis phenotype. However, variants in this gene would not currently be reported as it is not a protein coding gene. An Ensembl ID also needs to be added before it is promoted to green.
Craniosynostosis v2.50 RNU12 Eleanor Williams Gene: rnu12 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.49 RNU12 Eleanor Williams Tag Q3_21_rating tag was added to gene: RNU12.
Tag Q3_21_expert_review tag was added to gene: RNU12.
Genetic epilepsy syndromes v2.398 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Intractable epilepsy and neurological regression; Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924
Craniosynostosis v2.49 RNU12 Eleanor Williams Tag currently-ngs-unreportable tag was added to gene: RNU12.
Monogenic diabetes v2.43 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Berardinelli-Seip congenital lipodystrophy; Lipodystrophy, congenital generalized, type 2, 269700 to Lipodystrophy, congenital generalized, type 2, OMIM:269700
Lipodystrophy - childhood onset v2.16 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Lipodystrophy, congenital generalized, type 2, 269700 to Lipodystrophy, congenital generalized, type 2, OMIM:269700; Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924
Insulin resistance (including lipodystrophy) v1.13 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Lipodystrophy, congenital generalized, type 2, 269700 to Lipodystrophy, congenital generalized, type 2, OMIM:269700; Encephalopathy, progressive, with or without lipodystrophy, OMIM:615924
Familial diabetes v1.62 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Berardinelli-Seip congenital lipodystrophy to Lipodystrophy, congenital generalized, type 2, OMIM:269700
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.63 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Berardinelli-Seip congenital lipodystrophy to Lipodystrophy, congenital generalized, type 2, OMIM:269700
Genetic epilepsy syndromes v2.397 DLL1 Arina Puzriakova Tag Q3_21_rating was removed from gene: DLL1.
Tag for-review tag was added to gene: DLL1.
Primary immunodeficiency v2.452 LAMTOR2 Zornitza Stark reviewed gene: LAMTOR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 17195838, 24092934; Phenotypes: Immunodeficiency due to defect in MAPBP-interacting protein, MIM# 610798; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v2.49 RNU12 Eleanor Williams Phenotypes for gene: RNU12 were changed from CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations to CDAGS syndrome, OMIM:603116; craniosynostosis-anal anomalies-porokeratosis syndrome, MONDO:001128
Craniosynostosis v2.48 RNU12 Eleanor Williams edited their review of gene: RNU12: Changed phenotypes to: CDAGS syndrome, OMIM:603116, craniosynostosis-anal anomalies-porokeratosis syndrome, MONDO:0011287
Craniosynostosis v2.48 RNU12 Eleanor Williams reviewed gene: RNU12: Rating: ; Mode of pathogenicity: None; Publications: 34085356; Phenotypes: CDAGS syndrome, OMIM:603116; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.48 LTBP1 Eleanor Williams Tag Q3_21_rating tag was added to gene: LTBP1.
Limb disorders v2.48 LTBP1 Eleanor Williams Classified gene: LTBP1 as Amber List (moderate evidence)
Limb disorders v2.48 LTBP1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. Individuals from 3 unrelated families reported with brachydactyly as part of a broader phenotype.
Limb disorders v2.48 LTBP1 Eleanor Williams Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.47 LTBP1 Eleanor Williams gene: LTBP1 was added
gene: LTBP1 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to Cutis laxa, autosomal recessive, type IIE, OMIM:619451; Brachydactyly, HP:0001156; Clinodactyly, HP:0030084; Syndactyly, HP:0001159
Review for gene: LTBP1 was set to GREEN
Added comment: Associated with Cutis laxa, autosomal recessive, type IIE #619451 (AR) in OMIM.

PMID: 33991472 - Pottie et al 2021 - report 8 individuals from 4 unrelated consanguineous families with 4 different homozygous premature truncating LTBP1 variants. Core clinical features include cutis laxa, craniosynostosis, a copper beaten calvarium, short stature, and discernible craniofacial characteristics. Brachydactyly was noted in 7/8 individuals, Clinodactyly in 7/8 individuals and Syndactyly in 5/8 individuals.
Sources: Literature
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams changed review comment from: Short stature was noted in 8/8 (100%) of the patients reported in PMID:33991472; to: Short stature was noted in 8/8 (100%) and Genua vara (bow-leggedness) in 3/8 (37.5) of the patients reported in PMID:33991472
Ehlers Danlos syndromes v2.63 LTBP1 Eleanor Williams Classified gene: LTBP1 as Amber List (moderate evidence)
Ehlers Danlos syndromes v2.63 LTBP1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber with a recommendation for green rating following GMS review. 3 families reported where joint hyperlaxity is noted.
Ehlers Danlos syndromes v2.63 LTBP1 Eleanor Williams Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Ehlers Danlos syndromes v2.62 LTBP1 Eleanor Williams Phenotypes for gene: LTBP1 were changed from Cutis laxa; craniofacial dysmorphism; altered skeletal development, including short stature; brachydactyly; clinodactyly to Cutis laxa, autosomal recessive, type IIE, OMIM:619451; Joint hyperlaxity
Ehlers Danlos syndromes v2.61 LTBP1 Eleanor Williams Publications for gene: LTBP1 were set to PMID: 33991472
Ehlers Danlos syndromes v2.60 LTBP1 Eleanor Williams Tag Q3_21_rating tag was added to gene: LTBP1.
Ehlers Danlos syndromes v2.60 LTBP1 Eleanor Williams edited their review of gene: LTBP1: Changed rating: GREEN; Changed publications to: 33991472; Changed phenotypes to: Cutis laxa, autosomal recessive, type IIE, OMIM:619451, Joint hyperlaxity; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndromes v2.60 LTBP1 Eleanor Williams commented on gene: LTBP1
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams commented on gene: LTBP1: Short stature was noted in 8/8 (100%) of the patients reported in PMID:33991472
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype added 28-07-2021
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams Phenotypes for gene: LTBP1 were changed from inherited cutis laxa MONDO:0100237 to inherited cutis laxa MONDO:0100237; Cutis laxa, autosomal recessive, type IIE, OMIM:619451
Craniosynostosis v2.48 LTBP1 Eleanor Williams Tag Q3_21_rating tag was added to gene: LTBP1.
Craniosynostosis v2.48 LTBP1 Eleanor Williams Classified gene: LTBP1 as Amber List (moderate evidence)
Craniosynostosis v2.48 LTBP1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis in 6/8 individuals
Craniosynostosis v2.48 LTBP1 Eleanor Williams Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.47 LTBP1 Eleanor Williams Phenotypes for gene: LTBP1 were changed from Craniosynostosis; cutis laxa; intelectual disability to Cutis laxa, autosomal recessive, type IIE, OMIM:619451; craniosynostosis, MONDO:0015469
Craniosynostosis v2.46 LTBP1 Eleanor Williams edited their review of gene: LTBP1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v2.46 LTBP1 Eleanor Williams reviewed gene: LTBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33991472; Phenotypes: Cutis laxa, autosomal recessive, type IIE, OMIM:619451, craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Craniosynostosis v2.46 CHD7 Eleanor Williams Classified gene: CHD7 as Amber List (moderate evidence)
Craniosynostosis v2.46 CHD7 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommedation of green rating following GMS review. 3 cases reported with a craniosynostosis phenotype and supported model organism data, although incomplete penetrance is noted.
Craniosynostosis v2.46 CHD7 Eleanor Williams Gene: chd7 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.45 CHD7 Eleanor Williams Phenotypes for gene: CHD7 were changed from craniosynostosis to CHARGE syndrome, OMIM:214800; CHARGE syndrome, MONDO:0008965
Craniosynostosis v2.44 CHD7 Eleanor Williams Publications for gene: CHD7 were set to 33844462; 30498854; 33288889
Craniosynostosis v2.43 CHD7 Eleanor Williams Tag Q3_21_rating tag was added to gene: CHD7.
Tag Q3_21_NHS_review tag was added to gene: CHD7.
Craniosynostosis v2.43 CHD7 Eleanor Williams reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: 33844462, 30498854, 33288889, 24975120, 22363697; Phenotypes: CHARGE syndrome, OMIM:214800, CHARGE syndrome, MONDO:0008965; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Craniosynostosis v2.43 ZNF462 Eleanor Williams Classified gene: ZNF462 as Amber List (moderate evidence)
Craniosynostosis v2.43 ZNF462 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. Metopic ridging or craniosynostosis reported in 6 cases with a plausible disease causing variant in ZNF462.
Craniosynostosis v2.43 ZNF462 Eleanor Williams Gene: znf462 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.42 ZNF462 Eleanor Williams Phenotypes for gene: ZNF462 were changed from Weiss-Kruszka syndrome, MIM# 618619 to Weiss-Kruszka syndrome, OMIM:618619; weiss-kruszka syndrome, MONDO:0032836
Craniosynostosis v2.41 ZNF462 Eleanor Williams Publications for gene: ZNF462 were set to 28513610
Craniosynostosis v2.40 ZNF462 Eleanor Williams Tag Q3_21_rating tag was added to gene: ZNF462.
Craniosynostosis v2.40 ZNF462 Eleanor Williams reviewed gene: ZNF462: Rating: GREEN; Mode of pathogenicity: None; Publications: 28513610, 31361404; Phenotypes: Weiss-Kruszka syndrome, OMIM:618619, weiss-kruszka syndrome, MONDO:0032836; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.697 SMAD3 Eleanor Williams commented on gene: SMAD3
Ehlers Danlos syndromes v2.60 SMAD3 Eleanor Williams commented on gene: SMAD3: Note one case with a biallelic variant reported:
PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected.
Skeletal dysplasia v2.109 SMAD3 Eleanor Williams commented on gene: SMAD3: Note one case with a biallelic variant reported:
PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected.
Arthrogryposis v3.113 SMAD3 Eleanor Williams commented on gene: SMAD3
Thoracic aortic aneurysm or dissection v1.121 SMAD3 Eleanor Williams commented on gene: SMAD3
Thoracic aortic aneurysm and dissection v1.15 SMAD3 Eleanor Williams commented on gene: SMAD3
Hereditary neuropathy v1.388 KIF1A Dmitrijs Rots reviewed gene: KIF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SPASTIC PARAPLEGIA 30, NESCAV SYNDROME; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Craniosynostosis v2.40 SMAD3 Eleanor Williams changed review comment from: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature.

PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis.

PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given.

Looking at reported phenotypes for LDS patients with a SMAD3 variant:
PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant.

PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned.; to: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature.

PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis.

PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given.

Looking at reported phenotypes for LDS patients with a SMAD3 variant and craniosynostosis phenotype:
PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant.

PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned.
Craniosynostosis v2.40 SMAD3 Eleanor Williams reviewed gene: SMAD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 29392890, 31569402, 32935439; Phenotypes: Loeys-Dietz syndrome 3 OMIM:613795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1206 DLL1 Arina Puzriakova Phenotypes for gene: DLL1 were changed from Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis to Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, OMIM:618709
Genetic epilepsy syndromes v2.397 DLL1 Arina Puzriakova Phenotypes for gene: DLL1 were changed from Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis to Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, OMIM:618709
Genetic epilepsy syndromes v2.396 DLL1 Arina Puzriakova Tag Q3_21_rating tag was added to gene: DLL1.
Fetal anomalies v1.697 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600 to Acromesomelic dysplasia, Demirhan type, OMIM:609441
Fetal anomalies v1.696 BMPR1B Arina Puzriakova Added comment: 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.
Fetal anomalies v1.696 BMPR1B Arina Puzriakova Mode of inheritance for gene: BMPR1B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.695 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from BRACHYDACTYLY TYPE A2 to Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600
Limb disorders v2.46 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from Acromesomelic dysplasia, Demirhan type, 609441; Brachydactyly, type A1, D 616849; Brachydactyly, type A2, 112600 to Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600
Intellectual disability v3.1205 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from Brachydactyly, type A2, 112600; Chrondrodysplasia, acromesomelic, with genital anomalies, 609441 to Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600
Skeletal dysplasia v2.109 BMPR1B Arina Puzriakova Phenotypes for gene: BMPR1B were changed from Brachydactyly, type A1, D 616849; Brachydactyly, type A2 112600; Acromesomelic dysplasia, Demirhan type 609441 to Acromesomelic dysplasia, Demirhan type, OMIM:609441; Brachydactyly, type A1, D, OMIM:616849; Brachydactyly, type A2, OMIM:112600
Intellectual disability v3.1204 BMPR1B Arina Puzriakova Mode of inheritance for gene: BMPR1B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1203 PTPN4 Ivone Leong Phenotypes for gene: PTPN4 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Primary immunodeficiency v2.452 CXCR2 Arina Puzriakova Phenotypes for gene: CXCR2 were changed from WHIM syndrome 2 619407 to WHIM syndrome 2, OMIM:619407
Intellectual disability v3.1202 PTPN4 Ivone Leong Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Primary immunodeficiency v2.451 CXCR2 Arina Puzriakova Classified gene: CXCR2 as Red List (low evidence)
Primary immunodeficiency v2.451 CXCR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Only a single family with variants in this gene and WHIM syndrome described to date. Rating Red until further evidence emerges.
Primary immunodeficiency v2.451 CXCR2 Arina Puzriakova Gene: cxcr2 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.450 PLG Arina Puzriakova Tag founder-effect was removed from gene: PLG.
Primary immunodeficiency v2.450 PLG Arina Puzriakova changed review comment from: Comment on list classification: Discussed with Helen Brittain (Genomics England Clinical Team) regarding the founder effect and reduced penetrance associated with the angioedema-specific variant (c.988A>G, p.K330E) in this gene - 'it goes slightly against our usual rule of needing another source to corroborate that it is the variant itself, but the evidence is reasonably compelling and this is harder if there happens to be a narrow pathogenic variant spectrum e.g. gain of function missense. In view of the reduced penetrance, and this slight doubt, I would prefer to ask the opinion of the evaluation working group'

Therefore rating Amber with the recommendation of expert review at the next GMS panel update (tagged)

Note: this phenotype is also now listed in OMIM (MIM# 619360); to: Comment on list classification: Discussed with Helen Brittain (Genomics England Clinical Team) regarding the reduced penetrance and recurrence of the angioedema-specific variant (c.988A>G, p.K330E) in this gene - 'it goes slightly against our usual rule of needing another source to corroborate that it is the variant itself, but the evidence is reasonably compelling and this is harder if there happens to be a narrow pathogenic variant spectrum e.g. gain of function missense. In view of the reduced penetrance, and this slight doubt, I would prefer to ask the opinion of the evaluation working group'

Therefore rating Amber with the recommendation of expert review at the next GMS panel update (tagged)

Note: this phenotype is also now listed in OMIM (MIM# 619360)
Primary immunodeficiency v2.450 PLG Arina Puzriakova Publications for gene: PLG were set to 28795768; 29548426; 29987869; 31131012; 32066472; 32065705; 32181895
Primary immunodeficiency v2.449 PLG Arina Puzriakova edited their review of gene: PLG: Changed rating: AMBER; Changed publications to: 28795768, 29548426, 29952006, 30809376, 31131012, 32066472, 32065705, 32181895, 33799813
Primary immunodeficiency v2.449 PLG Arina Puzriakova changed review comment from: Bork et al. 2018 (PMID: 28795768) found a recurrent variant (c.988A>G, p.K330E) in 13 German families with hereditary angioedema. Haplotype analysis indicated that this is a likely founder variant. However, the variant is associated with incomplete penetrance as there are several asymptomatic carriers within the families and the variant can be found at low freq in the European population in gnomAD - but has been classified as 'Pathogenic'. There is no evidence of other relevant variants but this seems to be an accepted causal variant in the literature and several subsequent publications have identified additional cases (PMIDs: 29548426; 31131012; 32066472; 32065705; 32181895). There is some data that suggests the variant might affect plasminogen glycosylation (PMIDs: 29548426; 32181895), however multiple patients have also been identified with normal plasminogen activity.; to: Bork et al. 2018 (PMID: 28795768) found a recurrent variant (c.988A>G, p.K330E) in 13 German families with hereditary angioedema. However, the variant is associated with incomplete penetrance as there are several asymptomatic carriers within the families and the variant can be found at low freq in the European population in gnomAD - but has been classified as 'Pathogenic'.

There is no evidence of other relevant variants but this seems to be an accepted causal variant in the literature and several subsequent publications have identified additional cases (PMIDs: 29548426; 29952006; 30809376; 31131012; 32066472; 32065705; 32181895; 33799813). Most cases are of European ancestry and haplotype analysis performed by the original study (Bork et al. 2018) indicated a likely founder effect. However, 2 families in Japan have since been identified indicating the variant may be found in various ethnic populations (PMID: 29987869)

There is some data that suggests the variant might affect plasminogen glycosylation (PMIDs: 29548426; 32181895), however multiple patients have also been identified with normal plasminogen activity.
Corneal abnormalities v1.8 GSN Ivone Leong Phenotypes for gene: GSN were changed from Amyloidosis, Finnish type 105120; to Amyloidosis, Finnish type, OMIM:105120
Cardiomyopathies - including childhood onset v1.51 GSN Ivone Leong Phenotypes for gene: GSN were changed from Amyloidosis; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy; arrhytmia to Amyloidosis, Finnish type, OMIM:105120; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy, MONDO:0004994; arrhythmia
Cardiomyopathies - including childhood onset v1.50 GSN Ivone Leong Publications for gene: GSN were set to PMID: 33499149; PMID:26339870
Primary immunodeficiency v2.449 PLG Arina Puzriakova Publications for gene: PLG were set to PMID: 28795768
Primary immunodeficiency v2.448 PLG Arina Puzriakova Classified gene: PLG as Amber List (moderate evidence)
Primary immunodeficiency v2.448 PLG Arina Puzriakova Added comment: Comment on list classification: Discussed with Helen Brittain (Genomics England Clinical Team) regarding the founder effect and reduced penetrance associated with the angioedema-specific variant (c.988A>G, p.K330E) in this gene - 'it goes slightly against our usual rule of needing another source to corroborate that it is the variant itself, but the evidence is reasonably compelling and this is harder if there happens to be a narrow pathogenic variant spectrum e.g. gain of function missense. In view of the reduced penetrance, and this slight doubt, I would prefer to ask the opinion of the evaluation working group'

Therefore rating Amber with the recommendation of expert review at the next GMS panel update (tagged)

Note: this phenotype is also now listed in OMIM (MIM# 619360)
Primary immunodeficiency v2.448 PLG Arina Puzriakova Gene: plg has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.76 ASPH Ivone Leong Tag Q3_21_rating tag was added to gene: ASPH.
Tag Q3_21_NHS_review tag was added to gene: ASPH.
Structural eye disease v1.76 ASPH Ivone Leong Added comment: Comment on publications: Additional case; however, I could not access the article.
Structural eye disease v1.76 ASPH Ivone Leong Publications for gene: ASPH were set to 31274573; 24768550; 31012784
Structural eye disease v1.75 ASPH Ivone Leong Classified gene: ASPH as Amber List (moderate evidence)
Structural eye disease v1.75 ASPH 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 (probable). 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.
Structural eye disease v1.75 ASPH Ivone Leong Gene: asph has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.447 PLG Arina Puzriakova changed review comment from: Penetrance for gene PLG was set from 'unknown' to 'incomplete'; to: Penetrance for PLG on this panel was set from 'unknown' to 'incomplete'
Primary immunodeficiency v2.447 PLG Arina Puzriakova commented on gene: PLG: Penetrance for gene PLG was set from 'unknown' to 'incomplete'
Primary immunodeficiency v2.447 PLG Arina Puzriakova Penetrance for gene PLG was set from to unknown
Primary immunodeficiency v2.446 PLG Arina Puzriakova Tag founder-effect tag was added to gene: PLG.
Tag Q3_21_expert_review tag was added to gene: PLG.
Primary immunodeficiency v2.446 PLG Arina Puzriakova reviewed gene: PLG: Rating: ; Mode of pathogenicity: None; Publications: 28795768, 29548426, 31131012, 32066472, 32065705, 32181895; Phenotypes: Angioedema, hereditary, 4, OMIM:619360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency v2.446 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from Angioedema, hereditary, 4, OMIM:619360 to Angioedema, hereditary, 4, OMIM:619360
Primary immunodeficiency v2.445 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from Non-C1 Hereditary Angioedema to Angioedema, hereditary, 4, OMIM:619360
Hydrocephalus v2.115 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from Plasminogen deficiency, type I, OMIM:217090 to Plasminogen deficiency, type I, OMIM:217090; Dysplasminogenemia, OMIM:217090
Thrombophilia v1.20 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from 217090 Plasminogen deficiency, type I to Plasminogen deficiency, type I, OMIM:217090; Dysplasminogenemia, OMIM:217090
Fetal anomalies v1.694 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from Plasminogen deficiency, type I, OMIM:217090; Hypoplasminogenemia, MONDO:0009009 to Plasminogen deficiency, type I, OMIM:217090; Dysplasminogenemia, OMIM:217090
Inherited bleeding disorders v1.163 PLG Arina Puzriakova Phenotypes for gene: PLG were changed from Plasminogen deficiency to Plasminogen deficiency, type I, OMIM:217090; Dysplasminogenemia, OMIM:217090
Fetal anomalies v1.693 ASPH Ivone Leong Added comment: Comment on phenotypes: Previously:
FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS
Fetal anomalies v1.693 ASPH Ivone Leong Phenotypes for gene: ASPH were changed from FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS to Traboulsi syndrome, OMIM:601552
Structural eye disease v1.74 ASPH Ivone Leong Phenotypes for gene: ASPH were changed from ectopia lentis; facial dysmorphism; Traboulsi syndrome to Traboulsi syndrome, OMIM:601552
Fetal anomalies v1.692 MYOD1 Ivone Leong Tag Q3_21_rating was removed from gene: MYOD1.
Tag watchlist tag was added to gene: MYOD1.
Fetal anomalies v1.692 MYOD1 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 in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics) on Congenital myopathy panel. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association on this panel (Fetal anomalies). Therefore, this gene has been given an Amber rating.
Arthrogryposis v3.113 MYOD1 Ivone Leong Tag Q3_21_rating was removed from gene: MYOD1.
Tag watchlist tag was added to gene: MYOD1.
Arthrogryposis v3.113 MYOD1 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 in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics) on Congenital myopathy panel. This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association on this panel (Arthrogryposis). Therefore, this gene has been given an Amber rating.
Fetal anomalies v1.692 MYOD1 Ivone Leong Entity copied from Congenital myopathy v2.56
Fetal anomalies v1.692 MYOD1 Ivone Leong gene: MYOD1 was added
gene: MYOD1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: MYOD1.
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 26733463; 30403323; 31260566
Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975
Arthrogryposis v3.113 MYOD1 Ivone Leong Entity copied from Congenital myopathy v2.56
Arthrogryposis v3.113 MYOD1 Ivone Leong gene: MYOD1 was added
gene: MYOD1 was added to Arthrogryposis. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: MYOD1.
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 26733463; 30403323; 31260566
Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975
Congenital myopathy v2.56 MYOD1 Ivone Leong commented on gene: MYOD1: Affected individuals present with hypotonia and respiratory insufficiency. More severe cases develop features in utero and lead to contractures.
Genetic epilepsy syndromes v2.396 SYNCRIP Konstantinos Varvagiannis gene: SYNCRIP was added
gene: SYNCRIP was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937
Phenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology
Review for gene: SYNCRIP was set to AMBER
Added comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.

Features included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.

The 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.

Variants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.

Overall the variants reported to date include [NM_006372.5]:
1 - c.858_859del p.(Gly287Leufs*5)
2 - c.854dupA p.(Asn285Lysfs*8)
3 - c.734T>C p.(Leu245Pro)
4 - chr6:85605276-85683190 deletion (GRCh38)
5 - c.629T>C p.(Phe210Ser)
6 - c.1573_1574delinsTT p.(Gln525Leu)
7 - c.1247_1250del p.(Arg416Lysfs*145)
8 - c.1518_1519insC p.(Ala507Argfs*14)

[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]

SYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.

Mutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.

The missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.

There are no additional studies performed.

Overall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]

Animal models are not discussed.

There is no associated phenotype in OMIM or PanelApp AUS.
This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes.
Sources: Literature
Intellectual disability v3.1201 SYNCRIP Konstantinos Varvagiannis reviewed gene: SYNCRIP: Rating: AMBER; Mode of pathogenicity: None; Publications: 34157790, 30504930, 27479843, 23020937; Phenotypes: Global developmental delay, Intellectual disability, Autism, Myoclonic atonic seizures, Abnormality of nervous system morphology; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cerebellar hypoplasia v1.53 L1CAM Dmitrijs Rots gene: L1CAM was added
gene: L1CAM was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: L1CAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: L1CAM were set to PMID: 3147431
Phenotypes for gene: L1CAM were set to Cerebellar hypoplasia
Penetrance for gene: L1CAM were set to Complete
Review for gene: L1CAM was set to GREEN
gene: L1CAM was marked as current diagnostic
Added comment: In PMID: 31474318 found 3 patient with DNM variant and cerebellar hypoplasia, and additionally summarized another 13 from the literature (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 PDGFRB Dmitrijs Rots gene: PDGFRB was added
gene: PDGFRB was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRB were set to PMID: 31474318
Phenotypes for gene: PDGFRB were set to Cerebellar hypoplasia
Penetrance for gene: PDGFRB were set to Complete
Review for gene: PDGFRB was set to GREEN
Added comment: In PMID: 31474318 found 4 patients with DNM variants and cerebellar hypoplasia, and additionally summarized another 1 from the literature (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 FOXP1 Dmitrijs Rots gene: FOXP1 was added
gene: FOXP1 was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: FOXP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP1 were set to PMID: 31474318
Phenotypes for gene: FOXP1 were set to Mental retardation with language impairment and with or without autistic features
Penetrance for gene: FOXP1 were set to Complete
Review for gene: FOXP1 was set to GREEN
gene: FOXP1 was marked as current diagnostic
Added comment: In PMID: 31474318 found 11 patient with DNM AHDC1 variant and cerebellar hypoplasia (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 WDR37 Dmitrijs Rots gene: WDR37 was added
gene: WDR37 was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR37 were set to PMID: 31474318
Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome
Penetrance for gene: WDR37 were set to Complete
Review for gene: WDR37 was set to GREEN
gene: WDR37 was marked as current diagnostic
Added comment: In PMID: 31474318 found 5 patient with DNM WDR37 variant and cerebellar hypoplasia (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 BCL11A Dmitrijs Rots gene: BCL11A was added
gene: BCL11A was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: BCL11A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BCL11A were set to PMID: 31474318
Phenotypes for gene: BCL11A were set to intellectual disability; Cerebellar hypoplasia
Penetrance for gene: BCL11A were set to Complete
Review for gene: BCL11A was set to GREEN
Added comment: In PMID: 31474318 found 3 patient with DNM AHDC1 variant and cerebellar hypoplasia, and additionally summarized another 9 from the literature (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 AUTS2 Dmitrijs Rots gene: AUTS2 was added
gene: AUTS2 was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: AUTS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AUTS2 were set to PMID: 31474318
Phenotypes for gene: AUTS2 were set to intellectual disability; Cerebellar hypoplasia
Penetrance for gene: AUTS2 were set to Complete
Review for gene: AUTS2 was set to AMBER
Added comment: In PMID: 31474318 found in 2/5 patient with DNM AUTS2 variant and cerebellar hypoplasia (see suplements of the paper).
Sources: Literature
Cerebellar hypoplasia v1.53 AHDC1 Dmitrijs Rots gene: AHDC1 was added
gene: AHDC1 was added to Cerebellar hypoplasia. Sources: Literature
Mode of inheritance for gene: AHDC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AHDC1 were set to PMID: 31474318
Phenotypes for gene: AHDC1 were set to intellectual disability; Cerebellar hypoplasia
Penetrance for gene: AHDC1 were set to Complete
Review for gene: AHDC1 was set to GREEN
Added comment: In PMID: 31474318 found one patient with DNM AHDC1 variant and cerebellar hypoplasia, and additionally summarized another 4 from the literature (see suplements of the paper).
Sources: Literature
Cardiomyopathies - including childhood onset v1.49 GSN Dmitrijs Rots gene: GSN was added
gene: GSN was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: GSN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GSN were set to PMID: 33499149; PMID:26339870
Phenotypes for gene: GSN were set to Amyloidosis; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy; arrhytmia
Penetrance for gene: GSN were set to Incomplete
Review for gene: GSN was set to GREEN
gene: GSN was marked as current diagnostic
Added comment: Causes Amyloidosis, Finnish type with multisystem involvement. Cardiomyopathy reported in >6% of patients and arrhytmia (without specifying types) in >30% from >200-individual large cohort from Finland. PMID:26339870.
Sources: Literature
Hereditary neuropathy NOT PMP22 copy number v1.30 GSN Dmitrijs Rots gene: GSN was added
gene: GSN was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: GSN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GSN were set to PMID: 33499149; 26339870
Phenotypes for gene: GSN were set to Amyloidosis; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy; arrhytmia
Penetrance for gene: GSN were set to Complete
Review for gene: GSN was set to GREEN
gene: GSN was marked as current diagnostic
Added comment: Causes Amyloidosis, Finnish type with multisystem involvement. Peripheral and cranial neuropathy each reported in >70% of patients from >200 big cohort from Finland. PMID:26339870.
Sources: Literature
Intellectual disability v3.1201 CAMK4 Konstantinos Varvagiannis gene: CAMK4 was added
gene: CAMK4 was added to Intellectual disability. Sources: Literature,Other
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
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).

----

There is no associated phenotype in OMIM, G2P, PanelApp AUS.

In SysID CAMK4 is listed among the current primary ID genes.

----

Please consider inclusion in other relevant panels.
Sources: Literature, Other
Craniosynostosis v2.40 ACTG2 Zornitza Stark Deleted their review
Intellectual disability v3.1201 ATP9A Konstantinos Varvagiannis edited their review of gene: ATP9A: Changed publications to: http://dx.doi.org/10.1136/jmedgenet-2021-107843
Intellectual disability v3.1201 ATP9A Konstantinos Varvagiannis gene: ATP9A was added
gene: ATP9A was added to Intellectual disability. Sources: Literature,Other
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP9A were set to Global developmental delay; Intellectual disability; Postnatal microcephaly; Failure to thrive; Abnormality of the abdomen
Penetrance for gene: ATP9A were set to Complete
Review for gene: ATP9A was set to AMBER
Added comment: Vogt, Verheyen et al (2021 - http://dx.doi.org/10.1136/jmedgenet-2021-107843) report 3 affected individuals from 2 unrelated consanguineous families.

Features included DD, variable ID (Fam1: sib1-mild, sib2-possible, Fam2: severe), postnatal microcephaly (-2.33 to -3.58 SD), failure to thrive as well as gastrointestinal symptoms (nausea, vomiting, GE reflux).

These subjects were homozygous for pLoF ATP9A variants private to each family.

Previous investigations incl. karyotype, aCGH and transferrin electophoresis (CDGs) and were unremarkable.

Diagnosis was made by exome sequencing and homozygosity mapping. Affected sibs from the first family were homozygous for a stopgain variant [NM_006045.3:c.868C>Τ / p.(Arg290*)]. The subject from the second family was homozygous for a variant affecting the consensus (donor) splice site [c.642+1G>A - same RefSeq]. Both variants were absent from gnomAD. Sanger sequencing was used to confirm variants, carrier status of the parents and unaffected sibs in both families.

Sequencing of cDNA from the individual homozygous for the splicing variant demonstrated skipping of exon 7 with the variant likely leading to frameshift and introduction of a premature stop codon.

qPCR in dermal fibroblasts from affected individuals from both families revealed expression downregulation of ATP9A (14% and 4% respectively for the stopgain and splice variant). Study at the protein level was not possible due to absence of antibody against endogenous ATP9A.

ATP9A encodes ATPase phospholipid transporting 9A (similarly to ATP9B) belonging to the subclass 2 of the P4-ATPase family. As the authors comment, the protein is mainly expressed in the brain although the precise function or subcellular distribution of endogenous ATP9A are unknown.

A previous study showed that overexpressed ATP9A in HeLa cells localizes to early/recycling endosomes and the trans-Golgi network, being required for endocytic recycling of the transferrin receptor to the plasma membrane. ATP9A (in complex with DOP1B and MON2) functionally interacts with the SNX3-retromer. A previous ATP9A knockdown cell line suggested dysregulation of >100 genes with ARPC3 (actin-related protein 2/3 complex subunit 3) being strongly upregulated.

Overall ATP9A appears to have a role in endosome trafficking pathways as well as to inhibit secretion of exosomes at the plasma membrane likely due to alteration of the actin cytoskeleton.

In line with the role of APT9A in early/recycling endosomes and identified interactions, the authors demonstrated overexpression of ARPC3 and SNX3. Study of genes encoding other known interacting proteins was not possible due to poor expression in fibroblasts.

As the authors note, mutations in genes encoding proteins of the Golgi and endosomal trafficking are important for brain development and have been associated with postnatal microcephaly.

In OMIM, G2P, SysID there is no associated phenotype.

The gene is included in the ID panel of PanelApp AUS with amber rating.
Sources: Literature, Other
Mitochondrial disorders v2.47 ACSL4 Andžela Lazdāne gene: ACSL4 was added
gene: ACSL4 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: ACSL4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ACSL4 were set to PMID: 33340416
Phenotypes for gene: ACSL4 were set to Long-chain fatty acid-CoA ligase 4 deficiency; Mental retardation; Autistic features; Intellectual disability
Review for gene: ACSL4 was set to GREEN
Added comment: X-linked intellectual disability type 63.
The gene is included in international classification of inherited metabolic disorders (ICIMD), Disorders of lipid metabolism.
IEM Nosology Group (IEMbase): Disorders of cytoplasmic triglyceride metabolism.
Sources: Literature
Inborn errors of metabolism v2.154 EHHADH Andžela Lazdāne gene: EHHADH was added
gene: EHHADH was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: EHHADH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EHHADH were set to PMID: 33340416
Phenotypes for gene: EHHADH were set to L-bifunctional protein deficiency; Metabolic acidosis; Increased amino acids in urine
Review for gene: EHHADH was set to AMBER
Added comment: Fanconi renotubular syndrome type 3.
The EHHADH gene is included in international classification of inherited metabolic disorders (ICIMD), Disorders of peroxisomal fatty acid oxidation.
IEM Nosology Group (IEMbase): Disorders of peroxisomal β-oxidation.
Sources: Literature
Craniosynostosis v2.40 MASP1 Eleanor Williams Classified gene: MASP1 as Amber List (moderate evidence)
Craniosynostosis v2.40 MASP1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a green recommendation for GMS review. Publications from Basdemirci et al and Atik et al suggest further cases where craniosynostosis is a feature.
Craniosynostosis v2.40 MASP1 Eleanor Williams Gene: masp1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.39 MASP1 Eleanor Williams Phenotypes for gene: MASP1 were changed from 3MC syndrome 1 257920 to 3MC syndrome 1, OMIM:257920; 3MC syndrome 1, MONDO:0009770
Craniosynostosis v2.38 MASP1 Eleanor Williams Publications for gene: MASP1 were set to
Craniosynostosis v2.37 MASP1 Eleanor Williams Mode of inheritance for gene: MASP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Craniosynostosis v2.36 MASP1 Eleanor Williams Tag Q2_21_rating was removed from gene: MASP1.
Tag Q3_21_rating tag was added to gene: MASP1.
Craniosynostosis v2.36 MASP1 Eleanor Williams Tag Q2_21_rating tag was added to gene: MASP1.
Craniosynostosis v2.36 MASP1 Eleanor Williams edited their review of gene: MASP1: Added comment: Checking for further reported cases:

PMID: 30601195 - Basdemirci et al 2019 - 3 siblings with 3MC syndrome in which a novel homozygous missense mutation, p.V704G, in MASP1 was identified in 2 of the siblings (not clear if the 3rd sibling was analysed). Craniosynostosis/skull asymmetry is reported in 2 siblings but no details given.

PMID: 29407414 - Graul-Neumann et al 2018 - 1adult female with a homozygous 2kb deletion, partially affecting exon 12 of MASP1 found by trio exome sequencing. She has the characteristic facial gestalt and typical multiple congenital anomalies but lacking the key feature cleft lip and palate. At birth craniofacial dysmorphism with skull asymmetry, open sutura metopica and facial asymmetry were noted among other features.

PMID: 26419238 - Atik et al 2015 - report on 6 unrelated children with 3MC1 syndrome. Sanger sequencing of MASP1 found 2 different splice site variants, and 3 different missense variants in the 6 probands. Two are reported to have craniosynostosis/skull asymmetry but no details given.

No mention of craniosynostosis or skull asymmetry:

PMID: 21035106 - Sirmaci et al 2010 - 3 individuals from 2 consanguineous Turkish families with 3MC. A missense and nonsense mutation in MASP1 were found by WES and Sanger sequencing in the two families respectively. Craniosynostosis is NOT mentioned as part of the phenotype.; Changed publications to: 30601195, 29407414, 26419238, 21035106, 21258343, 26789649
Structural eye disease v1.73 ASPH Julia Baptista gene: ASPH was added
gene: ASPH was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASPH were set to 31274573; 24768550; 31012784
Phenotypes for gene: ASPH were set to ectopia lentis; facial dysmorphism; Traboulsi syndrome
Review for gene: ASPH was set to GREEN
gene: ASPH was marked as current diagnostic
Added comment: Sources: Literature
Craniosynostosis v2.36 HNRNPK Eleanor Williams Classified gene: HNRNPK as Amber List (moderate evidence)
Craniosynostosis v2.36 HNRNPK Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis and variants in this gene.
Craniosynostosis v2.36 HNRNPK Eleanor Williams Gene: hnrnpk has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.35 HNRNPK Eleanor Williams Phenotypes for gene: HNRNPK were changed from Au-Kline syndrome, MIM# 616580 to Au-Kline syndrome, OMIM:616580
Craniosynostosis v2.34 HNRNPK Eleanor Williams Publications for gene: HNRNPK were set to 26173930; 26954065; 29904177
Craniosynostosis v2.33 HNRNPK Eleanor Williams reviewed gene: HNRNPK: Rating: GREEN; Mode of pathogenicity: None; Publications: 26173930, 26954065, 28771707, 29904177, 24501764, 25348648, 28374925; Phenotypes: Au-Kline syndrome, OMIM:616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1201 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from Mental retardation, X-linked syndromic, Raymond type, 300799; MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED (MRXSZ) to Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
Genetic epilepsy syndromes v2.396 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from epilepsy; intellectual disability; Mental retardation, X-linked syndromic, Raymond type, 300799 to epilepsy; intellectual disability; Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
DDG2P v2.39 ZDHHC9 Ivone Leong Added comment: Comment on phenotypes: Previously:
MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED 300799
DDG2P v2.39 ZDHHC9 Ivone Leong Phenotypes for gene: ZDHHC9 were changed from MENTAL RETARDATION SYNDROMIC X-LINKED ZDHHC9-RELATED 300799 to Mental retardation, X-linked syndromic, Raymond type, OMIM:300799
Hereditary neuropathy v1.388 XK Ivone Leong Phenotypes for gene: XK were changed from McLeod syndrome with or without chronic granulomatous disease, 300842; Mceod syndrome, Onset 25-60, acanthocytes and Huntington-like syndrome, also epilepsy, cardiomyopathy, axonal motor neuropathy to McLeod syndrome with or without chronic granulomatous disease,OMIM:300842; McLeod syndrome, Onset 25-60, acanthocytes and Huntington-like syndrome, also epilepsy, cardiomyopathy, axonal motor neuropathy
Rare anaemia v1.24 XK Ivone Leong Phenotypes for gene: XK were changed from 300842 McLeod syndrome to McLeod syndrome with or without chronic granulomatous disease,OMIM:300842
Cytopenias and congenital anaemias v1.87 XK Ivone Leong Phenotypes for gene: XK were changed from McLeod syndrome with or without chronic granulomatous disease, 300842 to McLeod syndrome with or without chronic granulomatous disease,OMIM:300842
Early onset dystonia v1.88 XK Ivone Leong Phenotypes for gene: XK were changed from McLeod syndrome with or without chronic granulomatous disease OMIM 300842 to McLeod syndrome with or without chronic granulomatous disease,OMIM:300842
DDG2P v2.38 WNT10B Ivone Leong Phenotypes for gene: WNT10B were changed from SPLIT-HAND/FOOT MALFORMATION TYPE 6 225300 to Split-hand/foot malformation 6, OMIM:225300
Fetal anomalies v1.691 WNT10B Ivone Leong Phenotypes for gene: WNT10B were changed from Split-hand/foot malformation 6, OMIM:225300 to Split-hand/foot malformation 6, OMIM:225300
Skeletal dysplasia v2.108 WNT10B Ivone Leong Phenotypes for gene: WNT10B were changed from Split-hand/foot malformation 6 225300 to Split-hand/foot malformation 6, OMIM:225300
Fetal anomalies v1.690 WNT10B Ivone Leong Phenotypes for gene: WNT10B were changed from SPLIT-HAND/FOOT MALFORMATION TYPE 6 to Split-hand/foot malformation 6, OMIM:225300
Limb disorders v2.45 WNT10B Ivone Leong Phenotypes for gene: WNT10B were changed from Split-hand/foot malformation 6 225300 to Split-hand/foot malformation 6, OMIM:225300
Ectodermal dysplasia v1.25 WNT10A Ivone Leong Phenotypes for gene: WNT10A were changed from Schopf-Schulz-Passarge syndrome, OMIM:224750; Odontoonychodermal dysplasia, OMIM:257980 to Schopf-Schulz-Passarge syndrome, OMIM:224750; Odontoonychodermal dysplasia, OMIM:257980
Ectodermal dysplasia v1.24 WNT10A Ivone Leong Phenotypes for gene: WNT10A were changed from Schopf-Schulz-Passarge syndrome 224750; Odontoonychodermal dysplasia 257980 to Schopf-Schulz-Passarge syndrome, OMIM:224750; Odontoonychodermal dysplasia, OMIM:257980
Ectodermal dysplasia without a known gene mutation v1.22 WNT10A Ivone Leong Phenotypes for gene: WNT10A were changed from Odontoonychodermal dysplasia 257980; Schopf-Schulz-Passarge syndrome 224750 to Odontoonychodermal dysplasia, OMIM:257980; Schopf-Schulz-Passarge syndrome, OMIM:224750
Craniosynostosis v2.33 FGF10 Eleanor Williams Classified gene: FGF10 as Amber List (moderate evidence)
Craniosynostosis v2.33 FGF10 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Craniosynostosis v2.33 FGF10 Eleanor Williams Gene: fgf10 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.32 FGF10 Eleanor Williams Phenotypes for gene: FGF10 were changed from Craniosynostosis to craniosynostosis, MONDO:0015469
Craniosynostosis v2.31 FGF10 Eleanor Williams changed review comment from: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) were identified in 2 patients.; to: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) in FGF10 were identified in 2 patients.
Craniosynostosis v2.31 FGF10 Eleanor Williams reviewed gene: FGF10: Rating: AMBER; Mode of pathogenicity: None; Publications: 29215649; Phenotypes: craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Craniosynostosis v2.31 B3GAT3 Eleanor Williams Tag Q3_21_rating tag was added to gene: B3GAT3.
Craniosynostosis v2.31 ACTG2 Eleanor Williams Classified gene: ACTG2 as No list
Craniosynostosis v2.31 ACTG2 Eleanor Williams Added comment: Comment on list classification: Keeping this gene grey as it is not the correct gene for the panel (should be ACTG1).
Craniosynostosis v2.31 ACTG2 Eleanor Williams Gene: actg2 has been removed from the panel.
Craniosynostosis v2.30 ACTG2 Eleanor Williams commented on gene: ACTG2
Craniosynostosis v2.30 ACTG1 Eleanor Williams Classified gene: ACTG1 as Amber List (moderate evidence)
Craniosynostosis v2.30 ACTG1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber, with the recommendation of green rating following GMS review. More than 3 cases reported with disease-associated variants in this gene, with Trigonocephaly/metopic ridge reported as part of the phenotype.
Craniosynostosis v2.30 ACTG1 Eleanor Williams Gene: actg1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.29 ACTG1 Eleanor Williams Tag Q3_21_rating tag was added to gene: ACTG1.
Craniosynostosis v2.29 ACTG1 Eleanor Williams gene: ACTG1 was added
gene: ACTG1 was added to Craniosynostosis. Sources: Literature
missense tags were added to gene: ACTG1.
Mode of inheritance for gene: ACTG1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACTG1 were set to 22366783; 25052316; 27240540
Phenotypes for gene: ACTG1 were set to Baraitser-Winter syndrome 2, OMIM:614583
Review for gene: ACTG1 was set to GREEN
Added comment: Associated with Baraitser-Winter syndrome 2 OMIM:614583 (AD) in OMIM.

PMID: 22366783 - Rivière et al 2012 - 8 patients with Baraitser-Winter syndrome in which a heterozygous missense mutation was identified in the ACTG1 gene. In 7 patients the mutation was found to have occurred de novo (no parental DNA in 8th patient). Trigonocephaly was noted in 7 of the patients.

PMID: 25052316 - Verloes et al 2015 - report on 1 new case of a patient with a missense variant in ACTG1 (same variant as reported in Riviere et al) and bring together information from the Riviere patients with this one. They state that Trigonocephaly/metopic ridge is reported in 4/8 cases (50%) which contradicts the table in the Riviere paper which puts the number as higher.

PMID: 27240540 - Donato et al 2016 - report on 7 new unrelated patients with 6 mutations in ACTG1. Clinical photographs were available for 6 of these patients, and only 1/6 displayed a metopic ridge.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.137 C9orf72_GGGGCC Sarah Leigh Tag Q2_21_rating was removed from STR: C9orf72_GGGGCC.
Tag STR tag was added to STR: C9orf72_GGGGCC.
Childhood onset dystonia or chorea or related movement disorder v1.137 C9orf72_GGGGCC Sarah Leigh Tag STR was removed from STR: C9orf72_GGGGCC.
Childhood onset dystonia or chorea or related movement disorder v1.137 C9orf72_GGGGCC Sarah Leigh Classified STR: C9orf72_GGGGCC as Red List (low evidence)
Childhood onset dystonia or chorea or related movement disorder v1.137 C9orf72_GGGGCC Sarah Leigh Added comment: Comment on list classification: Reviews for C9orf72 gene on this panel from Zornitza Stark (Australian Genomics), James Polke (North Thames GLH) & Helen Brittain (Genomics England Clinical Fellow)(https://panelapp.genomicsengland.co.uk/panels/847/gene/C9orf72/#!review), together recommend a Red rating, as the phenotype associated with this variant in this gene has an adult onset and is therefore not appropriate for a childhood gene panel.
Childhood onset dystonia or chorea or related movement disorder v1.137 C9orf72_GGGGCC Sarah Leigh Str: c9orf72_ggggcc has been classified as Red List (Low Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.136 C9orf72 Sarah Leigh edited their review of gene: C9orf72: Added comment: Helen Brittain (Genomics England Clinical Fellow) suggested a Red rating, as the phenotype associated with variants in this gene has an adult onset and therefore is not appropriate for a childhood gene panel.; Changed rating: RED
Craniosynostosis v2.28 ACTB Eleanor Williams Classified gene: ACTB as Amber List (moderate evidence)
Craniosynostosis v2.28 ACTB Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. There are more than 3 cases with plausible disease causing variants in this gene, and a relevant phenotype.
Craniosynostosis v2.28 ACTB Eleanor Williams Gene: actb has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.27 ACTB Eleanor Williams Phenotypes for gene: ACTB were changed from Baraitser-Winter syndrome 1, MIM# 243310 to Baraitser-Winter syndrome 1, OMIM:243310; Baraitser-Winter syndrome 1, MONDO:0009470
Craniosynostosis v2.26 ACTB Eleanor Williams Publications for gene: ACTB were set to
Craniosynostosis v2.25 ACTB Eleanor Williams Tag missense tag was added to gene: ACTB.
Tag Q3_21_rating tag was added to gene: ACTB.
Craniosynostosis v2.25 ACTB Eleanor Williams reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: 22366783, 23649928, 23756437; Phenotypes: Baraitser-Winter syndrome 1, OMIM:243310, Baraitser-Winter syndrome 1, MONDO:0009470; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mitochondrial disorders v2.47 CMPK2 Andžela Lazdāne gene: CMPK2 was added
gene: CMPK2 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to PMID: 33340416
Phenotypes for gene: CMPK2 were set to Mitochondrial UMP-CMP kinase 2 deficiency; Developmental delay; Failure to thrive
Review for gene: CMPK2 was set to GREEN
Added comment: Mitochondrial UMP-CMP kinase is a component of the salvage pathway for nucleotide synthesis.
IEM Nosology Group (IEMbase): Disorders of mitochondrial DNA depletion, multiple deletion, or intergenomic communication.
The CMPK2 gene is included in International classification of inherited metabolic disorders (ICIMD), Disorders of mitochondrial DNA maintenance and replication.
Sources: Literature
Clefting v2.46 SEPT9 Eleanor Williams Classified gene: SEPT9 as Green List (high evidence)
Clefting v2.46 SEPT9 Eleanor Williams Added comment: Comment on list classification: There is only 1 report of clefting in a patient with a variant in SEPT9 and a diagnosis of HNA. Other reports of clefting are in patients in which the molecular cause of the disease were not established. Therefore, the recommendation is to demote this gene from green to amber following GMS review.
Clefting v2.46 SEPT9 Eleanor Williams Gene: sept9 has been classified as Green List (High Evidence).
Clefting v2.45 SEPT9 Eleanor Williams Publications for gene: SEPT9 were set to
Clefting v2.44 SEPT9 Eleanor Williams Tag Q3_21_rating tag was added to gene: SEPT9.
Clefting v2.44 SEPT9 Eleanor Williams reviewed gene: SEPT9: Rating: AMBER; Mode of pathogenicity: None; Publications: 11739810, 18492087, 30019529, 31619932, 28503616, 20019224, 19939853, 19451530, 19139049, 16186812; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Clefting v2.44 MED12 Eleanor Williams Phenotypes for gene: MED12 were changed from Lujan-Fryns syndrome, 309520; Opitz-Kaveggia syndrome, 305450; OKS; submucous cleft palate to Hardikar syndrome, OMIM:612726; cholestasis-pigmentary retinopathy-cleft palate syndrome, MONDO:0012997
Clefting v2.43 MED12 Eleanor Williams Publications for gene: MED12 were set to 12784307
Clefting v2.42 MED12 Eleanor Williams Mode of inheritance for gene: MED12 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Clefting v2.41 MED12 Eleanor Williams Classified gene: MED12 as Amber List (moderate evidence)
Clefting v2.41 MED12 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber with the recommendation of a green rating following GMS review. There are 7 reported cases with cleft lip/palate and a variant identified in MED12.
Clefting v2.41 MED12 Eleanor Williams Gene: med12 has been classified as Amber List (Moderate Evidence).
Clefting v2.40 MED12 Eleanor Williams Tag Q3_21_rating tag was added to gene: MED12.
Clefting v2.40 MED12 Eleanor Williams reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33244166; Phenotypes: Hardikar syndrome, OMIM:612726, cholestasis-pigmentary retinopathy-cleft palate syndrome, MONDO:0012997; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Clefting v2.40 ESCO2 Eleanor Williams Classified gene: ESCO2 as Green List (high evidence)
Clefting v2.40 ESCO2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green. Sufficient cases reported with clefting a feature in Roberts-SC phocomelia syndrome. Additionally 2 (likely founder) cases reported with clefting in probands with Juberg-Hayward syndrome.
Clefting v2.40 ESCO2 Eleanor Williams Gene: esco2 has been classified as Green List (High Evidence).
Clefting v2.39 ESCO2 Eleanor Williams Phenotypes for gene: ESCO2 were changed from ROBERTS SYNDROME; RBS, SC PHOCOMELIA SYNDROME to Roberts-SC phocomelia syndrome, OMIM:268300; Roberts-SC phocomelia syndrome, MONDO:0100253
Clefting v2.38 ESCO2 Eleanor Williams Publications for gene: ESCO2 were set to
Clefting v2.37 ESCO2 Eleanor Williams reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977150, 32255174, 15821733, 16380922, 18411254, 24864645; Phenotypes: Roberts-SC phocomelia syndrome, OMIM:268300, Roberts-SC phocomelia syndrome, MONDO:0100253; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.154 IDH1 Andžela Lazdāne gene: IDH1 was added
gene: IDH1 was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: IDH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IDH1 were set to PMID: 33340416
Phenotypes for gene: IDH1 were set to Failure to thrive; Psychomotor delay; Feeding difficulties; Increased D-2-Hydroxyglutaric acid in urine
Review for gene: IDH1 was set to AMBER
Added comment: Isocitrate dehydrogenase 1 deficiency.

IEM Nosology Group (IEMbase):Disorders of the Krebs cycle. The IDH1 gene is included in International classification of inherited metabolic disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature
Hypertrophic cardiomyopathy - teen and adult v2.22 ALPK3 Dmitrijs Rots reviewed gene: ALPK3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32480058; Phenotypes: Hypertrophic cardiomyopathy; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Inborn errors of metabolism v2.154 ACAT2 Andžela Lazdāne reviewed gene: ACAT2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:33340416; Phenotypes: Developmental delay; Mode of inheritance: None
Inborn errors of metabolism v2.154 ACAT2 Andžela Lazdāne Deleted their review
Inborn errors of metabolism v2.154 ACAT2 Andžela Lazdāne commented on gene: ACAT2: ACAT2 gene is included in international classification of inherited metabolic
disorders (ICIMD).
Inborn errors of metabolism v2.154 ACAT2 Andžela Lazdāne changed review comment from: Acetoacetyl-CoA thiolase deficiency (cytosolic)

IEM Nosology Group:Disorders of ketone body metabolism
Sources: Literature; to: Acetoacetyl-CoA thiolase deficiency (cytosolic)

IEM Nosology Group:Disorders of ketone body metabolism
Sources: Literature
Inborn errors of metabolism v2.154 ACAT2 Andžela Lazdāne gene: ACAT2 was added
gene: ACAT2 was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: ACAT2 was set to Unknown
Publications for gene: ACAT2 were set to PMID:33340416
Phenotypes for gene: ACAT2 were set to Developmental delay
Review for gene: ACAT2 was set to AMBER
Added comment: Acetoacetyl-CoA thiolase deficiency (cytosolic)

IEM Nosology Group:Disorders of ketone body metabolism
Sources: Literature
Mitochondrial disorders v2.47 IDH1 Andžela Lazdāne edited their review of gene: IDH1: Changed rating: AMBER; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne edited their review of gene: ACAT2: Changed rating: AMBER; Changed mode of inheritance: Unknown
Mitochondrial disorders v2.47 IDH1 Andžela Lazdāne changed review comment from: Cytosolic NADP+-dependent isocitrate dehydrogenase 1 superactivity. IDH1 is a dimeric cytosolic NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate.
The IDH1 gene is included in International classification of inherited metabolic disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature; to: Cytosolic NADP+-dependent isocitrate dehydrogenase 1 superactivity. IDH1 is a dimeric cytosolic NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate.
The IDH1 gene is included in International classification of inherited metabolic disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature
Mitochondrial disorders v2.47 IDH1 Andžela Lazdāne gene: IDH1 was added
gene: IDH1 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: IDH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IDH1 were set to PMID: 33340416
Phenotypes for gene: IDH1 were set to Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
Review for gene: IDH1 was set to GREEN
Added comment: Cytosolic NADP+-dependent isocitrate dehydrogenase 1 superactivity. IDH1 is a dimeric cytosolic NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) that catalyzes decarboxylation of isocitrate into alpha-ketoglutarate.
The IDH1 gene is included in International classification of inherited metabolic disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature
Mitochondrial disorders v2.47 SLC13A3 Andžela Lazdāne gene: SLC13A3 was added
gene: SLC13A3 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: SLC13A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A3 were set to PMID: 33340416; PMID: 30635937
Phenotypes for gene: SLC13A3 were set to Sodium dicarboxylate cotransporter 3 deficiency; Increased urinary dicarboxylic acids, alpha-ketoglutarate, fumarate, N-acetylaspartate; Encephalopathy; Ataxia
Penetrance for gene: SLC13A3 were set to Complete
Review for gene: SLC13A3 was set to GREEN
Added comment: Based on the literature SLC13A3 gene variants cause acute reversible leukoencephalopathy and alpha-ketoglutarate accumulation. Patient had hypotonia, abnormal movements, and dysarthria associated with white matter abnormalities and increased urinary alpha-ketoglutarate and NAA. CSF analysis showed increased lactate. Laboratory studies showed increased urinary excretion of alpha-ketoglutarate, succinate, fumarate, and N-acetylaspartate (NAA). These organic acids were also increased in the cerebrospinal fluid (CSF).

The SLC13A3 gene is included an international classification of inherited metabolic disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature
Mitochondrial disorders v2.47 SLC13A5 Andžela Lazdāne gene: SLC13A5 was added
gene: SLC13A5 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: SLC13A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A5 were set to PMID: 33340416
Phenotypes for gene: SLC13A5 were set to Plasma membrane citrate transporter deficiency; Epileptic encephalopathy; Delayed psychomotor development.
Penetrance for gene: SLC13A5 were set to Complete
Review for gene: SLC13A5 was set to GREEN
Added comment: The SLC13A5 gene encodes a tricarboxylate plasma transporter with a preference for citrate. The SLC13A5 gene should be include in Mitochondrial disorder panel because it is included in International Classification of Inborn Metabolic Disorders (ICIMD), Disorders of the Krebs cycle.
Sources: Literature
Clefting v2.37 PLCB4 Eleanor Williams Phenotypes for gene: PLCB4 were changed from Cleft palate to Auriculocondylar syndrome 2, OMIM:614669; auriculocondylar syndrome 2, MONDO:0013845
Clefting v2.36 PLCB4 Eleanor Williams Publications for gene: PLCB4 were set to
Clefting v2.35 PLCB4 Eleanor Williams Mode of inheritance for gene: PLCB4 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Clefting v2.34 PLCB4 Eleanor Williams Classified gene: PLCB4 as Amber List (moderate evidence)
Clefting v2.34 PLCB4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber as there are two cases of auriculocondylar syndrome 2 associated with variants in this gene where cleft palate is part of the phenotype.
Clefting v2.34 PLCB4 Eleanor Williams Gene: plcb4 has been classified as Amber List (Moderate Evidence).
Clefting v2.33 PLCB4 Eleanor Williams edited their review of gene: PLCB4: Changed rating: AMBER; Changed publications to: 16114046, 32201334, 27007857, 23913798, 2560091, 23315542; Changed phenotypes to: Auriculocondylar syndrome 2, OMIM:614669, auriculocondylar syndrome 2, MONDO:0013845; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.136 AFG3L2 Sarah Leigh changed review comment from: The review by Zornitza Stark (5 Sep 2020), has raised concerns about the relevance of the phenotypes associated with variants in AFG3L2 to scope of this panel.
Helen Brittain (Genomics England Clinical Fellow) has suggested this gene should be rated Amber on Childhood onset dystonia or chorea or related movement disorder panel.
AFG3L2 is already Green on Ataxia and cerebellar anomalies - narrow (https://panelapp.genomicsengland.co.uk/panels/477/gene/AFG3L2) and Hereditary ataxia - adult onset (https://panelapp.genomicsengland.co.uk/panels/466/gene/AFG3L2) panels.; to: The review by Emily Jones (9 Jul 2019) and Zornitza Stark (5 Sep 2020), have raised concerns about the relevance of the phenotypes associated with variants in AFG3L2 to scope of this panel.
Helen Brittain (Genomics England Clinical Fellow) has suggested this gene should be rated Amber on Childhood onset dystonia or chorea or related movement disorder panel.
AFG3L2 is already Green on Ataxia and cerebellar anomalies - narrow (https://panelapp.genomicsengland.co.uk/panels/477/gene/AFG3L2) and Hereditary ataxia - adult onset (https://panelapp.genomicsengland.co.uk/panels/466/gene/AFG3L2) panels.
Clefting v2.33 PLCB4 Eleanor Williams commented on gene: PLCB4
Childhood onset dystonia or chorea or related movement disorder v1.136 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1200 CEP85L Sarah Leigh Tag Q3_21_rating tag was added to gene: CEP85L.
Childhood onset dystonia or chorea or related movement disorder v1.136 FXN Sarah Leigh reviewed gene: FXN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1200 CEP85L Sarah Leigh edited their review of gene: CEP85L: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least nine variants reported in nine unrelated families. PMID 32097630 comments that - the CEP85L gene as a whole is tolerant to loss of function and to missense variation. However, the 4 missense variants that have been identified in patients affect a 15-aa region of the protein that is highly intolerant to missense variation, the splicing and start-loss variants are predicted to produce a shortened protein that excludes the same 15-aa region. It is speculated that variants in this constrained region, may act through a dominant-negative mechanism.
Intellectual disability was apparent in eight of the families studied, ranging from mild (three families) to moderate (five families).
Supportive studies were also presented (PMID 32097630, 32097629).; Changed rating: GREEN
Intellectual disability v3.1200 CEP85L Sarah Leigh Classified gene: CEP85L as Amber List (moderate evidence)
Intellectual disability v3.1200 CEP85L Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1200 CEP85L Sarah Leigh Gene: cep85l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1199 CEP85L Sarah Leigh Phenotypes for gene: CEP85L were changed from Intellectual disability; epilepsy, lissencephaly to Lissencephaly 10, OMIM:618873; Lissencephaly 10, MONDO:0030031
Skeletal Muscle Channelopathies v1.37 PYGM Eleanor Williams commented on gene: PYGM
Skeletal muscle channelopathy v1.31 PYGM Eleanor Williams Tag Q2_21_rating was removed from gene: PYGM.
Skeletal muscle channelopathy v1.31 PYGM Eleanor Williams changed review comment from: Comment on list classification: Leaving the rating as green, but with a recommendation for a red rating following GMS review because this gene encodes an enzyme not a channel. However, the phenotype may overlap with channelopathies.; to: Comment on list classification: Leaving rating as Green but with a recommendation for review by the GMS test evaluation group as to suitability for this panel. This gene encodes an enzyme not a channel. However, the phenotype may overlap with channelopathies.
Skeletal Muscle Channelopathies v1.37 SLC2A1 Eleanor Williams commented on gene: SLC2A1
Skeletal muscle channelopathy v1.31 SLC2A1 Eleanor Williams changed review comment from: Comment on list classification: Leaving this gene green but with a recommendation for a red rating following GMS review as to whether it is useful to have this gene on panel although variants seem to result in a brain channelopathy rather than a skeletal muscle one; to: Comment on list classification: Leaving rating as Green but with a recommendation for review by the GMS test evaluation group as to suitability for this panel. Variants seem to result in a brain channelopathy rather than a skeletal muscle one
Skeletal muscle channelopathy v1.31 SLC2A1 Eleanor Williams Tag Q2_21_rating was removed from gene: SLC2A1.
Skeletal Muscle Channelopathies v1.37 SLC1A3 Eleanor Williams Classified gene: SLC1A3 as Green List (high evidence)
Skeletal Muscle Channelopathies v1.37 SLC1A3 Eleanor Williams Added comment: Comment on list classification: Leaving as green for consistency with the GMS Skeletal muscle channelopathy panel (panel 542).
Skeletal Muscle Channelopathies v1.37 SLC1A3 Eleanor Williams Gene: slc1a3 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.31 SLC1A3 Eleanor Williams changed review comment from: Comment on list classification: Leaving the rating as Green but with a recommendation for red rating following GMS review as to whether it is useful to have this gene on panel although variants seem to result in a brain channelopathy rather than a skeletal muscle one.; to: Comment on list classification: Leaving rating as Green but with a recommendation for review by the GMS test evaluation group as to suitability for this panel. Variants seem to result in a brain channelopathy rather than a skeletal muscle one.
Skeletal muscle channelopathy v1.31 SLC1A3 Eleanor Williams Tag Q2_21_rating was removed from gene: SLC1A3.
Skeletal Muscle Channelopathies v1.36 CACNA1A Eleanor Williams Classified gene: CACNA1A as Green List (high evidence)
Skeletal Muscle Channelopathies v1.36 CACNA1A Eleanor Williams Added comment: Comment on list classification: Leaving as green for consistency with the GMS Skeletal muscle channelopathy panel (panel 542).
Skeletal Muscle Channelopathies v1.36 CACNA1A Eleanor Williams Gene: cacna1a has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.31 CACNA1A Eleanor Williams Tag Q2_21_rating was removed from gene: CACNA1A.
Skeletal muscle channelopathy v1.31 ATP1A2 Eleanor Williams Tag Q2_21_rating was removed from gene: ATP1A2.
Skeletal muscle channelopathy v1.31 CACNA1A Eleanor Williams changed review comment from: Comment on list classification: Leaving rating as green but with a recommendation for red rating following GMS review. As reported by Zornitza Stark variants in this gene appear to be associated with brain channelopathies rather than skeletal muscle.; to: Comment on list classification: Leaving rating as Green but with a recommendation for review by the GMS test evaluation group as to suitability for this panel. As reported by Zornitza Stark variants in this gene appear to be associated with brain channelopathies rather than skeletal muscle.
Skeletal Muscle Channelopathies v1.35 ATP1A2 Eleanor Williams Classified gene: ATP1A2 as Green List (high evidence)
Skeletal Muscle Channelopathies v1.35 ATP1A2 Eleanor Williams Added comment: Comment on list classification: Leaving as green for consistency with the GMS Skeletal muscle channelopathy panel (panel 542).
Skeletal Muscle Channelopathies v1.35 ATP1A2 Eleanor Williams Gene: atp1a2 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.31 ATP1A2 Eleanor Williams changed review comment from: Comment on list classification: Leaving rating as Green but with a recommendation of a red rating following GMS review, as there is only one case reported associated with a skeletal muscle phenotype.; to: Comment on list classification: Leaving rating as Green but with a recommendation for review by GMS evaluation group as to suitability for this panel. There is only one case reported associated with a skeletal muscle phenotype.
Inborn errors of metabolism v2.154 PEX6 Sarah Leigh Tag Q3_21_MOI was removed from gene: PEX6.
Inborn errors of metabolism v2.154 PEX6 Sarah Leigh Tag Q3_21_MOI tag was added to gene: PEX6.
Inborn errors of metabolism v2.154 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308; 29220678; 20301621
Inborn errors of metabolism v2.153 PEX6 Sarah Leigh Phenotypes for gene: PEX6 were changed from Disorders of peroxisome biogenesis; Peroxisome biogenesis disorder 4B 614863; Peroxisome biogenesis disorder 4A (Zellweger) 614862 to Peroxisome biogenesis disorder 4A (Zellweger) OMIM:614862; peroxisome biogenesis disorder 4A (Zellweger) MONDO:0013930; Peroxisome biogenesis disorder 4B OMIM:614863; peroxisome biogenesis disorder 4B MONDO:0013931
Inborn errors of metabolism v2.153 PEX6 Sarah Leigh Publications for gene: PEX6 were set to 27604308
Inborn errors of metabolism v2.152 PEX6 Sarah Leigh reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220678, 20301621; Phenotypes: Peroxisome biogenesis disorder 4A (Zellweger) OMIM:614862, peroxisome biogenesis disorder 4A (Zellweger) MONDO:0013930, Peroxisome biogenesis disorder 4B OMIM:614863, peroxisome biogenesis disorder 4B MONDO:0013931; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1198 DPYSL5 Ivone Leong Tag Q3_21_rating tag was added to gene: DPYSL5.
Intellectual disability v3.1198 DPYSL5 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.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

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

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis. Age range from 2.5 years to 33 years.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1198 DPYSL5 Ivone Leong Classified gene: DPYSL5 as Amber List (moderate evidence)
Intellectual disability v3.1198 DPYSL5 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.

PMID: 33894126. 10 individuals (2 of whom are related). 7/7 had severe ID, 9/9 DD and hypotonia, 3/6 ataxia, 3/10 seizures, 6/7 cerebellar hypoplasia and 7/10 corpus callosum agenesis.

Based on literature and expert review, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1198 DPYSL5 Ivone Leong Gene: dpysl5 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v2.25 CHD5 Ivone Leong Tag watchlist tag was added to gene: CHD5.
Craniosynostosis v2.25 CHD5 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 (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

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 associated with a phenotype in Gene2Phenotype (possible) but not in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

As less than half the cases had craniosynostosis, this gene has been given an Amber rating awaiting more cases.
Genetic epilepsy syndromes v2.395 CHD5 Ivone Leong Tag Q3_21_rating tag was added to gene: CHD5.
Intellectual disability v3.1197 CHD5 Ivone Leong Tag Q3_21_rating tag was added to gene: CHD5.
Craniosynostosis v2.25 CHD5 Ivone Leong Entity copied from Intellectual disability v3.1197
Craniosynostosis v2.25 CHD5 Ivone Leong gene: CHD5 was added
gene: CHD5 was added to Craniosynostosis. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Genetic epilepsy syndromes v2.395 CHD5 Ivone Leong Entity copied from Intellectual disability v3.1197
Genetic epilepsy syndromes v2.395 CHD5 Ivone Leong gene: CHD5 was added
gene: CHD5 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Intellectual disability v3.1197 CHD5 Ivone Leong Classified gene: CHD5 as Amber List (moderate evidence)
Intellectual disability v3.1197 CHD5 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 in OMIM.

PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants).

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 v3.1197 CHD5 Ivone Leong Gene: chd5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1196 CHD5 Ivone Leong Phenotypes for gene: CHD5 were changed from Intellectual disability; Epilepsy to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027
Undiagnosed metabolic disorders v1.469 ABCB7 Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as there is no evidence that carrier females have ataxia.
Undiagnosed metabolic disorders v1.469 ABCB7 Ivone Leong Mode of inheritance for gene: ABCB7 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary ataxia v1.235 ABCB7 Ivone Leong Added comment: Comment on mode of inheritance: MOI 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" as there is no evidence that carrier females have ataxia.
Hereditary ataxia v1.235 ABCB7 Ivone Leong Mode of inheritance for gene: ABCB7 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hereditary ataxia - adult onset v2.81 ABCB7 Ivone Leong reviewed gene: ABCB7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v2.222 ABCB7 Ivone Leong Tag Q3_21_MOI tag was added to gene: ABCB7.
Ataxia and cerebellar anomalies - narrow panel v2.222 ABCB7 Ivone Leong reviewed gene: ABCB7: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Rare anaemia v1.23 ABCB7 Ivone Leong Tag Q3_21_MOI tag was added to gene: ABCB7.
Rare anaemia v1.23 ABCB7 Ivone Leong reviewed gene: ABCB7: 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)
Cytopenias and congenital anaemias v1.86 ABCB7 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "X-LINKED: hemizygous mutation in males, biallelic mutations in females" to "X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)" as some carrier females have ring sideroblasts, dimorphic peripheral bloode smear, hypochromic and microcytic erythrocytes but no evidence of ataxia.
Cytopenias and congenital anaemias v1.86 ABCB7 Ivone Leong Mode of inheritance for gene: ABCB7 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)
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong Tag watchlist tag was added to gene: MYF5.
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong changed review comment from: PMID:29887215. 3 families and 5 patients. All patients have external ophthalmoplegia, 3/5 torticollis, 4/5 scoliosis, 0/5 hypotonia/weakness.

After consulting the Genomics England Clinical Team it was decided to leave this gene as Amber on this panel.; to: PMID:29887215. 3 families and 5 patients. 2 families from the same village Turkey with the same variant (c.23_32delAGTTCTCACC) and 1 family from Yemen (c.283C>T). All patients have external ophthalmoplegia, 3/5 torticollis, 4/5 scoliosis, 0/5 hypotonia/weakness.

After consulting the Genomics England Clinical Team it was decided that this gene is appropriate for the Congenital fibrosis of the extraocular muscles panel. This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). As 2 of the cases could be due to founder effect (Turkish families) and only 1 other case, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating until more evidence is available.
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong Entity copied from Congenital myopathy v2.56
Congenital fibrosis of the extraocular muscles v1.12 MYF5 Ivone Leong gene: MYF5 was added
gene: MYF5 was added to Congenital fibrosis of the extraocular muscles. Sources: Expert Review Amber,Expert list,Literature
Mode of inheritance for gene: MYF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYF5 were set to 29887215
Phenotypes for gene: MYF5 were set to Ophthalmoplegia, external, with rib and vertebral anomalies, OMIM:618155
Mode of pathogenicity for gene: MYF5 was set to Other
Congenital myopathy v2.56 MYF5 Ivone Leong reviewed gene: MYF5: Rating: AMBER; Mode of pathogenicity: None; Publications: 29887215; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.114 P4HB Ivone Leong reviewed gene: P4HB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ehlers Danlos syndromes v2.60 IPO8 Ivone Leong Entity copied from Thoracic aortic aneurysm and dissection v1.15
Ehlers Danlos syndromes v2.60 IPO8 Ivone Leong gene: IPO8 was added
gene: IPO8 was added to Ehlers Danlos syndromes. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: IPO8.
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604; 34010605
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Primary immunodeficiency v2.444 IPO8 Ivone Leong Tag Q3_21_expert_review tag was added to gene: IPO8.
Primary immunodeficiency v2.444 IPO8 Ivone Leong Classified gene: IPO8 as Amber List (moderate evidence)
Primary immunodeficiency v2.444 IPO8 Ivone Leong Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). This gene is associated with a phenotype in Gene2Phenotype but not OMIM. As immune dysregulation is not seen in all affected individuals (PMID:34010604) and PMID:34010605 did not investigate the immune status of their cohort this gene has been given an Amber rating until further cases are available.
Primary immunodeficiency v2.444 IPO8 Ivone Leong Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.443 IPO8 Ivone Leong Tag watchlist tag was added to gene: IPO8.
Epidermolysis bullosa and congenital skin fragility v1.49 NAXD Ivone Leong Deleted their comment
Epidermolysis bullosa and congenital skin fragility v1.49 NAXD Ivone Leong edited their review of gene: NAXD: Added comment: After consulting the clinical team at Genomics England, this gene has been added to this panel with an Amber rating (pending more evidence) as there is a skin phenotype is present in patients and may be the first things the patient is being seen for (PMID: 33224489).; Changed rating: AMBER
Epidermolysis bullosa and congenital skin fragility v1.49 NAXD Ivone Leong Tag Q2_21_rating was removed from gene: NAXD.
Tag watchlist tag was added to gene: NAXD.
Epidermolysis bullosa and congenital skin fragility v1.49 NAXD Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.189
Epidermolysis bullosa and congenital skin fragility v1.49 NAXD Ivone Leong gene: NAXD was added
gene: NAXD was added to Epidermolysis bullosa and congenital skin fragility. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 33224489; 31755961
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321
Hypogonadotropic hypogonadism idiopathic v1.44 CLPP Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is currently not enough evidence to support a gene-disease association as the phenotypes among the patients vary. This gene has been given an Amber rating until more cases are available.
Hypogonadotropic hypogonadism idiopathic v1.44 CLPP Ivone Leong Tag Q3_21_rating was removed from gene: CLPP.
Tag watchlist tag was added to gene: CLPP.
Hypogonadotropic hypogonadism idiopathic v1.44 CLPP Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.189
Hypogonadotropic hypogonadism idiopathic v1.44 CLPP Ivone Leong gene: CLPP was added
gene: CLPP was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: CLPP.
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27899912; 23541340; 25956234; 26970254; 27087618; 27650058
Phenotypes for gene: CLPP were set to Perrault syndrome 3, OMIM:614129
Hypogonadotropic hypogonadism v1.33 CLPP Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (probable). There is currently not enough evidence to support a gene-disease association as the phenotypes among the patients vary. This gene has been given an Amber rating until more cases are available.
Hypogonadotropic hypogonadism v1.33 CLPP Ivone Leong Tag Q3_21_rating was removed from gene: CLPP.
Tag watchlist tag was added to gene: CLPP.
Hypogonadotropic hypogonadism v1.33 CLPP Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.189
Hypogonadotropic hypogonadism v1.33 CLPP Ivone Leong gene: CLPP was added
gene: CLPP was added to Hypogonadotropic hypogonadism. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: CLPP.
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27899912; 23541340; 25956234; 26970254; 27087618; 27650058
Phenotypes for gene: CLPP were set to Perrault syndrome 3, OMIM:614129
White matter disorders and cerebral calcification - narrow panel v1.189 CLPP Ivone Leong Classified gene: CLPP as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.189 CLPP 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. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.189 CLPP Ivone Leong Gene: clpp has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.188 CLPP Ivone Leong Tag Q3_21_rating tag was added to gene: CLPP.
Nephrocalcinosis or nephrolithiasis v2.21 ATP6V0A4 Arina Puzriakova Publications for gene: ATP6V0A4 were set to
Renal tubulopathies v2.27 ATP6V0A4 Arina Puzriakova Publications for gene: ATP6V0A4 were set to
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: ATP6V0A4.
Tag watchlist_moi tag was added to gene: ATP6V0A4.
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Added comment: Comment on mode of inheritance: Literature search showed that a single Japanese individual was reported in 2016 (PMID: 27274828) with a supposedly pathogenic heterozygous variant p.S544L. Hypokalemia, nephrocalcinosis and alkaluria suggesting distal renal tubular acidosis (dRTA) were detected, but metabolic acidosis was not evident. In 2020, a second Han Chinese family with five dRTA patients was reported (PMID: 32123165) who harboured the same p.S544L heterozygous variant. Some patients in this family were more severely affected than the previous case, displaying more severe complete dRTA with hypokalemia, osteoporosis, and kidney stones. Note this family also harboured 3 other homozygous variants in the ATP6V0A4 gene but these were ruled out, presumably due to MAF.

Apart from these two reports’ alternations in ATP6V0A4 have been found to be inherited recessively (heterozygous parent carriers are unaffected), and multiple such cases have been described in literature (references added to publications list).

At this moment there is only enough evidence to support an Amber rating for the monoallelic form - single heterozygous variant identified in 2 families from a similar ethnic background which does not suffice the inclusion criteria.

MOI should be changed from 'BOTH mono- and biallelic' to 'BIALLELIC' only at the next GMS panel review (tagged) until additional evidence emerges supporting heterozygous variants as disease-causing.
Nephrocalcinosis or nephrolithiasis v2.20 ATP6V0A4 Arina Puzriakova Mode of inheritance for gene: ATP6V0A4 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Bleeding and platelet disorders v1.30 TNXB Arina Puzriakova reviewed gene: TNXB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, classic-like, 1, OMIM:606408; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.30 COL3A1 Arina Puzriakova commented on gene: COL3A1: Correspondence from Dr Neeti Ghali & Dr Fleur van Dijk, Consultant Clinical Geneticists, EDS National Diagnostic Service (15/07/2021) indicating that inclusion of COL3A1 as Green on this panel would be beneficial as they receive referrals from haematologists asking to consider this form of vascular EDS, associated with significant bruising and haematoma formation.
Bleeding and platelet disorders v1.30 TNXB Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: TNXB.
Tag Q3_21_expert_review tag was added to gene: TNXB.
Bleeding and platelet disorders v1.30 COL3A1 Arina Puzriakova Tag Q2_21_expert_review was removed from gene: COL3A1.
Tag Q3_21_NHS_review tag was added to gene: COL3A1.
Tag Q3_21_expert_review tag was added to gene: COL3A1.
Bleeding and platelet disorders v1.30 COL3A1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: COL3A1.
Genetic epilepsy syndromes v2.394 CEP85L Rachel Challis reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: 32097629, 32097630; Phenotypes: Intellectual disability, epilepsy, lissencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1195 CEP85L Rachel Challis gene: CEP85L was added
gene: CEP85L was added to Intellectual disability. Sources: NHS GMS
Mode of inheritance for gene: CEP85L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CEP85L were set to 32097629; 32097630
Phenotypes for gene: CEP85L were set to Intellectual disability; epilepsy, lissencephaly
Penetrance for gene: CEP85L were set to unknown
Review for gene: CEP85L was set to GREEN
gene: CEP85L was marked as current diagnostic
Added comment: Recommend adding as Green gene to GMS - R29 Intellectual disability panel.

Monoallelic missense and loss of function variants in CEP85L are associated with Lissencephaly (OMIM 618873). Over 10 unrelated families have been described with de novo and inherited rare variants in CEP85L. Functional work in cell lines and knockdown of Cep85l in mice confirms the role of CEP85L in neuronal migration.
PMID: 32097629
PMID: 32097630
Sources: NHS GMS
Malformations of cortical development v2.45 CEP85L Rachel Challis reviewed gene: CEP85L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID 32097629, 32097630; Phenotypes: Intellectual disability, epilepsy, lissencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Nephrocalcinosis or nephrolithiasis v2.19 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from distal renal tubular acidosis; Compensated or uncomensated dRTA and/or recurrent stone formation, usually with hypocitraturia. +/- deafness; Renal tubular acidosis, distal, autosomal recessive to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Hearing loss v2.179 ATP6V0A4 Arina Puzriakova Publications for gene: ATP6V0A4 were set to
Hearing loss v2.178 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Disorders of sex development v2.49 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Renal tubular acidosis, distal, autosomal recessive, 602722 to Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Renal tubulopathies v2.26 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from Distal Renal Tubular Acidosis, Recessive; Renal tubular acidosis, distal, autosomal recessive, 602722; Distal renal tubular acidosis; Autosomal recessive distal renal tubular acidosis to Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Limb girdle muscular dystrophy v2.20 CAV3 Ivone Leong Tag Q3_21_MOI tag was added to gene: CAV3.
Limb girdle muscular dystrophy v2.20 CAV3 Ivone Leong edited their review of gene: CAV3: Added comment: MOI should be changed to Both monoallelic and biallelic to match the MOI for CAV3 in Rhabdomyolysis and metabolic muscle disorders panel.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Rhabdomyolysis and metabolic muscle disorders v1.48 CAV3 Ivone Leong Added comment: Comment on phenotypes: Previously:
Muscular dystrophy, limb-girdle, type IC 607801;Myopathy, distal, Tateyama type 614321;Rippling muscle disease 606072
Rhabdomyolysis and metabolic muscle disorders v1.48 CAV3 Ivone Leong Phenotypes for gene: CAV3 were changed from Muscular dystrophy, limb-girdle, type IC 607801; Myopathy, distal, Tateyama type 614321; Rippling muscle disease 606072 to Myopathy, distal, Tateyama type, OMIM:614321; Rippling muscle disease, OMIM:606072
Limb girdle muscular dystrophy v2.20 CAV3 Ivone Leong Added comment: Comment on phenotypes: Previously: Limb-Girdle Muscular Dystrophy, Dominant;Muscular dystrophy, limb-girdle, type IC, 607801;Rippling muscle disease, 606072;Creatine phosphokinase, elevated serum, 123320;Myopathy, distal, Tateyama type, 614321;Cardiomyopathy, familial hypertrophic, 192600; Limb-girdle muscular dystrophy
Limb girdle muscular dystrophy v2.20 CAV3 Ivone Leong Phenotypes for gene: CAV3 were changed from Limb-Girdle Muscular Dystrophy, Dominant; Muscular dystrophy, limb-girdle, type IC, 607801; Rippling muscle disease, 606072; Creatine phosphokinase, elevated serum, 123320; Myopathy, distal, Tateyama type, 614321; Cardiomyopathy, familial hypertrophic, 192600; Limb-girdle muscular dystrophy to Rippling muscle disease 2, OMIM:606072; Myopathy, distal, Tateyama type, OMIM:614321
Haematological malignancies cancer susceptibility v2.18 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Class: BM failure syndrome (typ AR); Ataxia telangiectasia; leukaemia; lymphoma; medulloblastoma; glioma; ataxia-telangiectasia; Lymphoma, ALL (particularly T-ALL); Leukaemia to Ataxia-telangiectasia, OMIM:208900; T-cell prolymphocytic leukemia, somatic
Neurodegenerative disorders - adult onset v2.176 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Dystonia; Ataxia-Telangiectasia; Ataxia telangiectasia; Ataxia-telangiectasia, to Ataxia-telangiectasia, OMIM:208900
Primary immunodeficiency v2.443 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia, 208900; Ataxia telangiectasia (ATM); immunodeficiency; Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations; Combined immunodeficiencies with associated or syndromic features to Ataxia-telangiectasia, OMIM:208900; Combined immunodeficiencies with associated or syndromic features; Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations
Hereditary ataxia v1.234 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-Telangiectasia ; Ataxia-telangiectasia, to Ataxia-telangiectasia, OMIM:208900
Hereditary haemorrhagic telangiectasia v2.7 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia, 208900 to Ataxia-telangiectasia, OMIM:208900
Ataxia and cerebellar anomalies - narrow panel v2.222 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia,; Ataxia-Telangiectasia to Ataxia-telangiectasia, OMIM:208900
Early onset dystonia v1.87 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Dystonia; Ataxia telangiectasia to Ataxia-telangiectasia, OMIM:208900
Primary ovarian insufficiency v1.44 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia 208900 to Ataxia-telangiectasia, OMIM:208900
COVID-19 research v1.79 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia telangiectasia (ATM); immunodeficiency; Combined immunodeficiencies with associated or syndromic features; Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations; Ataxia-telangiectasia, 208900 to Ataxia-telangiectasia, OMIM:208900; Combined immunodeficiencies with associated or syndromic features; Ataxia, telangiectasia, pulmonary infections, lymphoreticular and other malignancies, increased alpha fetoprotein, increased radiosensitivity, chromosomal instability and chromosomal translocations
Haematological malignancies for rare disease v1.4 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Class: BM failure syndrome (typ AR); Ataxia telangiectasia; leukaemia; lymphoma; medulloblastoma; glioma; ataxia-telangiectasia; Lymphoma, ALL (particularly T-ALL); Leukaemia to Ataxia-telangiectasia, OMIM:208900; T-cell prolymphocytic leukemia, somatic
Tumour predisposition - childhood onset v2.22 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia Telangiectasia; 208900 to Ataxia-telangiectasia, OMIM:208900
Adult solid tumours for rare disease v1.24 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia Telangiectasia to Ataxia-telangiectasia, OMIM:208900
Adult solid tumours cancer susceptibility v2.13 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia Telangiectasia to Ataxia-telangiectasia, OMIM:208900
Childhood solid tumours cancer susceptibility v1.15 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia Telangiectasia to Ataxia-telangiectasia, OMIM:208900
Peroxisomal disorders v1.13 PEX6 Julia Baptista reviewed gene: PEX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220678, 20301621; Phenotypes: Zellweger syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic epilepsy syndromes v2.394 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.394 PCDHGC4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Genetic epilepsy syndromes v2.394 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.393 PCDHGC4 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (15/7/2021). At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (15/7/2021). At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh Classified gene: PCDHGC4 as Amber List (moderate evidence)
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1195 PCDHGC4 Sarah Leigh Gene: pcdhgc4 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.393 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Genetic epilepsy syndromes. Sources: Literature
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 syndrome
Review for gene: PCDHGC4 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Intellectual disability v3.1194 PCDHGC4 Sarah Leigh gene: PCDHGC4 was added
gene: PCDHGC4 was added to Intellectual disability. Sources: Literature
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 syndrome
Review for gene: PCDHGC4 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least eight variants reported in 19 members of nine unreleted families with a neurodevelopmental syndrome. Severe or moderate intellectual disabilty was found in eight families and seizures were evident in four families. Four of the variants were terminating, in silico analysis of the remaining missense (n=3) and splice variants were predicted to be pathogenic.
Sources: Literature
Inherited ovarian cancer (without breast cancer) v2.21 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia, 208900; Lymphoma, B-cell non-Hodgkin, somatic; {Breast cancer, susceptibility to}, 114480; Lymphoma, mantle cell; T-cell prolymphocytic leukemia, somatic; Breast and Ovarian Cancer to {Breast cancer, susceptibility to}, OMIM:114480
Familial breast cancer v1.14 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia, 208900; Lymphoma, B-cell non-Hodgkin, somatic; {Breast cancer, susceptibility to}, 114480; Lymphoma, mantle cell; T-cell prolymphocytic leukemia, somatic; Breast and Ovarian Cancer to {Breast cancer, susceptibility to}, OMIM:114480
Intellectual disability v3.1193 ATXN2L Ivone Leong Tag watchlist tag was added to gene: ATXN2L.
Intellectual disability v3.1193 ATXN2L Ivone Leong Classified gene: ATXN2L as Amber List (moderate evidence)
Intellectual disability v3.1193 ATXN2L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Amber rating.
Intellectual disability v3.1193 ATXN2L Ivone Leong Gene: atxn2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1192 EPHA7 Ivone Leong Tag watchlist tag was added to gene: EPHA7.
Intellectual disability v3.1192 EPHA7 Ivone Leong Classified gene: EPHA7 as Amber List (moderate evidence)
Intellectual disability v3.1192 EPHA7 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. This gene has been given an Amber rating based on expert review.
Intellectual disability v3.1192 EPHA7 Ivone Leong Gene: epha7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1191 EPHA7 Ivone Leong Phenotypes for gene: EPHA7 were changed from Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality to Global developmental delay; Intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality
Genetic epilepsy syndromes v2.392 HEATR5B Ivone Leong Entity copied from Intellectual disability v3.1190
Genetic epilepsy syndromes v2.392 HEATR5B Ivone Leong gene: HEATR5B was added
gene: HEATR5B was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: HEATR5B.
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1190 ERGIC3 Ivone Leong Tag watchlist tag was added to gene: ERGIC3.
Intellectual disability v3.1190 ERGIC3 Ivone Leong Classified gene: ERGIC3 as Amber List (moderate evidence)
Intellectual disability v3.1190 ERGIC3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not asssociated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Intellectual disability v3.1190 ERGIC3 Ivone Leong Gene: ergic3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1189 ERGIC3 Ivone Leong Phenotypes for gene: ERGIC3 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Cerebellar hypoplasia v1.53 HEATR5B Ivone Leong Entity copied from Intellectual disability v3.1188
Cerebellar hypoplasia v1.53 HEATR5B Ivone Leong gene: HEATR5B was added
gene: HEATR5B was added to Cerebellar hypoplasia. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: HEATR5B.
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Ataxia and cerebellar anomalies - narrow panel v2.221 HEATR5B Ivone Leong Entity copied from Intellectual disability v3.1188
Ataxia and cerebellar anomalies - narrow panel v2.221 HEATR5B Ivone Leong gene: HEATR5B was added
gene: HEATR5B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: HEATR5B.
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1188 HEATR5B Ivone Leong Classified gene: HEATR5B as Amber List (moderate evidence)
Intellectual disability v3.1188 HEATR5B 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 v3.1188 HEATR5B Ivone Leong Gene: heatr5b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1187 HEATR5B Ivone Leong Tag watchlist tag was added to gene: HEATR5B.
Intellectual disability v3.1187 HEATR5B Ivone Leong Phenotypes for gene: HEATR5B were changed from pontocerebellar hypoplasia; intellectual disability; seizures to pontocerebellar hypoplasia, MONDO:0020135; intellectual disability, MONDO:0001071; seizures
Intellectual disability v3.1186 JPH3 Ivone Leong Classified gene: JPH3 as Red List (low evidence)
Intellectual disability v3.1186 JPH3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. 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.
Intellectual disability v3.1186 JPH3 Ivone Leong Gene: jph3 has been classified as Red List (Low Evidence).
Intellectual disability v3.1185 KIF1B Ivone Leong Classified gene: KIF1B as Red List (low evidence)
Intellectual disability v3.1185 KIF1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is asssociated with a phenotype in OMIM but not Gene2Phenotype. 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.
Intellectual disability v3.1185 KIF1B Ivone Leong Gene: kif1b has been classified as Red List (Low Evidence).
Intellectual disability v3.1184 KIF1B Ivone Leong Phenotypes for gene: KIF1B were changed from Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay to Hypotonia; coloboma, MONDO:0001476; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Intellectual disability v3.1183 SAMD9L Ivone Leong Classified gene: SAMD9L as Red List (low evidence)
Intellectual disability v3.1183 SAMD9L 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, but nothing related to ID. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red status.
Intellectual disability v3.1183 SAMD9L Ivone Leong Gene: samd9l has been classified as Red List (Low Evidence).
Intellectual disability v3.1182 SAMD9L Ivone Leong Phenotypes for gene: SAMD9L were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Cataracts v2.76 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Autosomal dominant cutis laxa-3 (ADCL3); autosomal recessive cutis laxa type III (ARCL3) to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndrome MONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Inborn errors of metabolism v2.152 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Hypoprolinaemia, Cutis laxa, autosomal recessive, type IIIa (Disorders of ornithine or proline metabolism); Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150 to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndrome MONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Hyperammonaemia v1.9 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150 to Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150; ALDH18A1-related de Barsy syndrome MONDO:0009053
Undiagnosed metabolic disorders v1.468 ALDH18A1 Sarah Leigh Added comment: Comment on phenotypes: Hypoprolinaemia, Cutis laxa, autosomal recessive, type IIIa (Disorders of ornithine or proline metabolism);Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150
Undiagnosed metabolic disorders v1.468 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Hypoprolinaemia, Cutis laxa, autosomal recessive, type IIIa (Disorders of ornithine or proline metabolism); Cutis laxa, autosomal recessive, type IIIA (Delta-1-pyrroline 5 carboxylic acid synthetase deficiency) 219150 to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndrome MONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Arthrogryposis v3.112 MED12 Arina Puzriakova Classified gene: MED12 as Amber List (moderate evidence)
Arthrogryposis v3.112 MED12 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Arthrogryposis v3.112 MED12 Arina Puzriakova Gene: med12 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.111 MED12 Arina Puzriakova Phenotypes for gene: MED12 were changed from MED12-related disorders to MED12-related disorders; Opitz-Kaveggia syndrome, OMIM:305450; Ohdo syndrome, X-linked, OMIM:300895; Lujan-Fryns syndrome, OMIM:309520
Arthrogryposis v3.110 MED12 Arina Puzriakova Publications for gene: MED12 were set to 20301719
Arthrogryposis v3.109 MED12 Arina Puzriakova Tag Q3_21_rating tag was added to gene: MED12.
Arthrogryposis v3.109 MED12 Arina Puzriakova reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 565138, 7201743, 16700052, 17369503, 19938245, 25790323; Phenotypes: Opitz-Kaveggia syndrome, OMIM:305450, Ohdo syndrome, X-linked, OMIM:300895, Lujan-Fryns syndrome, OMIM:309520; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Thoracic aortic aneurysm and dissection v1.15 MED12 Arina Puzriakova Publications for gene: MED12 were set to
Thoracic aortic aneurysm and dissection v1.14 MED12 Arina Puzriakova Phenotypes for gene: MED12 were changed from Lujan-Fryns syndrome, 309520; Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders to Lujan-Fryns syndrome, OMIM:309520; Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders
Thoracic aortic aneurysm or dissection v1.121 MED12 Arina Puzriakova Phenotypes for gene: MED12 were changed from Lujan-Fryns syndrome, 309520; Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders to Lujan-Fryns syndrome, OMIM:309520; Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders
Thoracic aortic aneurysm or dissection v1.120 MED12 Arina Puzriakova Classified gene: MED12 as Red List (low evidence)
Thoracic aortic aneurysm or dissection v1.120 MED12 Arina Puzriakova Added comment: Comment on list classification: MED12 was previously demoted on the GMS equivalent panel (Thoracic aortic aneurysm and dissection v1.2) due to insufficient evidence. Therefore this gene has been demoted from Green to Red to reflect the most up-to-date knowledge here.
-----
There are reports of patients with Lujan-Fryns syndrome and aortic dilation, but these were not patients with MED12 variants. Patients reported with MED12 c.3020A>G did not have aortic involvement.
Thoracic aortic aneurysm or dissection v1.120 MED12 Arina Puzriakova Gene: med12 has been classified as Red List (Low Evidence).
Periodic fever syndromes v1.13 APOC2 Arina Puzriakova Phenotypes for gene: APOC2 were changed from Amyloidosis; Hyperlipoproteinemia, type Ib 207750 to Amyloidosis
Intellectual disability v3.1181 SPTBN1 Sarah Leigh Classified gene: SPTBN1 as Amber List (moderate evidence)
Intellectual disability v3.1181 SPTBN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1181 SPTBN1 Sarah Leigh Gene: sptbn1 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.391 SPTBN1 Sarah Leigh Classified gene: SPTBN1 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.391 SPTBN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Genetic epilepsy syndromes v2.391 SPTBN1 Sarah Leigh Gene: sptbn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1180 SPTBN1 Sarah Leigh gene: SPTBN1 was added
gene: SPTBN1 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: SPTBN1.
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to 34211179
Phenotypes for gene: SPTBN1 were set to autosomal dominant neurodevelopmental syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (as of 13/07/2021). At least 27 monoallelic variants reported in 29 individuals with neurodevelopmental abnormalities. Developmental delay was reported in 28/28 tested cases. Intellectual disabilty was reported in 21/24 tested cases (including severe in 5 cases, moderate to severe in 2 cases and moderate in 4 cases) and epilepsy/seizures was reported in 9/24 tested cases (including febrile seizures in 2 cases). Extensive supportive functional evidence was also reported (PMID 34211179).
Sources: Literature
Genetic epilepsy syndromes v2.390 SPTBN1 Sarah Leigh gene: SPTBN1 was added
gene: SPTBN1 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: SPTBN1.
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTBN1 were set to 34211179
Phenotypes for gene: SPTBN1 were set to autosomal dominant neurodevelopmental syndrome
Review for gene: SPTBN1 was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO (as of 13/07/2021). At least 27 monoallelic variants reported in 29 individuals with neurodevelopmental abnormalities. Developmental delay was reported in 28/28 tested cases. Intellectual disabilty was reported in 21/24 tested cases (including severe in 5 cases, moderate to severe in 2 cases and moderate in 4 cases) and epilepsy/seizures was reported in 9/24 tested cases (including febrile seizures in 2 cases). Extensive supportive functional evidence was also reported (PMID 34211179).
Sources: Literature
Severe multi-system atopic disease with high IgE v1.8 CARD11 Ivone Leong Phenotypes for gene: CARD11 were changed from multisystem atopic disease, eczema, raised IgE, low IgM, eosinophilia; B-cell expansion with NFKB and T-cell anergy 616452 AD to multisystem atopic disease, eczema, raised IgE, low IgM, eosinophilia; B-cell expansion with NFKB and T-cell anergy, OMIM:616452
Rhabdomyolysis and metabolic muscle disorders v1.47 CACNA1S Ivone Leong Phenotypes for gene: CACNA1S were changed from {Malignant hyperthermia susceptibility 5}, 601887 to {Malignant hyperthermia susceptibility 5}, OMIM:601887
Skeletal Muscle Channelopathies v1.34 CACNA1S Ivone Leong Publications for gene: CACNA1S were set to 15534250; 18835861
Skeletal Muscle Channelopathies v1.33 CACNA1S Ivone Leong Added comment: Comment on mode of inheritance: Changing MOI from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" based on the review by Eleanor Williams for the same gene on the "Skeletal muscle channelopathy" panel:

"PMID: 28012042 - Shartner et al 2017 - report 11 individuals with congenital myopathy from 7 unrelated families (Caucasian, Argentinean, or Vietnamese) and variants in CACNA1S identified through exome sequencing. The s from origin were included in this study. There were 3 sporadic cases (2 compound het, 1 het), 2 families with dominant inheritance, and 2 families with recessive inheritance . 10 different variants were identified.
Eleanor Williams (Genomics England Curator), 17 Mar 2021"
Skeletal Muscle Channelopathies v1.33 CACNA1S Ivone Leong Mode of inheritance for gene: CACNA1S was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1179 CAMK2A Ivone Leong Tag watchlist_moi tag was added to gene: CAMK2A.
Intellectual disability v3.1179 NAA20 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature; to: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 in this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Severe microcephaly v2.220 NAA20 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature; to: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 in this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1179 NAA20 Sarah Leigh Classified gene: NAA20 as Amber List (moderate evidence)
Intellectual disability v3.1179 NAA20 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be amber on this panel, based on two missense variants, which have supporting in silico and experimental evidence in cases with mild to severe intellectually disability (PMID 34230638).
Intellectual disability v3.1179 NAA20 Sarah Leigh Gene: naa20 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.220 NAA20 Sarah Leigh Classified gene: NAA20 as Amber List (moderate evidence)
Severe microcephaly v2.220 NAA20 Sarah Leigh Gene: naa20 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1178 NAA20 Sarah Leigh Added comment: Comment on phenotypes: Currently there is no phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Intellectual disability v3.1178 NAA20 Sarah Leigh Phenotypes for gene: NAA20 were changed from autosomal recessive developmental delay, intellectual disability, and microcephaly to autosomal recessive developmental delay, intellectual disability, and microcephaly
Severe microcephaly v2.219 NAA20 Sarah Leigh changed review comment from: Comment on phenotypes: Currently there is not phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).; to: Comment on phenotypes: Currently there is no phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Severe microcephaly v2.219 NAA20 Sarah Leigh Added comment: Comment on phenotypes: Currently there is not phenotype associated with this gene in OMIM, Gen2Phen or MONDO (13/07/2021).
Severe microcephaly v2.219 NAA20 Sarah Leigh Phenotypes for gene: NAA20 were changed from autosomal recessive developmental delay, intellectual disability, and microcephaly to autosomal recessive developmental delay, intellectual disability, and microcephaly
Intellectual disability v3.1177 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to 34230638
Phenotypes for gene: NAA20 were set to autosomal recessive developmental delay, intellectual disability, and microcephaly
Review for gene: NAA20 was set to AMBER
Added comment: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Severe microcephaly v2.218 NAA20 Sarah Leigh gene: NAA20 was added
gene: NAA20 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NAA20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAA20 were set to 34230638
Phenotypes for gene: NAA20 were set to autosomal recessive developmental delay, intellectual disability, and microcephaly
Review for gene: NAA20 was set to AMBER
Added comment: Not associated with a phenotype in OMIM nor Gen2Phen. Two missense variants reported as homozygotes in one family each. In silico predictions and in vitro functional studies provide evidence that these variants will adversely affect their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates (PMID 34230638). Children from these two families had developmental delay, intellectual disability (mild to moderate family 1, severe family 2).
The two children in family 1 in this study had a head circumcernces of -2.3 & -1.9 SD (which is not regarded as severe microcephaly).
The three children from family 2 this study had a head circumcernces of -3.5, -3.0 & -3.5 SD (which is regarded as severe microcephaly). Subtle dysmorphic features were also reported.
Sources: Literature
Intellectual disability v3.1176 CAMK2A Ivone Leong Added comment: Comment on phenotypes: Previously:
Intellectual disability
Intellectual disability v3.1176 CAMK2A Ivone Leong Phenotypes for gene: CAMK2A were changed from Intellectual disability to Mental retardation, autosomal dominant 53, OMIM:617798; ?Mental retardation, autosomal recessive 63, OMIM:618095
Intellectual disability v3.1175 CAMK2A Ivone Leong Added comment: Comment on publications: PMID:29784083. 2 siblings born from consanguineous parents from Jordan with homozygous missense variant. Both had severe ID.
Intellectual disability v3.1175 CAMK2A Ivone Leong Publications for gene: CAMK2A were set to 26350204; 29100089
Limb girdle muscular dystrophy v2.19 CAPN3 Ivone Leong Added comment: Comment on phenotypes: Previously:
Muscular dystrophy, limb-girdle, type 2A, 253600;Limb-Girdle Muscular Dystrophy, Recessive; Limb-girdle muscular dystrophy
Limb girdle muscular dystrophy v2.19 CAPN3 Ivone Leong Phenotypes for gene: CAPN3 were changed from Muscular dystrophy, limb-girdle, type 2A, 253600; Limb-Girdle Muscular Dystrophy, Recessive; Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 1, OMIM:253600
Membranoproliferative glomerulonephritis v2.21 C3 Ivone Leong Added comment: Comment on phenotypes: Previously:
Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 5,612925; C3 glomerulopathy; C3G; C3 deficiency, 613779; Immune complex MPGN; IC-MPGN
Membranoproliferative glomerulonephritis v2.21 C3 Ivone Leong Phenotypes for gene: C3 were changed from Haemolytic uraemic syndrome; aHUS; Hemolytic uremic syndrome, atypical, susceptibility to, 5,612925; C3 glomerulopathy; C3G; C3 deficiency, 613779; Immune complex MPGN; IC-MPGN to Hemolytic uremic syndrome, atypical, susceptibility to, 5, OMIM:612925; C3 glomerulopathy; C3G
Atypical haemolytic uraemic syndrome v2.9 C3 Ivone Leong Phenotypes for gene: C3 were changed from Hemolytic uremic syndrome, atypical, susceptibility to, 5, 612925 to Hemolytic uremic syndrome, atypical, susceptibility to, 5, OMIM:612925
Intellectual disability v3.1174 MYT1 Ivone Leong Classified gene: MYT1 as Red List (low evidence)
Intellectual disability v3.1174 MYT1 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 but not in OMIM. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Intellectual disability v3.1174 MYT1 Ivone Leong Gene: myt1 has been classified as Red List (Low Evidence).
Intellectual disability v3.1173 MYT1 Ivone Leong Added comment: Comment on publications: PMID:18341605. A case with de novo subtelomeric deletion on chromosome 20 containing MYT1 and PCMTD2. Both genes affect myelination and neural differentiation.

PMID:33710394. Authors also discuss that variants in MYT1 have been identified in patients with oculo-auriculo-vertebral spectrum (OAVS) who have normal intelligence.
Intellectual disability v3.1173 MYT1 Ivone Leong Publications for gene: MYT1 were set to 33710394
Intellectual disability v3.1172 MYT1 Ivone Leong Phenotypes for gene: MYT1 were changed from Intellectual disability to Intellectual disability, MONDO:0001071
Intellectual disability v3.1171 SRCAP Ivone Leong Publications for gene: SRCAP were set to
Severe early-onset obesity v2.40 PHIP Ivone Leong Tag Q3_21_rating tag was added to gene: PHIP.
Severe early-onset obesity v2.40 PHIP Ivone Leong Classified gene: PHIP as Amber List (moderate evidence)
Severe early-onset obesity v2.40 PHIP Ivone Leong Added comment: Comment on list classification: New gene added by David Hunt (Wessex Clinical Genetics Service). 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 early-onset obesity v2.40 PHIP Ivone Leong Gene: phip has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.39 PHIP Ivone Leong Tag Q3_21_NHS_review tag was added to gene: PHIP.
Familial non syndromic congenital heart disease v1.63 FLNA Arina Puzriakova Publications for gene: FLNA were set to 17190868, 8230166
Familial non syndromic congenital heart disease v1.62 FLNA Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'X-LINKED... biallelic mutations in females' to 'X-LINKED... monoallelic mutations in females may cause disease'.

Heterozygous females are more mildly affected than hemizygous males, but some healthy female carriers have also been described.
Familial non syndromic congenital heart disease v1.62 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA 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)
Pigmentary skin disorders v1.13 FLNA Arina Puzriakova Publications for gene: FLNA were set to
Pigmentary skin disorders v1.12 FLNA Arina Puzriakova Tag Q3_21_expert_review tag was added to gene: FLNA.
Pigmentary skin disorders v1.12 FLNA Arina Puzriakova edited their review of gene: FLNA: Added comment: Pigmentary abnormalities of the skin are a feature of terminal osseous dysplasia (MIM# 300244). Although the number of unrelated cases (>3) reaches the threshold for inclusion as diagnostic-grade, FLNA is associated with multiple phenotypes which do not include pigmentary anomalies. This gene is already Green on other relevant GMS panels such as Skeletal dysplasia v2.107, which should be sufficient for detecting this phenotype. Nonetheless, as there may be some added clinical benefit of inclusion, FLNA will be flagged for review at the next GMS panel update with regard to the most appropriate rating on this panel.; Changed rating: AMBER; Changed publications to: 17152064, 18792982, 20598277, 30561107; Changed phenotypes to: Terminal osseous dysplasia, OMIM:300244; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cutaneous photosensitivity with a likely genetic cause v1.8 HMBS Ivone Leong Tag Q3_21_expert_review tag was added to gene: HMBS.
Cutaneous photosensitivity with a likely genetic cause v1.8 HMBS Ivone Leong commented on gene: HMBS
Bleeding and platelet disorders v1.30 FLNA Arina Puzriakova Publications for gene: FLNA were set to 29449050; 21960593; 32299270
Inherited bleeding disorders v1.162 FLNA Arina Puzriakova Publications for gene: FLNA were set to
Bleeding and platelet disorders v1.29 FLNA Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'X-LINKED... biallelic mutations in females' to 'X-LINKED... monoallelic mutations in females may cause disease'.

FLNA-related periventricular nodular heterotopia (MIM# 300049) can be associated with macrothrombocytopenia and a bleeding tendency in some cases (PMID: 16684786; 21960593; 29449050; 32299270). Affected females with heterozygous variants in FLNA have been identified indicating XLD inheritance.

The association with macrothrombocytopenia has been supported by in vitro assays and animal model (PMID: 21652675; 21960593; 30602618; 31471375)
Bleeding and platelet disorders v1.29 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA 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)
Inherited bleeding disorders v1.161 FLNA Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'X-LINKED... biallelic mutations in females' to 'X-LINKED... monoallelic mutations in females may cause disease'.

FLNA-related periventricular nodular heterotopia (MIM# 300049) can be associated with macrothrombocytopenia and a bleeding tendency in some cases (PMID: 16684786; 21960593; 29449050; 32299270). Affected females with heterozygous variants in FLNA have been identified indicating XLD inheritance.

The association with macrothrombocytopenia has been supported by in vitro assays and animal model (PMID: 21652675; 21960593; 30602618; 31471375)
Inherited bleeding disorders v1.161 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA 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)
Cutaneous photosensitivity with a likely genetic cause v1.8 GATA1 Ivone Leong Tag Q3_21_rating tag was added to gene: GATA1.
Cutaneous photosensitivity with a likely genetic cause v1.8 GATA1 Ivone Leong Tag Q3_21_expert_review tag was added to gene: GATA1.
Cutaneous photosensitivity with a likely genetic cause v1.8 GATA1 Ivone Leong reviewed gene: GATA1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Inherited bleeding disorders v1.160 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Macrothrombocytopenia to Heterotopia, periventricular, 1, OMIM:300049; Macrothrombocytopenia
Cytopenia - NOT Fanconi anaemia v1.42 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Cytopenia - NOT Fanconi anaemia v1.41 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from to Heterotopia, periventricular, 1, OMIM:300049; Macrothrombocytopenia
Bleeding and platelet disorders v1.28 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from (NO OMIM NUMBER); Macrothrombocytopenia to Heterotopia, periventricular, 1, OMIM:300049; Macrothrombocytopenia
Cutaneous photosensitivity with a likely genetic cause v1.8 GATA1 Ivone Leong Publications for gene: GATA1 were set to
Arthrogryposis v3.109 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from FLNA-related disorders; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120; Terminal osseous dysplasia 300244 to Frontometaphyseal dysplasia 1, OMIM:305620; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244
Intellectual disability v3.1170 ASCC3 Ivone Leong Classified gene: ASCC3 as Amber List (moderate evidence)
Intellectual disability v3.1170 ASCC3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. New publication (https://doi.org/10.1016/j.xhgg.2021.100024) describing 11 individuals from 7 unrelated families (1 family was originally described in PMID: 21937992 and had mild ID). Patients had phenotypes ranging from mild to severe developmental dealys. As ID is not the prominant phenotype, this gene has been given an Amber rating.
Intellectual disability v3.1170 ASCC3 Ivone Leong Gene: ascc3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne edited their review of gene: ACAT2: Changed rating: GREEN
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne changed review comment from: Cytosolic acetoacetyl-CoA thiolase deficiency.
Inheritance - isolated cases.
Based on literature the ACAT2 gene encodes cytosolic acetoacetyl-CoA thiolase, which is important in the utilization of ketone bodies. ACAT2 gene can cause disorders of ketone body metabolism. ACAT2 gene is included in international classification of inherited metabolic
disorders (ICIMD).; to: Cytosolic acetoacetyl-CoA thiolase deficiency.
Inheritance - isolated cases.
Based on literature the ACAT2 gene encodes cytosolic acetoacetyl-CoA thiolase, which is important in the utilization of ketone bodies. ACAT2 gene can cause disorders of ketone body metabolism. ACAT2 gene is included in international classification of inherited metabolic
disorders (ICIMD).
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne reviewed gene: ACAT2: Rating: ; Mode of pathogenicity: None; Publications: PMID:33340416, PMID:20597, PMID:6150136; Phenotypes: Increased serum lactate and pyruvate, High levels of ketones, Low levels of cytosolic acetoacetyl-CoA thiolase, Hypotonia, Severe developmental delay; Mode of inheritance: None
Arthrogryposis v3.108 FLNA Arina Puzriakova Classified gene: FLNA as Amber List (moderate evidence)
Arthrogryposis v3.108 FLNA Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder on OMIM and G2P. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Arthrogryposis v3.108 FLNA Arina Puzriakova Gene: flna has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.107 FLNA Arina Puzriakova Tag Q3_21_rating tag was added to gene: FLNA.
Intellectual disability v3.1169 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Frontometaphyseal dysplasia, 305620Heterotopia, periventricular, ED variant, 300537FG syndrome 2, 300321Cardiac valvular dysplasia, X-linked, 314400Terminal osseous dysplasia, 300244Congenital short bowel syndrome, 300048; EPILEPTIC ENCEPHALOPATHY to Heterotopia, periventricular, 1, OMIM:300049; Otopalatodigital syndrome, type II, OMIM:304120; ?FG syndrome 2, OMIM:300321
Intellectual disability v3.1168 ASCC3 Ivone Leong Publications for gene: ASCC3 were set to 21937992; 26350204
Congenital myopathy v2.56 ASCC3 Ivone Leong Classified gene: ASCC3 as Amber List (moderate evidence)
Congenital myopathy v2.56 ASCC3 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 gene-disease association) but not OMIM. There is enough evidence for this gene to be Green.
Congenital myopathy v2.56 ASCC3 Ivone Leong Gene: ascc3 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne Deleted their review
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne Deleted their comment
Mitochondrial disorders v2.47 ACAT2 Andžela Lazdāne gene: ACAT2 was added
gene: ACAT2 was added to Mitochondrial disorders. Sources: Literature
Mode of inheritance for gene: ACAT2 was set to Other
Publications for gene: ACAT2 were set to 33340416; 20597; 6150136
Phenotypes for gene: ACAT2 were set to Increased serum lactate and pyruvate; high levels of ketones
Review for gene: ACAT2 was set to GREEN
Added comment: Cytosolic acetoacetyl-CoA thiolase deficiency
Inheritance - isolated cases
Sources: Literature
Malformations of cortical development v2.45 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Periventricular Heterotopia 300049; Melnick-Needles syndrome 309350; Otopalatodigital syndrome, type I 311300; Otopalatodigital syndrome, type II 304120 to Heterotopia, periventricular, 1, OMIM:300049
Intestinal failure v1.42 FLNA Arina Puzriakova Added comment: Comment on mode of inheritance: Female carriers do not exhibit gastrointestinal defects indicating XLR inheritance
Intestinal failure v1.42 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA 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
Ehlers Danlos syndromes v2.59 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from to Cardiac valvular dysplasia, X-linked, OMIM:314400; Heterotopia, periventricular, 1, OMIM:300049
Congenital myopathy v2.55 ASCC3 Ivone Leong Tag Q3_21_rating tag was added to gene: ASCC3.
Pigmentary skin disorders v1.12 FLNA Arina Puzriakova Added comment: Comment on mode of inheritance: Terminal osseous dysplasia (associated with pigmentary skin defects) is an X-linked dominant male-lethal disease
Pigmentary skin disorders v1.12 FLNA Arina Puzriakova Mode of inheritance for gene: FLNA 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)
Pigmentary skin disorders v1.11 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Terminal osseous dysplasia with pigmentary defects to Terminal osseous dysplasia, OMIM:300244
Thoracic aortic aneurysm and dissection v1.13 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders; Cardiac valvular dysplasia, X-linked 314400 to Cardiac valvular dysplasia, X-linked, OMIM:314400; Heterotopia, periventricular, 1, OMIM:300049
Thoracic aortic aneurysm or dissection v1.119 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders to Cardiac valvular dysplasia, X-linked, OMIM:314400; Heterotopia, periventricular, 1, OMIM:300049
Familial non syndromic congenital heart disease v1.61 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Cardiac valvular dysplasia, X-linked 314400 to Cardiac valvular dysplasia, X-linked, OMIM:314400
Intestinal failure v1.41 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Congenital short bowel syndrome, OMIM:300048 to Congenital short bowel syndrome, OMIM:300048; Intestinal pseudoobstruction, neuronal, OMIM:300048; ?FG syndrome 2, OMIM:300321
Gastrointestinal neuromuscular disorders v1.15 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Intestinal pseudoobstruction, neuronal 300048; Congenital short bowel syndrome 300048 to Congenital short bowel syndrome, OMIM:300048; Intestinal pseudoobstruction, neuronal, OMIM:300048
Congenital myopathy v2.55 TPM2 Ivone Leong commented on gene: TPM2: As there are only currently 2 homozygous cases, there is currently not enough evidence to support a change in MOI. It should also be noted that the parents (heterozygous for the variants) were asymptomatic.
Intellectual disability v3.1167 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1167 ACSL4 Ivone Leong Deleted their review
Intellectual disability v3.1167 ACSL4 Ivone Leong changed review comment from: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

Based on the available evidence the MOI should be 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)".; to: ACSL4 is said to be X-linked dominant in OMIM.

PMID: 12525535 - a family with 4 affected males, 1 unaffected male, 2 carrier females and 1 non-carrier female. All affected males full scale IQ (FSIQ) ranged from 43-71, unaffected male FSIQ is 116, carrier females ranged from 74-83 and non-carrier female is 133. All carrier females showed 100% skewed inactivation.

PMID: 11889465 - Family MRX63, all carrier females showed complete skewed X-inactivation. All affected males showed non-specific, non-progressive mental deficiency (moderate - severe). Carrier females showed highly variable cognitive capacities (normal to moderate).

As there are only 2 cases where carrier females have a phenotype, the MOI should be kept as "X-LINKED: hemizygous mutation in males, biallelic mutations in females".
Clefting v2.33 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Orofacial Clefting with skeletal anomalies; Otopalatodigital syndrome, type I, 311300 (includes clefting); Otopalatodigital syndrome, type II, 304120 (includes clefting); Melnick-Needles syndrome, 309350 (includes clefting); OTOPALATODIGITAL SYNDROME, TYPE I; OPD1, OTOPALATODIGITAL SYNDROME, TYPE II; OPD2, FRONTOMETAPHYSEAL DYSPLASIA 1; FMD1 to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120
Craniosynostosis v2.24 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from frontometaphyseal dysplasia; oto-palato-digital syndromes; melnick-needles syndrome to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120
Skeletal dysplasia v2.107 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Terminal osseous dysplasia 300244; Otopalatodigital syndrome, type II -304120; Otopalatodigital syndrome, type II 304120 XLD; Otopalatodigital syndrome, type I -311300; Melnick Needles syndrome 309350; Frontometaphyseal dysplasia 305620; Frontometaphyseal dysplasia 305620 XLR; Osteodysplasty Melnick Needles 309350 XLD to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244
Limb disorders v2.44 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Frontometaphyseal dysplasia 305620 XLR; Melnick-Needles syndrome, 309350; Osteodysplasty Melnick Needles 309350 XLD; Otopalatodigital syndrome, type II 304120 XLD; Terminal osseous dysplasia 300244 to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244
Radial dysplasia v1.14 FLNA Arina Puzriakova Phenotypes for gene: FLNA were changed from Melnick-Needles syndrome, 309350 to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244
Congenital myopathy v2.55 TPM2 Ivone Leong Phenotypes for gene: TPM2 were changed from CAP myopathy 2, OMIM:609285; Nemaline myopathy 4, autosomal dominant, OMIM:609285; Arthrogryposis multiplex congenita, distal, type1, OMIM:108120: Arthrogryposis, distal, type 2B, OMIM:601680; Congenital myopathy, MONDO:0019952; Multiple pterygium syndrome, MONDO:0017415 to CAP myopathy 2, OMIM:609285; Nemaline myopathy 4, autosomal dominant, OMIM:609285; Congenital myopathy, MONDO:0019952; Multiple pterygium syndrome, MONDO:0017415
Congenital myopathy v2.54 TPM2 Ivone Leong Phenotypes for gene: TPM2 were changed from CAP myopathy 2, OMIM:609285; Nemaline myopathy 4, autosomal dominant, OMIM:609285; Arthrogryposis multiplex congenita, distal, type1, OMIM:108120: Arthrogryposis, distal, type 2B, OMIM:601680 to CAP myopathy 2, OMIM:609285; Nemaline myopathy 4, autosomal dominant, OMIM:609285; Arthrogryposis multiplex congenita, distal, type1, OMIM:108120: Arthrogryposis, distal, type 2B, OMIM:601680; Congenital myopathy, MONDO:0019952; Multiple pterygium syndrome, MONDO:0017415
Congenital myopathy v2.53 TPM2 Ivone Leong Added comment: Comment on publications: PMID: 19155175 and 33558124 describe the 2 homozygous cases
Congenital myopathy v2.53 TPM2 Ivone Leong Publications for gene: TPM2 were set to 12592607; 11738357; 17434307; 24692096; 32092148; 27726070
Congenital myopathy v2.52 TPM2 Ivone Leong Phenotypes for gene: TPM2 were changed from CAP myopathy 2 609285; Nemaline myopathy 4, autosomal dominant 609285; Arthrogryposis multiplex congenita, distal, type1 108120: Arthrogryposis, distal, type 2B 601680 to CAP myopathy 2, OMIM:609285; Nemaline myopathy 4, autosomal dominant, OMIM:609285; Arthrogryposis multiplex congenita, distal, type1, OMIM:108120: Arthrogryposis, distal, type 2B, OMIM:601680
Congenital myopathy v2.51 TNNC2 Ivone Leong Tag Q3_21_rating tag was added to gene: TNNC2.
Congenital myopathy v2.51 TNNC2 Ivone Leong Classified gene: TNNC2 as Amber List (moderate evidence)
Congenital myopathy v2.51 TNNC2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is currently 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.
Congenital myopathy v2.51 TNNC2 Ivone Leong Gene: tnnc2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.50 TNNC2 Ivone Leong Phenotypes for gene: TNNC2 were changed from congenital myopathy to congenital myopathy, MONDO:0019952
Congenital myopathy v2.49 TNNC2 Ivone Leong Added comment: Comment on publications: PMID:26924529 was incorrectly entered for TNNC2
Congenital myopathy v2.49 TNNC2 Ivone Leong Publications for gene: TNNC2 were set to 26924529
Skeletal Muscle Channelopathies v1.32 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonia; MYOTONIC DYSTROPHY 1 (DM1) to Myotonic dystrophy 1, OMIM:160900
Distal myopathies v1.31 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from MYOTONIC DYSTROPHY 1 (DM1) to Myotonic dystrophy 1, OMIM:160900
Paroxysmal central nervous system disorders v1.16 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from MYOTONIC DYSTROPHY 1 (DM1); Myotonia to Myotonic dystrophy 1, OMIM:160900
Paediatric motor neuronopathies v1.69 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from spinal muscular atrophy, myotonic dystrophy (type 1), Prader-Willi syndrome, Angelman syndrome, and maternal UPD 14. to Myotonic dystrophy 1, OMIM:160900
Paediatric motor neuronopathies v1.68 DMPK Arina Puzriakova Mode of inheritance for gene: DMPK was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.689 DMPK_CTG Arina Puzriakova Tag STR tag was added to STR: DMPK_CTG.
Tag Q3_21_rating tag was added to STR: DMPK_CTG.
Tag Q3_21_expert_review tag was added to STR: DMPK_CTG.
DDG2P v2.37 DMPK_CTG Arina Puzriakova Tag STR tag was added to STR: DMPK_CTG.
Tag Q3_21_rating tag was added to STR: DMPK_CTG.
Tag Q3_21_expert_review tag was added to STR: DMPK_CTG.
Fetal anomalies v1.689 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Amber List (moderate evidence)
Fetal anomalies v1.689 DMPK_CTG Arina Puzriakova Added comment: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1. The DMPK gene was demoted and this STR was added to this panel to ensure that cases are appropriately detected.

Only relevant prenatally if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.
Fetal anomalies v1.689 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Amber List (Moderate Evidence).
DDG2P v2.37 DMPK_CTG Arina Puzriakova changed review comment from: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the the DMPK gene was demoted and this STR was added to capture this entity and ensure that cases are detected.

Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.; to: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the DMPK gene was demoted and this STR was added to ensure that cases are appropriately captured.

Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.
DDG2P v2.37 DMPK_CTG Arina Puzriakova changed review comment from: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the DMPK_CTG STR has been added to capture this entity and ensure that cases are detected.

Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.; to: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the the DMPK gene was demoted and this STR was added to capture this entity and ensure that cases are detected.

Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.
DDG2P v2.37 DMPK_CTG Arina Puzriakova Classified STR: DMPK_CTG as Amber List (moderate evidence)
DDG2P v2.37 DMPK_CTG Arina Puzriakova Added comment: Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the DMPK_CTG STR has been added to capture this entity and ensure that cases are detected.

Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.
DDG2P v2.37 DMPK_CTG Arina Puzriakova Str: dmpk_ctg has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.688 DMPK_CTG Arina Puzriakova Entity copied from Skeletal muscle channelopathy v1.31
Fetal anomalies v1.688 DMPK_CTG Arina Puzriakova STR: DMPK_CTG was added
STR: DMPK_CTG was added to Fetal anomalies. Sources: Expert Review Green,Expert list
Mode of inheritance for STR: DMPK_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DMPK_CTG were set to 7825566
Phenotypes for STR: DMPK_CTG were set to Myotonic dystrophy 1, OMIM:160900
DDG2P v2.36 DMPK_CTG Arina Puzriakova Entity copied from Skeletal muscle channelopathy v1.31
DDG2P v2.36 DMPK_CTG Arina Puzriakova STR: DMPK_CTG was added
STR: DMPK_CTG was added to DDG2P. Sources: Expert Review Green,Expert list
Mode of inheritance for STR: DMPK_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DMPK_CTG were set to 7825566
Phenotypes for STR: DMPK_CTG were set to Myotonic dystrophy 1, OMIM:160900
Skeletal muscle channelopathy v1.31 DMPK_CTG Arina Puzriakova Phenotypes for STR: DMPK_CTG were changed from Myotonic dystrophy 1, 16090 to Myotonic dystrophy 1, OMIM:160900
Fetal anomalies v1.687 DMPK Arina Puzriakova changed review comment from: Comment on list classification: This gene should be demoted from Green to Red at the next GMS review due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.; to: Comment on list classification: This gene should be demoted from Green to Red at the next GMS review due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.

DMPK_CTG STR will be added to the panel to capture this entity and ensure that cases are detected.
DDG2P v2.35 DMPK Arina Puzriakova Tag Q3_21_rating tag was added to gene: DMPK.
DDG2P v2.35 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
DDG2P v2.35 DMPK Arina Puzriakova Classified gene: DMPK as Green List (high evidence)
DDG2P v2.35 DMPK Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS review due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene.

However, the evidence level for this expansion is high (it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1), and as DDG2P is a component of the Paediatric disorders super panel, the DMPK_CTG STR will be added to the panel to capture this entity and ensure that cases are detected.
DDG2P v2.35 DMPK Arina Puzriakova Gene: dmpk has been classified as Green List (High Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.136 DMPK Arina Puzriakova changed review comment from: Comment on list classification: Demoted from Green to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.; to: Comment on list classification: Demoted from Amber to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Childhood onset dystonia or chorea or related movement disorder v1.136 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Childhood onset dystonia or chorea or related movement disorder v1.136 DMPK Arina Puzriakova Phenotypes for gene: DMPK were changed from Myotonic dystrophy 1, 16090 to Myotonic dystrophy 1, OMIM:160900
Childhood onset dystonia or chorea or related movement disorder v1.135 DMPK Arina Puzriakova Classified gene: DMPK as Red List (low evidence)
Childhood onset dystonia or chorea or related movement disorder v1.135 DMPK Arina Puzriakova Added comment: Comment on list classification: Demoted from Green to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Childhood onset dystonia or chorea or related movement disorder v1.135 DMPK Arina Puzriakova Gene: dmpk has been classified as Red List (Low Evidence).
Fetal anomalies v1.687 DMPK Arina Puzriakova Classified gene: DMPK as Green List (high evidence)
Fetal anomalies v1.687 DMPK Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS review due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Fetal anomalies v1.687 DMPK Arina Puzriakova Gene: dmpk has been classified as Green List (High Evidence).
Fetal anomalies v1.686 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Tag Q3_21_rating tag was added to gene: DMPK.
Severe Paediatric Disorders v1.81 DMPK Arina Puzriakova Classified gene: DMPK as Red List (low evidence)
Severe Paediatric Disorders v1.81 DMPK Arina Puzriakova Added comment: Comment on list classification: Demoted from Green to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Severe Paediatric Disorders v1.81 DMPK Arina Puzriakova Gene: dmpk has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.442 CD28 Arina Puzriakova Classified gene: CD28 as Red List (low evidence)
Primary immunodeficiency v2.442 CD28 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Rating Red as only a single family has been reported to date (PMID: 34214472). Some supportive functional data, but additional cases required prior to promoting this gene.
Primary immunodeficiency v2.442 CD28 Arina Puzriakova Gene: cd28 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.441 CXCR2 Zornitza Stark gene: CXCR2 was added
gene: CXCR2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CXCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CXCR2 were set to 24777453
Phenotypes for gene: CXCR2 were set to WHIM syndrome 2 619407
Review for gene: CXCR2 was set to RED
Added comment: 2 sisters with neutropaenia, myelokathexis, and recurrent bacterial infections and homozygous frameshift variant in this gene.
Sources: Literature
Intellectual disability v3.1167 HID1 Zornitza Stark gene: HID1 was added
gene: HID1 was added to Intellectual disability. Sources: Literature
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
Review for gene: HID1 was set to GREEN
Added comment: 7 individuals from 6 unrelated families reported. Clinical features included: hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy.
Sources: Literature
Intellectual disability v3.1167 KIF1B Zornitza Stark gene: KIF1B was added
gene: KIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1B were set to 33710394
Phenotypes for gene: KIF1B were set to Hypotonia; coloboma; hypoplasia of the corpus callosum; severe neurodevelopmental delay
Review for gene: KIF1B was set to RED
Added comment: Compound heterozygous missense variants reported in a woman with severe hypotonia, hypsarrhythmia, coloboma, hypoplasia of corpus callosum, severe neurodevelopmental delay.
Sources: Literature
Intellectual disability v3.1167 JPH3 Zornitza Stark gene: JPH3 was added
gene: JPH3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: JPH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH3 were set to 33824468
Phenotypes for gene: JPH3 were set to Intellectual disability; dystonia
Review for gene: JPH3 was set to RED
Added comment: One homozygous truncating variant (NM_020655.4: c.1740dup; p.(Val581Argfs*137)) found in a female individual affected with neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. No functional work.

STRs in this gene are associated with HD-like disorder.
Sources: Literature
Intellectual disability v3.1167 ERGIC3 Zornitza Stark gene: ERGIC3 was added
gene: ERGIC3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ERGIC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERGIC3 were set to 33710394; 31585110
Phenotypes for gene: ERGIC3 were set to Intellectual disability
Review for gene: ERGIC3 was set to AMBER
Added comment: PMID: 33710394 - two homozygous sibs with mild ID, a novel canonical splice (c.717+1G>A). Absent in gnomAD, no splice studies. Classed as a VUS.

PMID: 31585110 - 1 hom (p.Gln233Argfs*10) in a male 8yo with Growth retardation, Microcephaly, Learning disability, Facial dysmorphism, Abnormal pigmentation.
Sources: Literature
Severe microcephaly v2.217 NUF2 Zornitza Stark gene: NUF2 was added
gene: NUF2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Intellectual disability v3.1167 ZC3H14 Zornitza Stark reviewed gene: ZC3H14: Rating: AMBER; Mode of pathogenicity: None; Publications: 21734151, 33710394, 28666327; Phenotypes: Mental retardation, autosomal recessive 56 MIM#617125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1167 MYT1 Zornitza Stark gene: MYT1 was added
gene: MYT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYT1 were set to 33710394
Phenotypes for gene: MYT1 were set to Intellectual disability
Review for gene: MYT1 was set to RED
Added comment: Missense variant reported de novo in a patient with mild ID reported in a cohort study. Patient also had a COL9A2 variant and skeletal features. Authors referred to it as an extended phenotype and dual diagnosis.
Sources: Literature
Intellectual disability v3.1167 ATP1A2 Zornitza Stark changed review comment from: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.; to: Alternating hemiplegia: Although some of the symptoms of this condition are episodic, intellectual disability is a recognised feature.
Intellectual disability v3.1167 ATP1A2 Zornitza Stark edited their review of gene: ATP1A2: Added comment: PMID 33880529: six individuals with de novo missense variants reported and DD/EE/PMG.; Changed publications to: 33880529; Changed phenotypes to: Alternating hemiplegia of childhood 1, MIM# 104290, Developmental and epileptic encephalopathy
Intellectual disability v3.1167 HEATR5B Zornitza Stark gene: HEATR5B was added
gene: HEATR5B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: HEATR5B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEATR5B were set to 33824466
Phenotypes for gene: HEATR5B were set to pontocerebellar hypoplasia; intellectual disability; seizures
Review for gene: HEATR5B was set to AMBER
Added comment: Four affected children from two families presenting with pontocerebellar hypoplasiawith neonatal seizures, severe ID and motor delay. Two homozygous splice variants were reported (c.5051–1G>A and c.5050+4A>G) in intron 31 of HEATR5B gene. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. Homozygous knockout mice were not viable
Sources: Literature
Intellectual disability v3.1167 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Early motor and language development were normal but were delayed after the first year of life. Cognitive testing showed a verbal IQ of 55 and a visual performance IQ of 63. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Severe microcephaly v2.217 RING1 Eleanor Williams changed review comment from: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature; to: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13 which falls into the severe microcephaly category. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Severe microcephaly v2.217 RING1 Eleanor Williams gene: RING1 was added
gene: RING1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RING1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RING1 were set to 29386386
Phenotypes for gene: RING1 were set to microcephaly; intellectual disability
Review for gene: RING1 was set to RED
Added comment: Not associated with any phenotype in OMIM.

PMID: 29386386 - Pierce et al 2018 - report a 13 yo female with a de novo RING1 p.R95Q variant and syndromic neurodevelopmental disabilities. Head circumference at birth was -4.9 SD, and -4.2 SD at age 13. C. elegans with either the missense mutation or complete knockout of spat-3 (the suggested RING1 ortholog) were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance.
Sources: Literature
Genetic epilepsy syndromes v2.389 RNF2 Eleanor Williams Classified gene: RNF2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.389 RNF2 Eleanor Williams Added comment: Comment on list classification: Promoting to amber as there are 2 cases reported
Genetic epilepsy syndromes v2.389 RNF2 Eleanor Williams Gene: rnf2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.388 RNF2 Eleanor Williams gene: RNF2 was added
gene: RNF2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: RNF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RNF2 were set to 33864376
Phenotypes for gene: RNF2 were set to epilepsy; intellectual disability; intrauterine growth retardation
Review for gene: RNF2 was set to AMBER
Added comment: Not associated with any phenotype in OMIM.

PMID:33864376 (Luo et al 2021) report 2 cases of children with de novo missense variants (p.R70H and p.S82R) in RNF2 and a phenotype of intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Seizures started in infancy. Both variants are absent from gnomad. Functional studies in Drosophila showed that the disease-linked variants (p.R70H and p.S82R) behave as LoF alleles.
Sources: Literature
Retinal disorders v2.193 IRX6 Eleanor Williams Tag cnv tag was added to gene: IRX6.
Skeletal dysplasia v2.106 DLX5 Tracy Lester edited their review of gene: DLX5: Added comment: This gene is primarily monoallelic inheritance, many families reported. Biallelic inheritance has been rarely reported and seems to result in a more severe phenotype with deafness as well. Please update mode of inheritance to include monoallelic as well as biallelic, as a variant in this gene was almost missed because it was not in the tier 1 and 2. Thanks; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Set current diagnostic: yes
Retinal disorders v2.193 IRX5 Eleanor Williams edited their review of gene: IRX5: Changed phenotypes to: cone dystrophy, MONDO:0000455, retinitis pigmentosa, MONDO:0019200
Retinal disorders v2.193 IRX6 Eleanor Williams changed review comment from: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol 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.
Sources: Literature; to: Not associated with any disorder in OMIM or Gene2Phenotype.

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.
Sources: Literature
Retinal disorders v2.193 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.

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 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).
Retinal disorders v2.193 IRX5 Eleanor Williams edited their review of gene: IRX5: Changed publications to: 33891002, 28041643, 32045705, 22581230, 17230486
Retinal disorders v2.193 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.

Cone dystrophy
-------------------
PMID: 33891002 - Khol 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.

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. ; 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.

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).
Paediatric disorders - additional genes v1.94 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
Fetal anomalies v1.686 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
CAKUT v1.163 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
Skeletal dysplasia v2.106 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
VACTERL-like phenotypes v1.32 WBP11 Ivone Leong Phenotypes for gene: WBP11 were changed from malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, OMIM:619227
Fetal anomalies v1.685 TMEM94 Ivone Leong Phenotypes for gene: TMEM94 were changed from Intellectual developmental disorder with cardiac defects and dysmorphic facies to Intellectual developmental disorder with cardiac defects and dysmorphic facies, OMIM:618316
Unexplained paediatric onset end-stage renal disease v1.19 TBC1D8B Ivone Leong Added comment: Comment on phenotypes: Previously:
Steroid-resistant nephrotic syndrome
Unexplained paediatric onset end-stage renal disease v1.19 TBC1D8B Ivone Leong Phenotypes for gene: TBC1D8B were changed from Steroid-resistant nephrotic syndrome to Nephrotic syndrome, type 20, OMIM:301028
Proteinuric renal disease v2.51 TBC1D8B Ivone Leong Added comment: Comment on phenotypes: Previously:
Steroid-resistant nephrotic syndrome
Proteinuric renal disease v2.51 TBC1D8B Ivone Leong Phenotypes for gene: TBC1D8B were changed from Steroid-resistant nephrotic syndrome to Nephrotic syndrome, type 20, OMIM:301028
Intellectual disability v3.1166 PPP1R21 Ivone Leong Added comment: Comment on phenotypes: Previously:
Hepatosplenomegaly;Abnormality of the respiratory system;Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology
Intellectual disability v3.1166 PPP1R21 Ivone Leong Phenotypes for gene: PPP1R21 were changed from Hepatosplenomegaly; Abnormality of the respiratory system; Generalized hypotonia, Feeding difficulties, Profound global developmental delay, Abnormality of the face, Abnormality of vision, Abnormal heart morphology to Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities, OMIM:619383
Intellectual disability v3.1165 NTNG2 Ivone Leong Phenotypes for gene: NTNG2 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures to Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia, OMIM:618718
Mitochondrial disorders v2.47 NDUFAF8 Ivone Leong Phenotypes for gene: NDUFAF8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Inborn errors of metabolism v2.151 NDUFAF8 Ivone Leong Phenotypes for gene: NDUFAF8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Possible mitochondrial disorder - nuclear genes v1.49 NDUFAF8 Ivone Leong Phenotypes for gene: NDUFAF8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Mitochondrial disorder with complex I deficiency v1.14 NDUFAF8 Ivone Leong Phenotypes for gene: NDUFAF8 were changed from No OMIM phenotype to Mitochondrial complex I deficiency, nuclear type 34, OMIM:618776
Primary immunodeficiency v2.441 PDCD1 Arina Puzriakova Classified gene: PDCD1 as Red List (low evidence)
Primary immunodeficiency v2.441 PDCD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Rating Red as only a single patient reported to date with relevant phenotype (PMID: 34183838)
Primary immunodeficiency v2.441 PDCD1 Arina Puzriakova Gene: pdcd1 has been classified as Red List (Low Evidence).
Congenital myopathy v2.48 TPM2 Ivone Leong Publications for gene: TPM2 were set to 12592607; 11738357; 17434307; 24692096
Intellectual disability v3.1164 CUX2 Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: CUX2.
Intellectual disability v3.1164 CUX2 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'Monoallelic... paternally imprinted (maternal allele expressed)' to 'Monoallelic... NOT imprinted', in line with Tracy Lester's recent review highlighting there is no evidence of imprinting in this gene.
Intellectual disability v3.1164 CUX2 Arina Puzriakova Mode of inheritance for gene: CUX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myopathy v2.47 ASCC3 Ivone Leong Phenotypes for gene: ASCC3 were changed from congenital myopathy to congenital myopathy, MONDO:0019952
Congenital myopathy v2.46 MYOD1 Ivone Leong Tag Q3_21_rating tag was added to gene: MYOD1.
Congenital myopathy v2.46 MYOD1 Ivone Leong Classified gene: MYOD1 as Amber List (moderate evidence)
Congenital myopathy v2.46 MYOD1 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.
Congenital myopathy v2.46 MYOD1 Ivone Leong Gene: myod1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1163 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Changed phenotypes to: Developmental and epileptic encephalopathy
Intellectual disability v3.1163 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Sixteen individuals reported with DD/EE.; Changed publications to: 33880529; Changed phenotypes to: Alternating hemiplegia of childhood 2, MIM#614820, Developmental and epileptic encephalopathy
Intellectual disability v3.1163 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 33710394
Phenotypes for gene: SAMD9L were set to Intellectual disability
Review for gene: SAMD9L was set to RED
Added comment: Missense variant reported de novo in a patient with moderate ID, in a large cohort study. Authors described it as a phenotype expansion as ataxia-pancytopenia not found in that patient.
Sources: Literature
Skeletal ciliopathies v1.10 GRK2 Zornitza Stark gene: GRK2 was added
gene: GRK2 was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: GRK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRK2 were set to 33200460
Phenotypes for gene: GRK2 were set to Jeune asphyxiating thoracic dystrophy (ATD)
Review for gene: GRK2 was set to AMBER
Added comment: Two unrelated families reported and some functional data.
Sources: Literature
Primary lymphoedema v2.13 TIE1 Zornitza Stark gene: TIE1 was added
gene: TIE1 was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: TIE1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TIE1 were set to 32947856; 24764452
Phenotypes for gene: TIE1 were set to Lymphatic malformation 11, MIM# 619401
Review for gene: TIE1 was set to AMBER
Added comment: Three families reported, supportive animal model, though variants are missense and present at a low frequency in gnomad, hence Amber rating suggested.
Sources: Literature
Rare multisystem ciliopathy disorders v1.142 TTC26 Zornitza Stark gene: TTC26 was added
gene: TTC26 was added to Rare multisystem ciliopathy disorders. Sources: Literature
Mode of inheritance for gene: TTC26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC26 were set to 34177428; 32617964; 31595528; 24596149; 22718903
Phenotypes for gene: TTC26 were set to Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations
Review for gene: TTC26 was set to GREEN
Added comment: 9 families and functional data including zebrafish model.
Sources: Literature
Craniosynostosis v2.23 RNU12 Zornitza Stark gene: RNU12 was added
gene: RNU12 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU12 were set to 34085356
Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations
Review for gene: RNU12 was set to GREEN
Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Craniosynostosis is a major feature of the condition.
Sources: Literature
Renal tubulopathies v2.25 KCNJ16 Zornitza Stark gene: KCNJ16 was added
gene: KCNJ16 was added to Renal tubulopathies. Sources: Literature
Mode of inheritance for gene: KCNJ16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KCNJ16 were set to 33811157; 33840812
Phenotypes for gene: KCNJ16 were set to Renal tubulopathy; deafness
Review for gene: KCNJ16 was set to GREEN
Added comment: 8 unrelated families reported.
Sources: Literature
Skeletal dysplasia v2.105 SLCO2A1 Zornitza Stark reviewed gene: SLCO2A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23509104, 27134495, 33852188, 22331663, 27134495; Phenotypes: Hypertrophic osteoarthropathy, primary, autosomal dominant, MIM# 167100, Hypertrophic osteoarthropathy, primary, autosomal recessive 2, MIM# 614441; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v2.150 CLPB Zornitza Stark reviewed gene: CLPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25597510, 34140661; Phenotypes: 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropaenia, MIM# 616271; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurological ciliopathies v1.15 IFT74 Zornitza Stark gene: IFT74 was added
gene: IFT74 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT74 were set to 33531668
Phenotypes for gene: IFT74 were set to Joubert syndrome
Review for gene: IFT74 was set to GREEN
Added comment: Gene is associated with BBS. Note new publication:

PMID 33531668: Identified IFT74 as a JBTS-associated gene in 3 unrelated families through WES. All the affected individuals carried truncated variants and shared one missense variant (p.Q179E) found only in East Asians. The expression of the human p.Q179E-IFT74 variant displayed compromised rescue effects in zebrafish ift74 morphants. Attenuated ciliogenesis; altered distribution of IFT proteins and ciliary membrane proteins, including ARL13B, INPP5E, and GPR161; and disrupted hedgehog signaling were observed in patient fibroblasts with IFT74 variants.
Sources: Literature
Intellectual disability v3.1163 RFX4 Zornitza Stark gene: RFX4 was added
gene: RFX4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX4 were set to 33658631
Phenotypes for gene: RFX4 were set to ID, ASD, ADHD
Review for gene: RFX4 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX3 Zornitza Stark gene: RFX3 was added
gene: RFX3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX3 were set to 33658631
Phenotypes for gene: RFX3 were set to ID, ASD, ADHD
Review for gene: RFX3 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Intellectual disability v3.1163 RFX7 Zornitza Stark gene: RFX7 was added
gene: RFX7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: RFX7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RFX7 were set to 33658631
Phenotypes for gene: RFX7 were set to ID, ASD, ADHD
Review for gene: RFX7 was set to GREEN
Added comment: Report of 38 individuals (from 33 unrelated families) with de novo or inherited loss of function variants in RFX3 (15 families), RFX4 (4 families), and RFX7 (14 families), identified through WES. Individuals share neurobehavioural features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. These genes are potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Sources: Literature
Hypogonadotropic hypogonadism idiopathic v1.43 SEMA3F Zornitza Stark gene: SEMA3F was added
gene: SEMA3F was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3F were set to 33495532
Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism
Review for gene: SEMA3F was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates.
Sources: Literature
Hypogonadotropic hypogonadism idiopathic v1.43 PLXNA3 Zornitza Stark gene: PLXNA3 was added
gene: PLXNA3 was added to Hypogonadotropic hypogonadism idiopathic. Sources: Literature
Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLXNA3 were set to 33495532
Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism
Review for gene: PLXNA3 was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants.
In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.188 FARSA Zornitza Stark edited their review of gene: FARSA: Added comment: PMID 33598926: three additional families reported. Functional evidence was obtained with reduced FARS1 enzyme activity levels in fibroblasts or EBV-transformed lymphoblastoid cell lines (EBV-LCLs) of patients. Common to all was a chronic interstitial lung disease starting early in life and characterized by bilateral ground-glass opacification on HR-CT, and cholesterol pneumonitis in lung histology. Additional abnormalities in other organ systems include liver disease, neurological manifestations, and growth restriction.; Changed rating: GREEN; Changed publications to: 31355908, 33598926; Changed phenotypes to: Rajab interstitial lung disease with brain calcifications 2, MIM# 619013
Retinal disorders v2.193 IRX5 Eleanor Williams Phenotypes for gene: IRX5 were changed from cone dystrophy, MONDO:0000455 to cone dystrophy, MONDO:0000455; retinitis pigmentosa, MONDO:0019200
Retinal disorders v2.192 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.

Cone dystrophy
-------------------
PMID: 33891002 - Khol 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.; 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.

Cone dystrophy
-------------------
PMID: 33891002 - Khol 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.

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.
Retinal disorders v2.192 IRX5 Eleanor Williams Tag cnv tag was added to gene: IRX5.
Tag Q3_21_rating tag was added to gene: IRX5.
Retinal disorders v2.192 IRX5 Eleanor Williams Phenotypes for gene: IRX5 were changed from Retinitis pigmentosa to cone dystrophy, MONDO:0000455
Retinal disorders v2.191 IRX5 Eleanor Williams Publications for gene: IRX5 were set to 28041643
Retinal disorders v2.190 IRX5 Eleanor Williams Mode of pathogenicity for gene: IRX5 was changed from to Other
Retinal disorders v2.189 IRX5 Eleanor Williams Mode of inheritance for gene: IRX5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe early-onset obesity v2.39 PHIP David Hunt gene: PHIP was added
gene: PHIP was added to Severe early-onset obesity. Sources: Literature
Mode of inheritance for gene: PHIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHIP were set to 27900362; 29209020; 31167805; 32492392; 33867250
Phenotypes for gene: PHIP were set to Obesity; global developmental delay; intellectual disability; behavioral abnormality; dysmorphic facies
Penetrance for gene: PHIP were set to unknown
Review for gene: PHIP was set to GREEN
Added comment: Multiple peer-reviewed publications reporting a high rate of childhood-onset obesity in PHIP-related neurodevelopmental disorder (a.k.a. Chung-Jansen syndrome).
Sources: Literature
Retinal disorders v2.188 IRX6 Eleanor Williams changed review comment from: PMID: 33891002 - Khol 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.
Sources: Literature; to: Not associated with any disorder in OMIM or Gene2Phenotype.

PMID: 33891002 - Khol 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.
Sources: Literature
Retinal disorders v2.188 IRX6 Eleanor Williams edited their review of gene: IRX6: Changed rating: GREEN
Retinal disorders v2.188 IRX6 Eleanor Williams gene: IRX6 was added
gene: IRX6 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: IRX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IRX6 were set to 33891002
Phenotypes for gene: IRX6 were set to cone dystrophy, MONDO:0000455
Mode of pathogenicity for gene: IRX6 was set to Other
Added comment: PMID: 33891002 - Khol 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.
Sources: Literature
Retinal disorders v2.187 IRX5 Eleanor Williams edited their review of gene: IRX5: Changed mode of pathogenicity: Other
Retinal disorders v2.187 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.

Cone dystrophy
-------------------
PMID: 33891002 - Khol et al 2021 - report 3 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.; 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.

Cone dystrophy
-------------------
PMID: 33891002 - Khol 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.
Retinal disorders v2.187 IRX5 Eleanor Williams reviewed gene: IRX5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33891002; Phenotypes: cone dystrophy, MONDO:0000455; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1163 GNB2 Arina Puzriakova Classified gene: GNB2 as Amber List (moderate evidence)
Intellectual disability v3.1163 GNB2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Intellectual disability v3.1163 GNB2 Arina Puzriakova Gene: gnb2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1162 GNB2 Arina Puzriakova gene: GNB2 was added
gene: GNB2 was added to Intellectual disability. Sources: Literature
Q3_21_rating tags were added to gene: GNB2.
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GNB2 were set to 31698099; 33971351; 34183358
Phenotypes for gene: GNB2 were set to Intellectual disability
Review for gene: GNB2 was set to GREEN
Added comment: GNB2 is not yet associated with any phenotype in OMIM, but has a 'confirmed' disease confidence rating for 'GNB2-related developmental disorder (monoallelic)' in G2P.

At least 14 unrelated individuals with de novo monoallelic variants, including 5 recurrent variants in 13 individuals (PMIDs: 31698099; 33971351; 34183358). All patients (except one fetus owing to termination of pregnancy) have DD/ID of variable severity (mild to severe) which appeared to correlate with the variant each individual harboured. Other variable features include non-specific facial dysmorphism, hypotonia, and autistic behaviour.
Sources: Literature
Genetic epilepsy syndromes v2.387 DNM1 Arina Puzriakova Publications for gene: DNM1 were set to EuroEPINOMICS-RES Consortium (2014) AJHG 95:1-11; 25262651; 27066543
Genetic epilepsy syndromes v2.386 DNM1 Arina Puzriakova Tag watchlist tag was added to gene: DNM1.
Genetic epilepsy syndromes v2.386 DNM1 Arina Puzriakova Classified gene: DNM1 as Green List (high evidence)
Genetic epilepsy syndromes v2.386 DNM1 Arina Puzriakova Added comment: Comment on list classification: Currently, there is only enough evidence for an Amber rating for the biallelic form and so I have kept the MOI as just 'Monoallelic' at this time. If this is a genuine association, biallelic cases would still be picked by the Genomics England pipeline under this MOI. Added watchlist tag in anticipation of further biallelic cases emerging.
Genetic epilepsy syndromes v2.386 DNM1 Arina Puzriakova Gene: dnm1 has been classified as Green List (High Evidence).
Genetic epilepsy syndromes v2.385 DNM1 Arina Puzriakova reviewed gene: DNM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34172529; Phenotypes: Developmental and epileptic encephalopathy 31, OMIM:616346; Mode of inheritance: None
Hereditary ataxia v1.233 ABCB7 Ivone Leong Phenotypes for gene: ABCB7 were changed from Anemia, sideroblastic, with ataxia, ; Sideroblastic Anemia and Ataxia to Anemia, sideroblastic, with ataxia, OMIM:301310
Ataxia and cerebellar anomalies - narrow panel v2.220 ABCB7 Ivone Leong Phenotypes for gene: ABCB7 were changed from Anemia, sideroblastic, with ataxia,; Sideroblastic Anemia and Ataxia to Anemia, sideroblastic, with ataxia, OMIM:301310
Intellectual disability v3.1161 DNM1 Arina Puzriakova Phenotypes for gene: DNM1 were changed from EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 31, OMIM:616346
Genetic epilepsy syndromes v2.385 DNM1 Arina Puzriakova Phenotypes for gene: DNM1 were changed from Epileptic encephalopathy, early infantile, 31, 616346 to Developmental and epileptic encephalopathy 31, OMIM:616346
Cytopenias and congenital anaemias v1.85 ABCB7 Ivone Leong Added comment: Comment on phenotypes: Previously:
Sideroblastic Anemia and Ataxia
Cytopenias and congenital anaemias v1.85 ABCB7 Ivone Leong Phenotypes for gene: ABCB7 were changed from Sideroblastic Anemia and Ataxia; Anemia, sideroblastic, with ataxia, 301310 to Anemia, sideroblastic, with ataxia, OMIM:301310
Severe microcephaly v2.216 ATP9A Arina Puzriakova changed review comment from: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree, postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature; to: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree (2 mild, 1 severe), postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
Severe microcephaly v2.216 ATP9A Arina Puzriakova Classified gene: ATP9A as Amber List (moderate evidence)
Severe microcephaly v2.216 ATP9A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases/clinical evidence.
Severe microcephaly v2.216 ATP9A Arina Puzriakova Gene: atp9a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.215 ATP9A Arina Puzriakova gene: ATP9A was added
gene: ATP9A was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: ATP9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP9A were set to http://dx.doi.org/10.1136/jmedgenet-2021-107843
Phenotypes for gene: ATP9A were set to Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms
Review for gene: ATP9A was set to AMBER
Added comment: Vogt et al. 2021 report on 3 individuals from 2 unrelated consanguineous families with different homozygous truncating variants in ATP9A, presenting with DD/ID of variable degree, postnatal microcephaly (OFC range: −2.33 SD to −3.58 SD), failure to thrive, and gastrointestinal symptoms. Patient-derived fibroblasts showed reduced expression of ATP9A, and consistent with previous findings also overexpression of interacting partners, ARPC3 and SNX3.
Sources: Literature
DDG2P v2.34 ATP6V1A Arina Puzriakova edited their review of gene: ATP6V1A: Changed rating: GREEN; Changed publications to: 28065471, 33320377, 29668857, 32045939
DDG2P v2.34 ATP6V1A Arina Puzriakova Classified gene: ATP6V1A as Amber List (moderate evidence)
DDG2P v2.34 ATP6V1A Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
DDG2P v2.34 ATP6V1A Arina Puzriakova Gene: atp6v1a has been classified as Amber List (Moderate Evidence).
DDG2P v2.33 ATP6V1A Arina Puzriakova Tag Q2_21_rating was removed from gene: ATP6V1A.
Tag Q3_21_rating tag was added to gene: ATP6V1A.
DDG2P v2.33 ATP6V1A Arina Puzriakova Tag Q2_21_rating tag was added to gene: ATP6V1A.
DDG2P v2.33 ATP6V1A Arina Puzriakova Publications for gene: ATP6V1A were set to 28065471
DDG2P v2.32 ATP6V1A Arina Puzriakova Added comment: Comment on mode of inheritance: Despite the different disease confidence ratings associated with each MOI in G2P, there is enough evidence in the literature to support pathogenicity of both biallelic and monoallelic variants in ATP6V1A.

As DDG2P is a component panel of the Paediatric disorders super panel, the MOI has been updated from 'Biallelic' to 'Both mono- and biallelic' to ensure that all cases are captured.
DDG2P v2.32 ATP6V1A Arina Puzriakova Mode of inheritance for gene: ATP6V1A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.31 ATP6V1A Arina Puzriakova reviewed gene: ATP6V1A: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v2.31 ATP6V1A Arina Puzriakova Phenotypes for gene: ATP6V1A were changed from Autosomal Recessive Cutis Laxa to Autosomal Recessive Cutis Laxa (AR); Epileptic encephalopathy, infantile or early childhood, 3 (AD)
Ehlers Danlos syndromes v2.58 ATP6V1A Arina Puzriakova Publications for gene: ATP6V1A were set to 28065471
Intellectual disability v3.1160 ATP6V1A Arina Puzriakova Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3 618012; Cutis laxa, autosomal recessive, type IID 617403 to Developmental and epileptic encephalopathy 93, OMIM:618012
Severe Paediatric Disorders v1.80 ATP6V1A Arina Puzriakova Phenotypes for gene: ATP6V1A were changed from Epileptic encephalopathy, infantile or early childhood, 3, 618012; Cutis laxa, autosomal recessive, type IID, 617403 to Cutis laxa, autosomal recessive, type IID, OMIM:617403; Developmental and epileptic encephalopathy 93, OMIM:618012
Intellectual disability v3.1159 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from ATAXIA-TELANGIECTASIA; AT to Ataxia-telangiectasia, OMIM:208900
Hereditary neuropathy v1.387 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Hereditary Neuropathies; Ataxia-telangiectasia to Ataxia-telangiectasia, OMIM:208900; Hereditary Neuropathies
Hereditary ataxia - adult onset v2.81 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Ataxia-telangiectasia, 607585; Ataxia-Telangiectasia to Ataxia-telangiectasia, OMIM:208900
Hereditary neuropathy NOT PMP22 copy number v1.30 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Hereditary Neuropathies; Ataxia-telangiectasia to Ataxia-telangiectasia, OMIM:208900; Hereditary Neuropathies
Childhood onset dystonia or chorea or related movement disorder v1.134 ATM Arina Puzriakova Phenotypes for gene: ATM were changed from Dystonia; Ataxia telangiectasia, 208900 to Ataxia-telangiectasia, OMIM:208900
Intellectual disability v3.1158 ATP2C2 Eleanor Williams gene: ATP2C2 was added
gene: ATP2C2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATP2C2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP2C2 were set to 33864365; 28440294
Phenotypes for gene: ATP2C2 were set to language impairment, HP:0002463
Review for gene: ATP2C2 was set to RED
Added comment: PMID: 33864365 - Martinelli et al 2021 - report a family with a missense variant NM_001286527.2:c.304G>A, p.(Val102Met) in ATP2C2 in a father and two siblings with specific language impairment. However two other affected siblings did not have this variant. This variant was also reported by Chen et al. They found that the variant had a higher frequency in language cases (1.8%, N = 360) compared with cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). They postulate that variant is not sufficient on its own to cause a disorder but is a susceptibility factor which increases the risk for language impairment.

PMID: 28440294 - Chen et al 2017 - report 2 probands with severe learning impairment, and missense variants in ATP2C2 (NM_001286527: c.G304A:p.V102M and NM_001291454:exon21: c.C1936T:p.R646W).
Sources: Literature
Rhabdomyolysis and metabolic muscle disorders v1.46 OBSCN Eleanor Williams reviewed gene: OBSCN: Rating: RED; Mode of pathogenicity: None; Publications: 33438037; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.177 P2RX2 Eleanor Williams reviewed gene: P2RX2: Rating: ; Mode of pathogenicity: None; Publications: 33791800; Phenotypes: ; Mode of inheritance: None
Hypocalciuric hypercalcaemia v2.9 AP2S1 Eleanor Williams changed review comment from: PMID: 33729479 - Hannan et al 2021 - Created mice with the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, homozygous mice died perinatally, The heterozygous mice showed hypercalcaemia, hypermagnesaemia, hypophosphataemia. The phenotype can be ameliorated by treatment with cinacalcet.; to: Additional evidence from mouse model that is representative for FHH3 in humans:
PMID: 33729479 - Hannan et al 2021 - Created mice with the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, homozygous mice died perinatally, The heterozygous mice showed hypercalcaemia, hypermagnesaemia, hypophosphataemia. The phenotype can be ameliorated by treatment with cinacalcet.
Hypocalciuric hypercalcaemia v2.9 AP2S1 Eleanor Williams Publications for gene: AP2S1 were set to 23222959; 28176280; 24081735; 25993639; 26082470
Hypocalciuric hypercalcaemia v2.8 AP2S1 Eleanor Williams reviewed gene: AP2S1: Rating: ; Mode of pathogenicity: None; Publications: 33729479; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - childhood onset v2.45 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183; Spastic paraplegia
Hereditary spastic paraplegia - childhood onset v2.44 ATAD3A Arina Puzriakova reviewed gene: ATAD3A: Rating: ; Mode of pathogenicity: None; Publications: 28158749, 27640307, 33845882; Phenotypes: Harel-Yoon syndrome, OMIM:617183, Spastic paraplegia; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v1.48 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810
Mitochondrial disorders v2.46 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome 617183 to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810
Inborn errors of metabolism v2.150 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome 617183 to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Lactic acidosis; Methylglutaconic aciduria
Cerebral vascular malformations v2.55 CBL Zornitza Stark reviewed gene: CBL: Rating: GREEN; Mode of pathogenicity: None; Publications: 28343148, 25283271, 28589114; Phenotypes: early-onset moyamoya angiopathy, Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, 613563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.467 ATAD3A Arina Puzriakova Publications for gene: ATAD3A were set to 27640307
Undiagnosed metabolic disorders v1.466 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Lactic acidosis; Methylglutaconic aciduria; Neurological abnormalities; Cerebellar hypoplasia; Optic atrophy; Hypertrophic cardiomyopathy; Scoliosis; Spinal muscular atrophy to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Lactic acidosis; Methylglutaconic aciduria
Undiagnosed metabolic disorders v1.465 ATAD3A Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'Biallelic' to 'Both mono- and biallelic'.

At least 6 families with heterozygous variants (PMID: 27640307; 28158749) and 7 unrelated families with biallelic SNVs in this gene (PMID: 27640307; 29053797; 31727539; 32607449; 33845882). Metabolic evaluation often show elevated 3-methylglutaconate and lactate in patients with variants in this gene.
Undiagnosed metabolic disorders v1.465 ATAD3A Arina Puzriakova Mode of inheritance for gene: ATAD3A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.46 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome: optic atrophy, peripheral neuropathy, delayed psychomotor development, intellectual disability, spastic paraplegia (HAYOS), 617183 to Harel-Yoon syndrome, OMIM:617183
Hypertrophic cardiomyopathy - teen and adult v2.22 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183
Cataracts v2.75 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183
Fetal anomalies v1.684 ATAD3A Arina Puzriakova Publications for gene: ATAD3A were set to 27640307; 28327206
Fetal anomalies v1.683 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from ATAD3A disorder - global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy; ATAD3A disorder - global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy; Harel-Yoon syndrome, 617183 to ATAD3A disorder - global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy; Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810
DDG2P v2.30 ATAD3A Arina Puzriakova Tag watchlist was removed from gene: ATAD3A.
Tag Q3_21_MOI tag was added to gene: ATAD3A.
Fetal anomalies v1.682 ATAD3A Arina Puzriakova Tag watchlist was removed from gene: ATAD3A.
Tag Q3_21_MOI tag was added to gene: ATAD3A.
Fetal anomalies v1.682 ATAD3A Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel review.

At least 7 unrelated families have now been reported with biallelic SNVs in ATAD3A, including 5 families with Harel-Yoon syndrome, MIM# 617183 (PMID: 27640307; 32607449; 33845882) and 2 families with neonatal lethal pontocerebellar hypoplasia, MIM# 618810 (PMID: 29053797; 31727539). Both of these phenotypes are pertinent to this panel.
Fetal anomalies v1.682 ATAD3A Arina Puzriakova Mode of inheritance for gene: ATAD3A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
DDG2P v2.30 ATAD3A Arina Puzriakova Added comment: Comment on mode of inheritance: Although the MOI has been set to 'Monoallelic' only, to reflect the different disease confidence ratings associated with each MOI in G2P, there is enough evidence in the literature to support pathogenicity of biallelic variants in ATAD3A.

As DDG2P is a component panel of the Paediatric disorders super panel, the MOI should be updated to 'Both mono- and biallelic' to ensure that all cases are captured.
DDG2P v2.30 ATAD3A Arina Puzriakova Mode of inheritance for gene: ATAD3A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - narrow panel v2.219 ATAD3A Arina Puzriakova changed review comment from: Comment on mode of inheritance: Changed MOI from 'Both mono- and biallelic' to 'Biallelic' only.

ATAD3A is associated with Harel-Yoon syndrome (MIM# 617183) with both dominant and recessive patterns of inheritance. However, only families with the biallelic form displayed cerebellar atrophy (PMID: 27640307; 32607449; 33845882). Brain MRI results have been normal in heterozygous cases to date.

Furthermore, biallelic variants in ATAD3A are also associated with another phenotype comprising neonatal lethal pontocerebellar hypoplasia (MIM# 618810) - at least 13 unrelated families in literature, including 2 families with SNVs (PMID: 29053797; 31727539) and 11 families with deletions affecting ATAD3A (PMID: 27640307; 28549128; 29053797; 33845882); to: ATAD3A is associated with Harel-Yoon syndrome (MIM# 617183) with both dominant and recessive patterns of inheritance. However, only families with the biallelic form displayed cerebellar atrophy (PMID: 27640307; 32607449; 33845882). Brain MRI results have been normal in heterozygous cases to date (MOI set to 'Biallelic' only).

Furthermore, biallelic variants in ATAD3A are also associated with another phenotype comprising neonatal lethal pontocerebellar hypoplasia (MIM# 618810) - at least 13 unrelated families in literature, including 2 families with SNVs (PMID: 29053797; 31727539) and 11 families with deletions affecting ATAD3A (PMID: 27640307; 28549128; 29053797; 33845882)
Ataxia and cerebellar anomalies - narrow panel v2.219 ATAD3A Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Amber to Green, as the number of unrelated families (at least 7) with cerebellar/pontocerebellar hypoplasia and biallelic SNVs in ATAD3A reaches the threshold for inclusion on this panel.; to: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update - the number of unrelated families (at least 7) with cerebellar/pontocerebellar hypoplasia and biallelic SNVs in ATAD3A reaches the threshold for inclusion on this panel.
Ataxia and cerebellar anomalies - narrow panel v2.219 ATAD3A Arina Puzriakova Tag Q2_21_rating tag was added to gene: ATAD3A.
Ataxia and cerebellar anomalies - narrow panel v2.219 ATAD3A Arina Puzriakova Classified gene: ATAD3A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.219 ATAD3A Arina Puzriakova Gene: atad3a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.218 ATAD3A Arina Puzriakova Entity copied from Cerebellar hypoplasia v1.52
Ataxia and cerebellar anomalies - narrow panel v2.218 ATAD3A Arina Puzriakova gene: ATAD3A was added
gene: ATAD3A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Green,Expert Review
Mode of inheritance for gene: ATAD3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28549128; 29053797; 31727539; 32607449; 33845882
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810
Cerebellar hypoplasia v1.52 ATAD3A Arina Puzriakova Classified gene: ATAD3A as Green List (high evidence)
Cerebellar hypoplasia v1.52 ATAD3A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Amber to Green, as the number of unrelated families (at least 7) with cerebellar/pontocerebellar hypoplasia and biallelic SNVs in ATAD3A reaches the threshold for inclusion on this panel.
Cerebellar hypoplasia v1.52 ATAD3A Arina Puzriakova Gene: atad3a has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.51 ATAD3A Arina Puzriakova changed review comment from: Comment on mode of inheritance: Changed MOI from 'Both mono- and biallelic' to 'Biallelic' only.

ATAD3A is associated with Harel-Yoon syndrome (MIM# 617183) with both dominant and recessive patterns of inheritance. However, only the family with the biallelic form displayed cerebellar atrophy (PMID: 27640307; 32607449; 33845882). Brain MRI results have been normal in heterozygous cases to date.

Furthermore, biallelic variants in ATAD3A are also associated with another phenotype comprising neonatal lethal pontocerebellar hypoplasia (MIM# 618810) - at least 13 unrelated families in literature, including 2 families with SNVs (PMID: 29053797; 31727539) and 11 families with deletions affecting ATAD3A (PMID: 27640307; 28549128; 29053797; 33845882); to: Comment on mode of inheritance: Changed MOI from 'Both mono- and biallelic' to 'Biallelic' only.

ATAD3A is associated with Harel-Yoon syndrome (MIM# 617183) with both dominant and recessive patterns of inheritance. However, only families with the biallelic form displayed cerebellar atrophy (PMID: 27640307; 32607449; 33845882). Brain MRI results have been normal in heterozygous cases to date.

Furthermore, biallelic variants in ATAD3A are also associated with another phenotype comprising neonatal lethal pontocerebellar hypoplasia (MIM# 618810) - at least 13 unrelated families in literature, including 2 families with SNVs (PMID: 29053797; 31727539) and 11 families with deletions affecting ATAD3A (PMID: 27640307; 28549128; 29053797; 33845882)
Cerebellar hypoplasia v1.51 ATAD3A Arina Puzriakova edited their review of gene: ATAD3A: Changed rating: GREEN; Changed publications to: 27640307, 28549128, 29053797, 31727539, 32607449, 33845882; Changed phenotypes to: Harel-Yoon syndrome, OMIM:617183, Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.51 ATAD3A Arina Puzriakova Publications for gene: ATAD3A were set to 27640307; 25529582; 28549128; 29898916
Cerebellar hypoplasia v1.50 ATAD3A Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'Both mono- and biallelic' to 'Biallelic' only.

ATAD3A is associated with Harel-Yoon syndrome (MIM# 617183) with both dominant and recessive patterns of inheritance. However, only the family with the biallelic form displayed cerebellar atrophy (PMID: 27640307; 32607449; 33845882). Brain MRI results have been normal in heterozygous cases to date.

Furthermore, biallelic variants in ATAD3A are also associated with another phenotype comprising neonatal lethal pontocerebellar hypoplasia (MIM# 618810) - at least 13 unrelated families in literature, including 2 families with SNVs (PMID: 29053797; 31727539) and 11 families with deletions affecting ATAD3A (PMID: 27640307; 28549128; 29053797; 33845882)
Cerebellar hypoplasia v1.50 ATAD3A Arina Puzriakova Mode of inheritance for gene: ATAD3A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.49 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, OMIM:618810
Intellectual disability v3.1157 ACSL4 Ivone Leong Publications for gene: ACSL4 were set to
Intellectual disability v3.1156 ACSL4 Ivone Leong reviewed gene: ACSL4: Rating: ; Mode of pathogenicity: None; Publications: 12525535, 11889465; 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)
Primary immunodeficiency v2.440 PDCD1 Boaz Palterer gene: PDCD1 was added
gene: PDCD1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PDCD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD1 were set to 34183838
Phenotypes for gene: PDCD1 were set to Autoimmunity; splenomegaly; pneumonitis; tubercolosis
Penetrance for gene: PDCD1 were set to unknown
Added comment: Ogishi et al. described a patient with a homozygous frameshift mutation in the PDCD1 encoding the PD-1 protein. The patient presented with polyautoimmunity and tubercolosis, similarly to mice models of PD-1 deficiency and to patients treated with anti-PD-1 cancer immunotherapy.
Sources: Literature
Primary immunodeficiency v2.440 CD28 Boaz Palterer gene: CD28 was added
gene: CD28 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CD28 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD28 were set to 34214472
Phenotypes for gene: CD28 were set to cutaneous horn; immunodeficiency; papillomavirus infection; tree man syndrome; warts
Penetrance for gene: CD28 were set to unknown
Review for gene: CD28 was set to RED
Added comment: Beziat et al. describe 3 patients from a large kindred with homozygous mutations in CD28 causing loss of protein expression. The patients have severe HPV warts or tree man syndrome.
Extensive ex vivo functional data and mouse model are provided.
Sources: Literature
Intellectual disability v3.1156 ACSL4 Ivone Leong Tag Skewed X-inactivation tag was added to gene: ACSL4.
Intellectual disability v3.1156 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, MONDO:0010263
Intellectual disability v3.1155 ACSL4 Ivone Leong Phenotypes for gene: ACSL4 were changed from Mental retardation, X-linked 63, 300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR) to Mental retardation, X-linked 63, OMIM:300387; ALPORT SYNDROME WITH MENTAL RETARDATION MIDFACE HYPOPLASIA AND ELLIPTOCYTOSIS (ATS-MR)
Cardiomyopathies - including childhood onset v1.49 ACTA1 Ivone Leong commented on gene: ACTA1: Reviewed a number of publications about the association of ACTA1 with cardiomyopathy. All affected patients have heterozygous variants in ACTA1. Therefore, MOI should stay as Monoallelic.
Cardiomyopathies - including childhood onset v1.49 ACTA1 Ivone Leong Publications for gene: ACTA1 were set to 26888179; 16945537; 32969603
Cardiomyopathies - including childhood onset v1.48 ACTA1 Ivone Leong Publications for gene: ACTA1 were set to 26888179; 16945537
Arthrogryposis v3.107 ACTA1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACTA1.
Arthrogryposis v3.107 ACTA1 Ivone Leong reviewed gene: ACTA1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cardiomyopathies - including childhood onset v1.47 ACTA1 Ivone Leong Phenotypes for gene: ACTA1 were changed from Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Nemaline myopathy 3, autosomal dominant or recessive 161800; CMD with rigid spine; Myopathy, congenital, with fiber-type disproportion 1 255310 to Dilated cardiomyopathy, MONDO:0005021; Hypertrophic cardiomyopathy, MONDO:0005045; Nemaline myopathy 3, autosomal dominant or recessive, OMIM:161800; CMD with rigid spine; Myopathy, congenital, with fiber-type disproportion 1, OMIM:255310
Cardiomyopathies - including childhood onset v1.46 ACTA1 Ivone Leong Publications for gene: ACTA1 were set to doi:10. 1007/ s12265-016-9673-5; 16945537
Fetal anomalies v1.681 ACTA1 Ivone Leong Phenotypes for gene: ACTA1 were changed from NEMALINE MYOPATHY 3 to Nemaline myopathy 3, autosomal dominant or recessive, OMIM:161800
Arthrogryposis v3.107 ACTA1 Ivone Leong Phenotypes for gene: ACTA1 were changed from Nemaline myopathy 3, autosomal dominant or recessive 161800; Myopathy, actin, congenital, with excess of thin myofilaments 161800; Myopathy, actin, congenital, with cores 161800; nemaline myopathy; Nemaline myopathy 3, autosomal dominant or recessive, 161800Myopathy, actin, congenital, with excess of thin myofilaments, 161800Myopathy, actin, congenital, with cores, 161800Myopathy, congenital, with fiber-type disproportion 1, 255310; Nemaline Myopathy; CMD with rigid spine to Myopathy, actin, congenital, with cores, OMIM:161800; Myopathy, actin, congenital, with excess of thin myofilaments, OMIM:161800; Myopathy, congenital, with fiber-type disproportion 1, OMIM:255310; Nemaline myopathy 3, autosomal dominant or recessive, OMIM:161800; CMD with rigid spine
Congenital myopathy v2.45 ACTA1 Ivone Leong Phenotypes for gene: ACTA1 were changed from Myopathy, actin, congenital, with cores; Myopathy, actin, congenital, with excess of thin myofilaments; Myopathy, congenital, with fiber-type disproportion 1; Nemaline myopathy 3 to Myopathy, actin, congenital, with cores, OMIM:161800; Myopathy, actin, congenital, with excess of thin myofilaments, OMIM:161800; Myopathy, congenital, with fiber-type disproportion 1, OMIM:255310; Nemaline myopathy 3, autosomal dominant or recessive, OMIM:161800
Distal myopathies v1.30 ACTA1 Ivone Leong Phenotypes for gene: ACTA1 were changed from Nemaline myopathy 3, 161800 to Nemaline myopathy 3, autosomal dominant or recessive, OMIM:161800
Bleeding and platelet disorders v1.27 ACTB Ivone Leong Tag Q3_21_MOI tag was added to gene: ACTB.
Bleeding and platelet disorders v1.27 ACTB Ivone Leong reviewed gene: ACTB: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and platelet disorders v1.27 ACTB Ivone Leong Phenotypes for gene: ACTB were changed from (NO OMIM NUMBER); AD thrombocytopenia to thrombocytopenia, MONDO:0002049 (AD)
Genetic epilepsy syndromes v2.384 ACOX1 Ivone Leong edited their review of gene: ACOX1: Changed phenotypes to: Mitchell syndrome, OMIM:618960
Genetic epilepsy syndromes v2.384 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: 32169171; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.384 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
Genetic epilepsy syndromes v2.384 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Genetic epilepsy syndromes v2.383 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to 18536048
Genetic epilepsy syndromes v2.382 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to 18536048
Genetic epilepsy syndromes v2.382 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to
Genetic epilepsy syndromes v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI was removed from gene: ACOX1.
Genetic epilepsy syndromes v2.381 ACOX1 Ivone Leong Deleted their review
Genetic epilepsy syndromes v2.381 ACOX1 Ivone Leong Deleted their comment
Genetic epilepsy syndromes v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
Genetic epilepsy syndromes v2.381 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.188 ACOX1 Ivone Leong changed review comment from: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect.

Therefore, MOI should be changed from Biallelic to Both monoallelic and biallelic (but biallelic mutations cuase a more severe disease form).; to: Comment on mode of inheritance: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect. AD causes Mitchell syndrome (OMIM:618960) and AR causes Peroxisomal acyl-CoA oxidase deficiency (OMIM:264470).

Therefore, MOI should be changed from Biallelic to Both monoallelic and biallelic (but biallelic mutations cuase a more severe disease form).
Inherited white matter disorders v1.129 ACOX1 Ivone Leong changed review comment from: Comment on mode of inheritance: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect. Therefore, MOI should be changed from Biallelic to Both monoallelic and biallelic (but biallelic mutations cuase a more severe disease form).; to: Comment on mode of inheritance: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect. AD causes Mitchell syndrome (OMIM:618960) and AR causes Peroxisomal acyl-CoA oxidase deficiency (OMIM:264470).

Therefore, MOI should be changed from Biallelic to Both monoallelic and biallelic (but biallelic mutations cuase a more severe disease form).
Intellectual disability v3.1154 EPHA7 Konstantinos Varvagiannis gene: EPHA7 was added
gene: EPHA7 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EPHA7 were set to 34176129; 19664229
Phenotypes for gene: EPHA7 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality
Penetrance for gene: EPHA7 were set to Incomplete
Review for gene: EPHA7 was set to AMBER
Added comment: Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.

The 6q microdeletion included additional ID-related genes in at least one case (eg. ZNF292 in P12) while one subject (P4) harbored also a 7q11.23 Williams syndrome deletion.

Confirmation (e.g. with FISH or qPCR) and segregation analyses were performed. 9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

Sequencing of an ID gene panel was performed for 5 subjects (P1-4 (sibs) and P9) and exome for 4 ones (P1,2,10,11). CNVs in all these subjects were not limited to EPHA7. These investigations did not reveal other variants responsible for the phenotype of these subjects.

EPHA7 encodes ephrin receptor A7. As the authors comment, ephrin receptors are the largest family of transmembrane receptor tyrosine kinases. These receptors interact with membrane bound ephrins and binding activates the tyrosine kinase activity of the receptor.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Finally the authors comment on a previous report of a de novo 2.16 Mb microdeletion spanning EPHA7 and another gene (TSG1). This deletion, reported by Traylor et al (2009 - PMID: 19664229) was identified in a 15-month old male with DD, microcephaly and dysmorphic features.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].

In DECIPHER there are 2 indivuals (DDD participants) with de novo missense variants and abnormality of the nervous system.

As a result this gene can be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.133 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency, 264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Fetal anomalies v1.680 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from ADRENOLEUKODYSTROPHY PSEUDONEONATAL; Peroxisomal acyl-CoA oxidase deficiency, 264470 to ADRENOLEUKODYSTROPHY PSEUDONEONATAL; Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Inborn errors of metabolism v2.149 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency; Peroxisomal acyl-CoA oxidase 1 deficiency (Disorders of peroxisomal alpha-, beta and omega-oxidation) to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Peroxisomal disorders v1.13 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470 to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Undiagnosed metabolic disorders v1.464 ACOX1 Ivone Leong Added comment: Comment on phenotypes: Previously:
Peroxisomal acyl-CoA oxidase 1 deficiency (Disorders of peroxisomal alpha-, beta and omega-oxidation);Peroxisomal acyl-CoA oxidase deficiency
Undiagnosed metabolic disorders v1.464 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase 1 deficiency (Disorders of peroxisomal alpha-, beta and omega-oxidation); Peroxisomal acyl-CoA oxidase deficiency to Peroxisomal acyl-CoA oxidase deficiency, OMIM:264470
Inherited white matter disorders v1.129 ACOX1 Ivone Leong Added comment: Comment on mode of inheritance: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect. Therefore, MOI should be changed from Biallelic to Both monoallelic and biallelic (but biallelic mutations cuase a more severe disease form).
Inherited white matter disorders v1.129 ACOX1 Ivone Leong Mode of inheritance for gene: ACOX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Inherited white matter disorders v1.128 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to 25655951; 11815777; 17458872; Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_648
Inherited white matter disorders v1.127 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960
White matter disorders and cerebral calcification - narrow panel v1.188 ACOX1 Ivone Leong Phenotypes for gene: ACOX1 were changed from Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Peroxisomal acyl-CoA oxidase deficiency 264470; General Leukodystrophy & Mitochondrial Leukoencephalopathy; Mitchell syndrome, OMIM:618960
White matter disorders and cerebral calcification - narrow panel v1.187 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
White matter disorders and cerebral calcification - narrow panel v1.187 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: 32169171; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.187 ACOX1 Ivone Leong Publications for gene: ACOX1 were set to Parikh et al. Molecular Genetics and Metabolism 114 (2015) 501_648; 17458872; 25655951; 11815777
Congenital muscular dystrophy v2.12 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from congenital muscular dystrophies; Congenital disorder of glycosylation, type Ie 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Congenital muscular dystrophy v2.11 DPM1 Arina Puzriakova Publications for gene: DPM1 were set to 23109149; 23856421
Congenital muscular dystrophy v2.10 DPM1 Arina Puzriakova Tag watchlist tag was added to gene: DPM1.
Congenital muscular dystrophy v2.10 DPM1 Arina Puzriakova reviewed gene: DPM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 10642597, 10642602, 15669674, 16641202, 23856421, 27481510, 28139241, 30653653; Phenotypes: Congenital disorder of glycosylation, type Ie, OMIM:608799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.214 DPM1 Arina Puzriakova changed review comment from: At least 12 individuals from 10 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.; to: At least 12 individuals from 10 unrelated families described in literature. 11/12 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.
Severe microcephaly v2.214 DPM1 Arina Puzriakova changed review comment from: At least 13 individuals from 11 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.; to: At least 12 individuals from 10 unrelated families described in literature. 12/13 had a variable degree of microcephaly - a sufficient number of cases (>3) had microcephaly of relevant severity to this panel. Acquired postnatally, and progressive in some cases.
Undiagnosed metabolic disorders v1.463 ALDH18A1 Sarah Leigh Publications for gene: ALDH18A1 were set to 27604308; 24816252
Inborn errors of metabolism v2.148 ALDH18A1 Sarah Leigh Publications for gene: ALDH18A1 were set to 27604308; 24816252; 29903433
Inborn errors of metabolism v2.147 ALDH18A1 Sarah Leigh edited their review of gene: ALDH18A1: Changed rating: GREEN
Inborn errors of metabolism v2.147 ALDH18A1 Sarah Leigh commented on gene: ALDH18A1: The mode of inheritance for this gene should be BOTH monoallelic and biallelic, autosomal or pseudoautosomal, as reduced levels of proline, ornithine, arginine, and citrulline have been reported in cases with both monoallelic and biallelic ALDH18A1 variants (PMIDs 11092761; 22170564; 26320891).
Undiagnosed metabolic disorders v1.462 ALDH18A1 Sarah Leigh reviewed gene: ALDH18A1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.462 ALDH18A1 Sarah Leigh Tag Q3_21_MOI tag was added to gene: ALDH18A1.
Inborn errors of metabolism v2.147 ALDH18A1 Sarah Leigh Tag Q3_21_MOI tag was added to gene: ALDH18A1.
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova edited their review of gene: ARHGEF9: Changed publications to: 17893116, 18615734, 28589176, 27238888, 30048823, 33600053, 32939676
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Tag Q3_21_MOI tag was added to gene: ARHGEF9.
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Added comment: Comment on mode of inheritance: Currently, the MOI in OMIM is set to XLR. Heterozygous mothers of affected males have been reported as unaffected, which combined with the fact that the first few affected females presented a skewed XCI pattern (PMIDs: 17893116; 18615734; 28589176), led to consider this defect as an XLR disorder affecting females when XCI is skewed.

However, review of the literature revealed that the chromosomal aberrations identified in these all of cases occurred de novo with one allele remaining as normal and cases with random XCI have since been reported (PMID: 27238888; 30048823). More recently, at least 4 unrelated affected females have also been identified with heterozygous SNVs and a random XCI pattern (PMIDs: 33600053; 32939676).

Overall this indicates that monoallelic variants in ARHGEF9 can cause disease in females and so the MOI should be changed from XLR to XLD (tagged)
Intellectual disability v3.1154 ARHGEF9 Arina Puzriakova Mode of inheritance for gene: ARHGEF9 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Haematological malignancies for rare disease v1.3 ACD Ivone Leong Mode of inheritance for gene: ACD 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
Haematological malignancies cancer susceptibility v2.17 ACD Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as the patient with AR inheritance had a more severe phenotype.
Haematological malignancies cancer susceptibility v2.17 ACD Ivone Leong Mode of inheritance for gene: ACD 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
Cytopenia - NOT Fanconi anaemia v1.40 ACD Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" as the patient with AR inheritance had a more severe phenotype.
Cytopenia - NOT Fanconi anaemia v1.40 ACD Ivone Leong Mode of inheritance for gene: ACD 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
Disorders of sex development v2.48 ATRX Eleanor Williams commented on gene: ATRX
Intellectual disability v3.1153 ARHGEF9 Arina Puzriakova Phenotypes for gene: ARHGEF9 were changed from Epileptic encephalopathy, early infantile, 8, 300607; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8 to Developmental and epileptic encephalopathy 8, OMIM:300607
Genetic epilepsy syndromes v2.381 ARHGEF9 Arina Puzriakova Phenotypes for gene: ARHGEF9 were changed from Epileptic encephalopathy, early infantile, 8 300607 to Developmental and epileptic encephalopathy 8, OMIM:300607
Hyperammonaemia v1.8 ALDH18A1 Sarah Leigh changed review comment from: Comment when marking as ready: Associated with Cutis laxa, autosomal recessive, type IIIA (219150) in OMIM, not in G2P / DD. At least 6 homozygous variants reported. Hyperammonaemia only reported in two siblings (PMID 24767728); to: Comment when marking as ready: Associated with Cutis laxa, autosomal recessive, type IIIA (219150) in OMIM, not in G2P / DD. At least 6 homozygous variants reported. Hyperammonaemia only reported in two siblings (PMID 11092761;24767728)
Disorders of sex development v2.48 AR Arina Puzriakova Phenotypes for gene: AR were changed from Gender Assignment Gene Panel UKGTN; Androgen insensitivity,300068; Androgen insensitivity,partial,with/without breast cancer,312300; Hypospadias 1,X-linked,300633 to Gender Assignment Gene Panel UKGTN; Androgen insensitivity, OMIM:300068; Androgen insensitivity,partial,with/without breast cancer, OMIM:312300; Hypospadias 1,X-linked, OMIM:300633
Intellectual disability v3.1152 AR Arina Puzriakova Phenotypes for gene: AR were changed from SPINAL AND BULBAR MUSCULAR ATROPHY to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.67 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from spinal and bulbar muscular atrophy; gynecomastia; muscular weakness to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Paediatric motor neuronopathies v1.66 AR_CAG Arina Puzriakova Publications for STR: AR_CAG were set to
Paediatric motor neuronopathies v1.65 AR_CAG Arina Puzriakova Tag STR tag was added to STR: AR_CAG.
Tag Q2_21_rating tag was added to STR: AR_CAG.
Paediatric motor neuronopathies v1.65 AR_CAG Arina Puzriakova Classified STR: AR_CAG as Amber List (moderate evidence)
Paediatric motor neuronopathies v1.65 AR_CAG Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this STR to Green at the next GMS panel update.

The AR gene was already Green on this panel for Kennedy disease, MIM# 313200 (https://panelapp.genomicsengland.co.uk/panels/79/gene/AR/); however, this was downgraded as the disease mechanism is an expansion of 36 or more CAG trinucleotide repeats in the AR gene and there is a lack of phenotypic relevance for SNVs. STR testing is appropriate route for detecting cases.
Paediatric motor neuronopathies v1.65 AR_CAG Arina Puzriakova Str: ar_cag has been classified as Amber List (Moderate Evidence).
Paediatric motor neuronopathies v1.64 AR Arina Puzriakova Publications for gene: AR were set to
Amyotrophic lateral sclerosis/motor neuron disease v1.33 AR_CAG Arina Puzriakova Phenotypes for STR: AR_CAG were changed from Spinal and bulbar muscular atrophy or Kennedy diseases 313200 to Spinal and bulbar muscular atrophy or Kennedy diseases, OMIM:313200
Amyotrophic lateral sclerosis/motor neuron disease v1.32 AR_CAG Arina Puzriakova Publications for STR: AR_CAG were set to 20301508; 2481485
Paediatric motor neuronopathies v1.63 AR Arina Puzriakova Tag Q2_21_rating tag was added to gene: AR.
Paediatric motor neuronopathies v1.63 AR Arina Puzriakova changed review comment from: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene should be downgraded to Red. The disease-relevant STR (i.e. AR_CAG) is already Green on this panel which is the appropriate route for detecting cases.; to: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene should be downgraded to Red. The disease-relevant STR (i.e. AR_CAG) has been added to this panel with the recommendation of a Green classification at the next GMS review, which is the appropriate route for detecting cases.
Paediatric motor neuronopathies v1.63 AR Arina Puzriakova Classified gene: AR as Green List (high evidence)
Paediatric motor neuronopathies v1.63 AR Arina Puzriakova Added comment: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene should be downgraded to Red. The disease-relevant STR (i.e. AR_CAG) is already Green on this panel which is the appropriate route for detecting cases.
Paediatric motor neuronopathies v1.63 AR Arina Puzriakova Gene: ar has been classified as Green List (High Evidence).
Inborn errors of metabolism v2.147 ALDH18A1 Sarah Leigh Publications for gene: ALDH18A1 were set to 27604308; 24816252
Amyotrophic lateral sclerosis/motor neuron disease v1.31 AR Arina Puzriakova changed review comment from: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene should be downgraded to Red. The disease-relevant STR (i.e. AR_CAG) is already Green on this panel which is the appropriate route for detecting cases.; to: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene was downgraded to Red. The disease-relevant STR (i.e. AR_CAG) is already Green on this panel which is the appropriate route for detecting cases.
Amyotrophic lateral sclerosis/motor neuron disease v1.31 AR Arina Puzriakova Phenotypes for gene: AR were changed from Spinal and bulbar muscular atrophy of Kennedy, 313200 to Spinal and bulbar muscular atrophy of Kennedy, OMIM:313200
Amyotrophic lateral sclerosis/motor neuron disease v1.30 AR Arina Puzriakova Classified gene: AR as Red List (low evidence)
Amyotrophic lateral sclerosis/motor neuron disease v1.30 AR Arina Puzriakova Added comment: Comment on list classification: Nucleotide repeat expansion mechanism. In view of a lack of phenotypic relevance for SNVs and Kennedy disease (MIM# 313200), this gene should be downgraded to Red. The disease-relevant STR (i.e. AR_CAG) is already Green on this panel which is the appropriate route for detecting cases.
Amyotrophic lateral sclerosis/motor neuron disease v1.30 AR Arina Puzriakova Gene: ar has been classified as Red List (Low Evidence).
Familial hypercholesterolaemia v1.28 APOB Arina Puzriakova Phenotypes for gene: APOB were changed from Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013); Gene part of the 6-SNP LDL-C gene score calculation (Futema et al, 2015); Ag linked Hypobetalipoproteinemia; Hypobetalipoproteinemia, normotriglyceridemic; Hypercholesterolemia, due to ligand-defective apo B, 144010; Familial Hypercholesterolemia; Hypercholesterolemia; Familial Hypercholesterolaemia to Hypercholesterolemia, familial, 2, OMIM:144010
Severe microcephaly v2.214 DPM1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM1.
Severe microcephaly v2.214 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Severe microcephaly v2.213 DPM1 Arina Puzriakova Publications for gene: DPM1 were set to 16641202; 10642602; 10642597
Severe microcephaly v2.212 DPM1 Arina Puzriakova Classified gene: DPM1 as Amber List (moderate evidence)
Severe microcephaly v2.212 DPM1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe microcephaly v2.212 DPM1 Arina Puzriakova Gene: dpm1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.211 DPM1 Arina Puzriakova reviewed gene: DPM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10642597, 10642602, 15669674, 16641202, 23856421, 27481510, 28139241, 30653653; Phenotypes: Congenital disorder of glycosylation, type Ie, OMIM:608799; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1151 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie, 608799; CONGENITAL DISORDERS OF GLYCOSYLATION to Congenital disorder of glycosylation, type Ie, OMIM:608799
Genetic epilepsy syndromes v2.380 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie, 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Inborn errors of metabolism v2.146 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie 608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type Ie, OMIM:608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Undiagnosed metabolic disorders v1.462 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type Ie 608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type Ie, OMIM:608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Skeletal dysplasia v2.105 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie 608799 to Congenital disorder of glycosylation, type Ie, OMIM:608799
Arthrogryposis v3.106 DPM1 Arina Puzriakova Mode of inheritance for gene: DPM1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.105 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from congenital muscular dystrophies to Congenital disorder of glycosylation, type Ie, OMIM:608799
Congenital disorders of glycosylation v2.71 DPM1 Arina Puzriakova Phenotypes for gene: DPM1 were changed from Congenital disorder of glycosylation, type Ie 608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type Ie, OMIM:608799; GDP-Man:Dol-P mannosyltransferase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Hereditary ataxia v1.232 SAR1B Eleanor Williams Classified gene: SAR1B as Amber List (moderate evidence)
Hereditary ataxia v1.232 SAR1B Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene from Green to amber. This is a disorder of fat malabsorption. Only 1 report of a case (PMID: 10665502) reported with a Marinesco-Sjogren syndrome diagnosis in which the siblings showed severe cerebellar ataxia with truncal and limb ataxia. See reviews on GMS Hereditary ataxia - adult onset and Ataxia and cerebellar anomalies - narrow panel.
Hereditary ataxia v1.232 SAR1B Eleanor Williams Gene: sar1b has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.217 SAR1B Eleanor Williams Phenotypes for gene: SAR1B were changed from Chylomicron retention disease to Chylomicron retention disease, OMIM:246700
Ataxia and cerebellar anomalies - narrow panel v2.216 SAR1B Eleanor Williams Publications for gene: SAR1B were set to
Ataxia and cerebellar anomalies - narrow panel v2.215 SAR1B Eleanor Williams Classified gene: SAR1B as Green List (high evidence)
Ataxia and cerebellar anomalies - narrow panel v2.215 SAR1B Eleanor Williams Added comment: Comment on list classification: Leaving rating as green, but with recommendation of a red rating following GMS review. Ataxia rarely reported and as the expert reviewer notes this is secondary to malabsorption.
Ataxia and cerebellar anomalies - narrow panel v2.215 SAR1B Eleanor Williams Gene: sar1b has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.214 SAR1B Eleanor Williams Tag Q2_21_rating tag was added to gene: SAR1B.
Ataxia and cerebellar anomalies - narrow panel v2.214 SAR1B Eleanor Williams reviewed gene: SAR1B: Rating: RED; Mode of pathogenicity: None; Publications: 12692552, 3792776, 7601203, 2426307, 10521380, 10665502, 17945526; Phenotypes: Chylomicron retention disease, OMIM:246700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.23 SNRPE Arina Puzriakova changed review comment from: Comment on list classification: With addition of a further case identified in the 100K Project, as highlighted by Gavin Ryan (WMRGL), there is now enough evidence to promote this gene to Green status at the next GMS panel update (tagged); to: Comment on list classification: With addition of a further case identified in the 100K Project, as highlighted by Gavin Ryan (WMRGL), there is now enough evidence to promote this gene to Green status at the next GMS panel update (tagged)

Pan et al. 2021 (PMID: 33792916) also recently reported on 3 further unrelated patients with hypotrichosis who were found to harbour two novel heterozygous variants (c.54+2T>A and c.221T>C), and one previously reported variant (c.1A>G), in SNRPE
Intellectual disability v3.1150 FBXO31 Ivone Leong commented on gene: FBXO31: There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intellectual disability v3.1150 FBXO31 Ivone Leong Tag watchlist was removed from gene: FBXO31.
Tag Q2_21_rating tag was added to gene: FBXO31.
Intellectual disability v3.1150 FBXO31 Ivone Leong Publications for gene: FBXO31 were set to 24623383; 32989326
Congenital muscular dystrophy v2.10 JAG2 Eleanor Williams Classified gene: JAG2 as Amber List (moderate evidence)
Congenital muscular dystrophy v2.10 JAG2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for a green rating at the next review. 13 cases reported with muscular dystrophy and variants in JAG2.
Congenital muscular dystrophy v2.10 JAG2 Eleanor Williams Gene: jag2 has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v2.9 JAG2 Eleanor Williams Tag Q2_21_rating tag was added to gene: JAG2.
Congenital muscular dystrophy v2.9 JAG2 Eleanor Williams Phenotypes for gene: JAG2 were changed from muscular dystrophy to muscular dystrophy, MONDO:0020121
Congenital muscular dystrophy v2.8 JAG2 Eleanor Williams reviewed gene: JAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33861953; Phenotypes: muscular dystrophy, MONDO:0020121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.23 SNRPE Arina Puzriakova Publications for gene: SNRPE were set to 23246290
Non-syndromic hypotrichosis v1.8 SNRPE Arina Puzriakova Phenotypes for gene: SNRPE were changed from Hypotrichosis 11, 615059; HYPT11 to Hypotrichosis 11, OMIM:615059
Hereditary spastic paraplegia - childhood onset v2.44 ARL6IP1 Eleanor Williams Phenotypes for gene: ARL6IP1 were changed from Spastic paraplegia to Spastic paraplegia 61, autosomal recessive, OMIM:615685; hereditary spastic paraplegia 61, MONDO:0014304
Ectodermal dysplasia v1.22 SNRPE Arina Puzriakova Phenotypes for gene: SNRPE were changed from Hypotrichosis 11, 615059; HYPT11 to Hypotrichosis 11, OMIM:615059
Hereditary spastic paraplegia - childhood onset v2.43 ARL6IP1 Eleanor Williams Publications for gene: ARL6IP1 were set to Novarino et al. (2014); 24482476; 28471035
Hereditary spastic paraplegia - childhood onset v2.42 ARL6IP1 Eleanor Williams Classified gene: ARL6IP1 as Amber List (moderate evidence)
Hereditary spastic paraplegia - childhood onset v2.42 ARL6IP1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber but with recommendation for promotion to green at the next review. 4 cases reported with 3 different variants.
Hereditary spastic paraplegia - childhood onset v2.42 ARL6IP1 Eleanor Williams Gene: arl6ip1 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - childhood onset v2.41 ARL6IP1 Eleanor Williams Tag Q2_21_rating tag was added to gene: ARL6IP1.
Hereditary spastic paraplegia - childhood onset v2.41 ARL6IP1 Eleanor Williams reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 31272422, 30980493, 28471035; Phenotypes: Spastic paraplegia 61, autosomal recessive, OMIM:615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ectodermal dysplasia v1.21 SNRPE Arina Puzriakova Tag Q2_21_rating tag was added to gene: SNRPE.
Tag Q2_21_NHS_review tag was added to gene: SNRPE.
Ectodermal dysplasia v1.21 SNRPE Arina Puzriakova Classified gene: SNRPE as Amber List (moderate evidence)
Ectodermal dysplasia v1.21 SNRPE Arina Puzriakova Added comment: Comment on list classification: With addition of a further case identified in the 100K Project, as highlighted by Gavin Ryan (WMRGL), there is now enough evidence to promote this gene to Green status at the next GMS panel update (tagged)
Ectodermal dysplasia v1.21 SNRPE Arina Puzriakova Gene: snrpe has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.44 MYOD1 Ivone Leong Phenotypes for gene: MYOD1 were changed from Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, MIM# 618975 to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975
Congenital myopathy v2.43 HACD1 Ivone Leong Tag watchlist was removed from gene: HACD1.
Tag Q2_21_rating tag was added to gene: HACD1.
Congenital myopathy v2.43 HACD1 Ivone Leong edited their review of gene: HACD1: Added comment: This gene is associated with a relevant phenotype in Gene2Phenotype and not OMIM. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Congenital myopathy v2.43 HACD1 Ivone Leong Phenotypes for gene: HACD1 were changed from congenital myopathy to congenital myopathy, MONDO:0019952
Congenital myopathy v2.42 HACD1 Ivone Leong Added comment: Comment on publications: PMID: 33354762. Three additional cases.
Congenital myopathy v2.42 HACD1 Ivone Leong Publications for gene: HACD1 were set to 23933735; 15829503; 32426512; 33354762
Congenital myopathy v2.41 HACD1 Ivone Leong Publications for gene: HACD1 were set to 23933735; 15829503; 32426512
Congenital myopathy v2.40 HACD1 Ivone Leong Publications for gene: HACD1 were set to 23933735
Congenital myopathy v2.39 SLC25A42 Ivone Leong Tag watchlist tag was added to gene: SLC25A42.
Congenital myopathy v2.39 SLC25A42 Ivone Leong Classified gene: SLC25A42 as Amber List (moderate evidence)
Congenital myopathy v2.39 SLC25A42 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. Currently there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Congenital myopathy v2.39 SLC25A42 Ivone Leong Gene: slc25a42 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.20 LEF1 Arina Puzriakova Tag deletions tag was added to gene: LEF1.
Ectodermal dysplasia v1.20 LEF1 Arina Puzriakova Classified gene: LEF1 as Red List (low evidence)
Ectodermal dysplasia v1.20 LEF1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Levy et al. 2020 (PMID: 32022899) report 2 patients with signs of ectodermal dysplasia harbouring de novo deletions that overlap only at the regions containing LEF1. Supportive mouse model. Rating Red as currently there is no evidence of SNVs in LEF1 relating to this phenotype.
Ectodermal dysplasia v1.20 LEF1 Arina Puzriakova Gene: lef1 has been classified as Red List (Low Evidence).
White matter disorders - adult onset v1.25 EPRS Eleanor Williams Classified gene: EPRS as Amber List (moderate evidence)
White matter disorders - adult onset v1.25 EPRS Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with recommendation for green rating following GMS review. 4 unrelated cases. Presentation generally before age of 18 but after consultation with the Genomics England clinical team it was decided that it was also appropriate to propose as green on the adult onset panel.
White matter disorders - adult onset v1.25 EPRS Eleanor Williams Gene: eprs has been classified as Amber List (Moderate Evidence).
White matter disorders - adult onset v1.24 EPRS Eleanor Williams Publications for gene: EPRS were set to 29576217
White matter disorders - adult onset v1.23 EPRS Eleanor Williams Tag Q2_21_rating tag was added to gene: EPRS.
White matter disorders - adult onset v1.23 EPRS Eleanor Williams edited their review of gene: EPRS: Added comment: As reported by the expert reviewer PMID: 29576217 (Mendes et al 2018) reports 4 unrelated affected individuals with hypomyelination and biallelic (homozygous or compound het) pathogenic variants in EPRS. 5 variants in total identified (1 nonsense, 1 frameshift, 3 missense). Variants segregated with the disease in all 4 families. All 4 presented initially before the age of 18 and in all brain MRI showed a hypomyelinating leukodystrophy with thinning of the corpus callosum. In 3 cases the variant was identified by WES, in one by direct sequencing of EPRS1.

PMID: 33805425 - Sawaguchi et al 2021 - using a mouse model they show that EPRS1 variant Arg339-to-Ter (R339X) (found in one of the patients in Mendes et al in heterozgyous state with another variant) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells. Wild-type proteins are distributed throughout the cell bodies. This seems to inhibit cell morphological differentiation.; Changed rating: GREEN; Changed publications to: 29576217, 33805425; Changed phenotypes to: Leukodystrophy, hypomyelinating, 15, OMIM:617951; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.38 SLC25A42 Ivone Leong Phenotypes for gene: SLC25A42 were changed from muscle weakness, lactic acidosis, and muscle changes suggestive of mitochondrial dysfunction to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression, OMIM:618416
Congenital myopathy v2.37 SLC25A42 Ivone Leong Publications for gene: SLC25A42 were set to 26541337
Severe microcephaly v2.211 TP53RK Eleanor Williams Classified gene: TP53RK as Amber List (moderate evidence)
Severe microcephaly v2.211 TP53RK Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. Following consultation with the Genomics England clinical team it was decided that a green recommendation would be appropriate as primary microcephaly might be the presenting feature before renal issues appear.
Severe microcephaly v2.211 TP53RK Eleanor Williams Gene: tp53rk has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.210 TP53RK Eleanor Williams Tag Q2_21_rating tag was added to gene: TP53RK.
Severe microcephaly v2.210 TCF4 Eleanor Williams Classified gene: TCF4 as Red List (low evidence)
Severe microcephaly v2.210 TCF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. After consultation with the Genomics England Clinical Team it was decided that patients with Pitt-Hopkins syndrome are more likely to be following a route for explanation of global developmental delay/intellectual disability than severe microcephaly.
Severe microcephaly v2.210 TCF4 Eleanor Williams Gene: tcf4 has been classified as Red List (Low Evidence).
Severe Paediatric Disorders v1.79 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from ?Dyskeratosis congenita, autosomal dominant 6, 616553; ?Dyskeratosis congenita, autosomal recessive 7, 616553 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Haematological malignancies cancer susceptibility v2.16 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553; MDS, AML; Oral and GI squamous cell carcinoma
Adult solid tumours cancer susceptibility v2.12 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Primary immunodeficiency v2.440 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita 6, 616553; Dyskeratosis congenita 7, 616553; Hoyeraal-Hreidarsson syndrome to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Ductal plate malformation v1.17 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from ?Dyskeratosis congenita, autosomal dominant 6 (616553); ?Dyskeratosis congenita, autosomal recessive 7 (616553) to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Tumour predisposition - childhood onset v2.21 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
COVID-19 research v1.78 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita 6, 616553; Dyskeratosis congenita 7, 616553; Hoyeraal-Hreidarsson syndrome to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Haematological malignancies for rare disease v1.2 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553; MDS, AML; Oral and GI squamous cell carcinoma
Cytopenia - NOT Fanconi anaemia v1.39 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Classified gene: ACD as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Added comment: Comment on list classification: Only two families with DC who have variants in ACD have been reported since 2015 - one family with AD inheritance had only progressive bone marrow failure (PMID: 25205116) and one patient (patient B) with AR inheritance had a more severe phenotype (PMID: 25233904). However, this gene was rated Green on this and other panels following external clinical review - so this rating will be maintained at this time.
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Gene: acd has been classified as Green List (High Evidence).
Severe microcephaly v2.209 PTPN23 Eleanor Williams Classified gene: PTPN23 as Amber List (moderate evidence)
Severe microcephaly v2.209 PTPN23 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. 1 confirmed case with severe microcephaly plus several further cases of microcephaly, not all of which have the degree of severity stated. Genomics England clinician confirms proposal for green rating.
Severe microcephaly v2.209 PTPN23 Eleanor Williams Gene: ptpn23 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.208 PTPN23 Eleanor Williams Tag Q2_21_rating tag was added to gene: PTPN23.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova changed review comment from: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_rating); to: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_expert_review)
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_rating was removed from gene: ADAMTS13.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: ADAMTS13.
Thrombophilia v1.19 ADAMTS13 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: ADAMTS13.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova commented on gene: ADAMTS13: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_rating)
Fetal anomalies v1.679 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
DDG2P v2.29 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
Childhood onset dystonia or chorea or related movement disorder v1.132 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
Severe Paediatric Disorders v1.78 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
DDG2P v2.29 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.679 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe Paediatric Disorders v1.78 DMPK Dmitrijs Rots reviewed gene: DMPK: 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 v1.132 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure in early childhood v1.71 SETD5 Dmitrijs Rots gene: SETD5 was added
gene: SETD5 was added to Growth failure in early childhood. Sources: Literature
Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SETD5 were set to PMID: 28881385
Phenotypes for gene: SETD5 were set to intellectual disability; developmental delay; growth retardation; bone fragility
Penetrance for gene: SETD5 were set to Incomplete
Review for gene: SETD5 was set to GREEN
Added comment: In 13/25 published cases in the literature (sumarized in PMID: 28881385), growth retardation is reported. Additionally, two cases with bone fragility reported PMID: 34169511.
Sources: Literature
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ADAMTS13.
Tag Q2_21_NHS_review tag was added to gene: ADAMTS13.
Segmental overgrowth disorders v2.14 NLRP2 Sarah Leigh commented on gene: NLRP2: The Q2_21_expert_review tag has been added for the TEWG to consider whether or not the epigenetic effects of maternal variants in NLRP2 have in their children is appropriate for a Green gene rating.
Segmental overgrowth disorders v2.14 NLRP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: NLRP2.
Growth failure in early childhood v1.71 NLRP2 Sarah Leigh commented on gene: NLRP2: The Q2_21_expert_review tag has been added for the TEWG to consider whether or not the epigenetic effects of maternal variants in NLRP2 have in their children is appropriate for a Green gene rating.
Growth failure in early childhood v1.71 NLRP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: NLRP2.
Childhood onset dystonia or chorea or related movement disorder v1.132 FXN_GAA Sarah Leigh Publications for STR: FXN_GAA were set to
Intellectual disability v3.1149 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
Intellectual disability v3.1149 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Genetic epilepsy syndromes v2.379 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Genetic epilepsy syndromes v2.379 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
Childhood onset dystonia or chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh changed review comment from: Based on review by Zornitza Stark and opinion of Helen Brittain (Genomics England Clinical Fellow), the Q2_21_phenotype & Q2_21_expert_review tags have been added, in order to request the opinion of the TEWG regarding the relevance of phenotype associated with variants in ALDH18A1 for this panel (Childhood onset dystonia or chorea or related movement disorder).; to: Based on review by Zornitza Stark and the opinion of Helen Brittain (Genomics England Clinical Fellow), the Q2_21_phenotype & Q2_21_expert_review tags have been added, in order to request the opinion of the TEWG regarding the relevance of phenotype associated with variants in ALDH18A1 for this panel (Childhood onset dystonia or chorea or related movement disorder).
Childhood onset dystonia or chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh commented on gene: ALDH18A1
Childhood onset dystonia or chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: ALDH18A1.
Growth failure in early childhood v1.71 NLRP2 Sarah Leigh changed review comment from: Maternal bialliec variants may result in: epigentic distubance of IC2 in imprinting region at 11p15.5 in trans, resulting in Beckwith-Wiedemann syndrome (PMID 19300480), early embryonic arest, (causing infertility)(PMID 30877238). These findings are supported by a mouse knock out model (PMID 33090377). At least 9 human NLRP2 variants have been identified in families with the above clinical features.; to: Maternal bialliec variants may result in: epigentic distubance of IC2 in imprinting region at 11p15.5 in trans, resulting in Beckwith-Wiedemann syndrome (PMID 19300480), early embryonic arrest, (causing infertility)(PMID 30877238). These findings are supported by a mouse knock out model (PMID 33090377). At least 9 human NLRP2 variants have been identified in families with the above clinical features.
Intellectual disability v3.1149 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency v2.439 OAS1 Arina Puzriakova Phenotypes for gene: OAS1 were changed from Autoinflammatory Disorders; Pulmonary alveolar proteinosis, skin rash; OAS1 GOF to Autoinflammatory Disorders; Pulmonary alveolar proteinosis; Recurrent fever; Dermatitis; Inflammatory bowel disease; Hypogammaglobulinemia
Primary immunodeficiency v2.438 OAS1 Arina Puzriakova Mode of pathogenicity for gene: OAS1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency v2.437 OAS1 Arina Puzriakova edited their review of gene: OAS1: Added comment: Additional publication identified by Boaz Palterer (PMID:34145065) supports the inclusion of this gene as Green on this panel. There are now at least 4 different gain-of-function heterozygous variants in the OAS1 gene identified in 8 unrelated families with 10 affected individuals (P5 in PMID:34145065 and C-II-1 in PMID:29455859 refer to the same individual).; Changed rating: GREEN; Changed publications to: 34145065, 29455859; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v2.55 CHD4 Sarah Leigh Classified gene: CHD4 as Amber List (moderate evidence)
Cerebral vascular malformations v2.55 CHD4 Sarah Leigh Gene: chd4 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.54 SETD5 Sarah Leigh Publications for gene: SETD5 were set to 31474762
Cerebral vascular malformations v2.53 SETD5 Sarah Leigh Classified gene: SETD5 as Amber List (moderate evidence)
Cerebral vascular malformations v2.53 SETD5 Sarah Leigh Gene: setd5 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh Tag watchlist tag was added to gene: SETD5.
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh changed review comment from: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761.; to: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761, two further variants were found, but it was not possible to report their inheritance (PMID 31474762). Eight de novo SETD5 variants have been reported in Mental retardation, autosomal dominant 23 OMIM:615761 (PMIDs 24680889, 23020937, 25138099). However, none of these reported detailed neurological examinations that could have diagnosed Moyamoya disease.
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: SETD5.
Primary immunodeficiency v2.437 OAS1 Arina Puzriakova Publications for gene: OAS1 were set to 32086639; 29455859; 32048120
Primary immunodeficiency v2.436 IKZF3 Arina Puzriakova Publications for gene: IKZF3 were set to
Primary immunodeficiency v2.435 IKZF3 Arina Puzriakova Classified gene: IKZF3 as Red List (low evidence)
Primary immunodeficiency v2.435 IKZF3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). Rating Red as only a single family with B cell deficiency has been reported at this time. Includes supportive mouse model showing B cell developmental defects and T cell abnormalities (PMID:34155405).
Primary immunodeficiency v2.435 IKZF3 Arina Puzriakova Gene: ikzf3 has been classified as Red List (Low Evidence).
Hereditary ataxia - adult onset v2.80 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia - adult onset v2.80 XRCC1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: XRCC1.
Hereditary ataxia - adult onset v2.80 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Amber List (moderate evidence)
Hereditary ataxia - adult onset v2.80 XRCC1 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for GMS review to determine whether there is enough evidence to include XRCC1 on this panel as Green. Only one case with adult onset and the other two with onset in childhood, however inclusion may be justified to ensure identification of edge cases.
-----
Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia - adult onset v2.80 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed rating: GREEN; Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed rating: GREEN; Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova changed review comment from: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when biallelic. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.; to: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Green List (high evidence)
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene from Red to Green.
-----
Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Green List (High Evidence).
Hereditary ataxia v1.230 XRCC1 Arina Puzriakova Tag founder-effect tag was added to gene: XRCC1.
Hereditary ataxia - adult onset v2.79 XRCC1 Arina Puzriakova Tag watchlist was removed from gene: XRCC1.
Tag founder-effect tag was added to gene: XRCC1.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Tag founder-effect tag was added to gene: XRCC1.
Tag Q2_21_rating tag was added to gene: XRCC1.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when biallelic. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.230 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Hereditary ataxia - adult onset v2.79 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Ataxia and cerebellar anomalies - narrow panel v2.213 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Neurodegenerative disorders - adult onset v2.175 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Neurodegenerative disorders - adult onset v2.175 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Congenital myopathy v2.36 ACTN2 Ivone Leong Publications for gene: ACTN2 were set to 24692096; 30701273
Hereditary ataxia v1.229 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary neuropathy v1.386 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Spinocerebellar ataxia, autosomal recessive 26, 617633; Ataxia, developmental delay, azoospermia and hypogonadism, myotonia, sensory and motor axonal neuropathy to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary ataxia - adult onset v2.78 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia; Autosomal recessive spinocerebellar ataxia 26, 617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Ataxia and cerebellar anomalies - narrow panel v2.212 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary neuropathy NOT PMP22 copy number v1.29 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Ataxia, developmental delay, azoospermia and hypogonadism, myotonia, sensory and motor axonal neuropathy; Spinocerebellar ataxia, autosomal recessive 26, 617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Congenital myopathy v2.35 MYH8 Ivone Leong Tag Q2_21_phenotype tag was added to gene: MYH8.
Congenital myopathy v2.35 MYH8 Ivone Leong reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.35 MYH8 Ivone Leong Publications for gene: MYH8 were set to 17041932
Congenital myopathy v2.34 MYH8 Ivone Leong Phenotypes for gene: MYH8 were changed from Trismus-pseudocamptodactyly syndrome, 158300 to Trismus-pseudocamptodactyly syndrome, OMIM:158300
Congenital myopathy v2.33 MYL2 Ivone Leong Classified gene: MYL2 as Amber List (moderate evidence)
Congenital myopathy v2.33 MYL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a variant 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.
Congenital myopathy v2.33 MYL2 Ivone Leong Gene: myl2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.32 MYL2 Ivone Leong Tag Q2_21_rating tag was added to gene: MYL2.
Congenital myopathy v2.32 MYL2 Ivone Leong Added comment: Comment on publications: PMID:33731536 third case from Japan
Congenital myopathy v2.32 MYL2 Ivone Leong Publications for gene: MYL2 were set to 23365102; 27378946; 33731536
Intellectual disability v3.1149 JMJD1C Arina Puzriakova changed review comment from: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.; to: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges (added watchlist tag).
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Tag watchlist tag was added to gene: JMJD1C.
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Classified gene: JMJD1C as Amber List (moderate evidence)
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Gene: jmjd1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1148 JMJD1C Arina Puzriakova Phenotypes for gene: JMJD1C were changed from Intellectual disability to Intellectual disability; Autism
Intellectual disability v3.1147 JMJD1C Arina Puzriakova Publications for gene: JMJD1C were set to 26181491; 32996679
Intellectual disability v3.1146 JMJD1C Arina Puzriakova reviewed gene: JMJD1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26181491, 31954878, 32996679, 28378413, 22495311, 25363768, 17290275, 33591602; Phenotypes: Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Growth failure in early childhood v1.71 KDM3B Ivone Leong Tag Q2_21_rating was removed from gene: KDM3B.
Tag watchlist tag was added to gene: KDM3B.
Growth failure in early childhood v1.71 KDM3B Ivone Leong changed review comment from: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.; to: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to this panel. However, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Hearing loss v2.177 KDM3B Ivone Leong changed review comment from: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.; to: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to this panel. However, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Hearing loss v2.177 KDM3B Ivone Leong Tag Q2_21_rating was removed from gene: KDM3B.
Tag watchlist tag was added to gene: KDM3B.
Growth failure in early childhood v1.71 KDM3B Ivone Leong Entity copied from Intellectual disability v3.1146
Growth failure in early childhood v1.71 KDM3B Ivone Leong gene: KDM3B was added
gene: KDM3B was added to Growth failure in early childhood. Sources: Victorian Clinical Genetics Services,Expert Review Amber
Q2_21_rating tags were added to gene: KDM3B.
Mode of inheritance for gene: KDM3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KDM3B were set to 30929739
Phenotypes for gene: KDM3B were set to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Hearing loss v2.177 KDM3B Ivone Leong Entity copied from Intellectual disability v3.1146
Hearing loss v2.177 KDM3B Ivone Leong gene: KDM3B was added
gene: KDM3B was added to Hearing loss. Sources: Victorian Clinical Genetics Services,Expert Review Amber
Q2_21_rating tags were added to gene: KDM3B.
Mode of inheritance for gene: KDM3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KDM3B were set to 30929739
Phenotypes for gene: KDM3B were set to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Intellectual disability v3.1146 KDM3B Ivone Leong Added comment: Comment on publications: PMID: 30929739. 8/16 patients had short stature (< -2.5 SD) and 9/15 had neonatal feeding difficulties. 5/16 had joint hypermobility, 4/17 had hearing loss.
Intellectual disability v3.1146 KDM3B Ivone Leong Publications for gene: KDM3B were set to 30929739
Intellectual disability v3.1145 KDM3B Ivone Leong Tag Q2_21_rating tag was added to gene: KDM3B.
Intellectual disability v3.1145 KDM3B Ivone Leong commented on gene: KDM3B: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 Ivone Leong Classified gene: KIAA1161 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 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. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 Ivone Leong Gene: kiaa1161 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Tag Q2_21_rating tag was added to gene: KIAA1161.
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Added comment: Comment on mode of inheritance: MOI has been changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "Biallelic, autosomal or pseudoautosomal" after consulting the Genomics England Clinical Team. As not all carriers exhibit the phenotype and the age of for the carriers that do exhibit the phenotype is not appropriate for this panel. Therefore the Biallelic MOI was assigned.
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Mode of inheritance for gene: KIAA1161 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.184 KIAA1161 Ivone Leong Added comment: Comment on publications: PMID: 31951047 - "89.5% (34 of 38) of individuals with heterozygous mutations remained asymptomatic at the time of examination and 4 of them exhibited symptoms with uncertain clinical significance (nonspecific depression, epilepsy, and late‐onset parkinsonism)". Age at CT scans range from 28-84. "brain calcifications of varying severity, from mild calcifications limited to the basal ganglia that were hard to differentiate from physiological calcifications to diffuse and moderate calcium deposits".

PMID: 30656188 - 2 families, carriers were all asymptomatic. Family 1 had no calcifications/no information. Family 2, 3/4 carriers had symmetrical punctuate calcification limited to the globus pallidus. The carriers were scanned <40yo.

PMID: 30895394 - proband's father (carrier) had diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor. Scan age 68.

PMID: 31009047 - 3 families. Fathers of all probands were carriers. 2 had lenticulo-cerebellar calcifications - one of these 2 carriers had depression and cognitive impairment (age unknown), the other carrier was asymptomatic and was 65 yo when scan was done. 3rd father had calcifications restricted to the lenticular nuclei and was asymptomatic (age unknown).
White matter disorders and cerebral calcification - narrow panel v1.184 KIAA1161 Ivone Leong Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047; 33958240; 31440850
Inborn errors of metabolism v2.145 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to
Inborn errors of metabolism v2.144 FAR1 Arina Puzriakova Classified gene: FAR1 as Green List (high evidence)
Inborn errors of metabolism v2.144 FAR1 Arina Puzriakova Added comment: Comment on list classification: In view of the normal metabolic screening (excluding very specific functional work, which will not be in routine NHS practice) there is no clear alignment with the metabolic panels and therefore FAR1 should be demoted from Green to Red at the next GMS panel update (discussed with Helen Brittain, Genomic England Clinical Team)
Inborn errors of metabolism v2.144 FAR1 Arina Puzriakova Gene: far1 has been classified as Green List (High Evidence).
Inborn errors of metabolism v2.143 FAR1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: FAR1.
Inborn errors of metabolism v2.143 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: RED; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.379 FAR1 Arina Puzriakova changed review comment from: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, the rating was set to Amber for this allelic requirement. However, there is now also evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

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

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline)
Hereditary spastic paraplegia - childhood onset v2.41 FAR1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants (PMID: 33239752). Paediatric onset.
Sources: Literature; to: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants affecting the Arg480 residue (PMID: 33239752). Paediatric onset.
Sources: Literature
Cataracts v2.74 FAR1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature; to: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants affecting the Arg480 residue (PMID: 33239752)
Sources: Literature
Genetic epilepsy syndromes v2.379 FAR1 Arina Puzriakova Added comment: Comment on mode of inheritance: As only 2/4 families with biallelic variants in this gene presented with epilepsy, the rating was set to Amber for this allelic requirement. However, there is now also evidence supporting pathogenicity of monoallelic variants affecting the Arg480 residue, and the number of unrelated individuals with seizures (8) reaches the threshold for inclusion with the monoallelic MOI.

FAR1 will be flagged for GMS expert review to determine the most appropriate MOI and rating on this panel (note that if MOI is set to 'Monoallelic' only, patients with biallelic variants would still be picked up by the Genomics England pipeline)
Genetic epilepsy syndromes v2.379 FAR1 Arina Puzriakova Mode of inheritance for gene: FAR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Genetic epilepsy syndromes v2.378 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Genetic epilepsy syndromes v2.377 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
Genetic epilepsy syndromes v2.377 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary ataxia v1.228 NUS1 Dmitrijs Rots gene: NUS1 was added
gene: NUS1 was added to Hereditary ataxia. Sources: Literature
Mode of inheritance for gene: NUS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUS1 were set to 33731878; 32334381; 32485575; 31656175
Phenotypes for gene: NUS1 were set to intellectual disability; seizures; ataxia; dystonia; tremor
Penetrance for gene: NUS1 were set to Complete
Review for gene: NUS1 was set to GREEN
Added comment: Multiple patients (see below) with de novo or heterozygous variants reported. The phenotype include ID, seizures and/or movement disorder (including tremor, ataxia, dystonia). Functional analysis of patients fibroblasts shows"de novo NUS1 variants reduce NgBR and Niemann–Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation." (Yu et al,m 2021). Movement abnormalities and similar metabolic dysfunction in zebrafish model.

3 patients with ataxia reported in: PMID: 33731878
One patient with dystonia reported in: PMID: 32334381
One family with ataxia reported in: PMID: 32485575
Two cases with ataxia reported in: PMID: 31656175

Additionally, two cases from one family with homozygous missense variant, but NO ataxia is reported:PMID: 25066056
Sources: Literature
Inborn errors of metabolism v2.143 NUS1 Dmitrijs Rots reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33731878, 32334381, 32485575, 31656175, 25066056; Phenotypes: intellectual disability, seizures, ataxia, tremor, dystonia; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Inborn errors of metabolism v2.143 NUS1 Dmitrijs Rots Deleted their review
Inborn errors of metabolism v2.143 NUS1 Dmitrijs Rots reviewed gene: NUS1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33731878; Phenotypes: intellectual disability, seizures, ataxia, dystonia, tremor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v2.52 CNOT3 Sarah Leigh commented on gene: CNOT3: Q2_21_expert_review added in order to ask whether the evaluation working group would like to seek specialist opinion on this gene / disease association.
Cerebral vascular malformations v2.52 CNOT3 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CNOT3.
Cerebral vascular malformations v2.52 CNOT3 Sarah Leigh changed review comment from: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya disease MONDO:0016820, who also had some of the features of OMIM:618672.; to: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. PMID 31474762 reports at least two de novo variants (one nonsense & one missense) in two cases with Moyamoya disease MONDO:0016820, who also had some of the features of OMIM:618672.
An association between CNOT3 protein levels, NTNG1 variants and cerebral atherosclorosis has also been reported in PMID 34073619.
Cerebral vascular malformations v2.52 CHD4 Sarah Leigh Publications for gene: CHD4 were set to 31474762; 27616479; 27479907
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh changed review comment from: Q2_21_expert_review added in order to ask whether the evaluation working group would like to seek specialist opinion on this gene / disease association.; to: Q2_21_expert_review tag added in order to ask whether the evaluation working group would like to seek specialist opinion on this gene / disease association.
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh commented on gene: CHD4: Q2_21_expert_review added in order to ask whether the evaluation working group would like to seek specialist opinion on this gene / disease association.
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh Tag watchlist tag was added to gene: CHD4.
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh edited their review of gene: CHD4: Changed rating: AMBER
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh changed review comment from: Comment on list classification: Moyamoya disease MONDO:0016820 is relevant to this panel - Cerebral vascular malformations.
PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant is a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).; to: Comment on list classification: Moyamoya disease MONDO:0016820 is relevant to this panel - Cerebral vascular malformations.
PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant in a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh changed review comment from: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moyamoya disease MONDO:0016820, this is a new gene / condition association. Moyamoya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moyamoya.; to: Comment on list classification: Moyamoya disease MONDO:0016820 is relevant to this panel - Cerebral vascular malformations.
PMID 31474762 reports a single de novo missense variant in a case of Moyamoya angiopathy, six further CHD4 variants were also identified in this study, however, the pattern of inheritance was uncertain. PMID 27616479 found a CHD4 missense variant is a case who also had Moyama angiopathy and two further de novo missense variants were reported in probands with congenital heart disease who had neurodevelopmental deficit (PMID 28991257).
Congenital myopathy v2.31 MYL2 Ivone Leong Publications for gene: MYL2 were set to 23365102; 27378946
Cerebral vascular malformations v2.51 CHD4 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CHD4.
Congenital myopathy v2.30 MYL2 Ivone Leong Phenotypes for gene: MYL2 were changed from infantile muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy to infantile muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy; Cardiomyopathy, hypertrophic, 10, OMIM:608758
Congenital myopathy v2.29 MYF5 Ivone Leong Phenotypes for gene: MYF5 were changed from OPHTHALMOPLEGIA, EXTERNAL, WITH RIB AND VERTEBRAL ANOMALIES to Ophthalmoplegia, external, with rib and vertebral anomalies, OMIM:618155
Optic neuropathy v2.45 EPRS Ivone Leong reviewed gene: EPRS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Optic neuropathy v2.45 EPRS Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.183
Optic neuropathy v2.45 EPRS Ivone Leong gene: EPRS was added
gene: EPRS was added to Optic neuropathy. Sources: Expert Review Amber,Expert list
new-gene-name, Q2_21_rating tags were added to gene: EPRS.
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217; 33805425
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM# 617951
White matter disorders and cerebral calcification - narrow panel v1.183 EPRS Ivone Leong Publications for gene: EPRS were set to 29576217
White matter disorders - adult onset v1.23 EPRS Ivone Leong Phenotypes for gene: EPRS were changed from Leukodystrophy, hypomyelinating, 15, MIM# 617951 to Leukodystrophy, hypomyelinating, 15, OMIM:617951
Ataxia and cerebellar anomalies - narrow panel v2.211 GEMIN5 Arina Puzriakova Entity copied from Intellectual disability v3.1145
Ataxia and cerebellar anomalies - narrow panel v2.211 GEMIN5 Arina Puzriakova gene: GEMIN5 was added
gene: GEMIN5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: GEMIN5.
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, OMIM:619333
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova edited their review of gene: GEMIN5: Changed rating: GREEN
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: GEMIN5.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Classified gene: GEMIN5 as Amber List (moderate evidence)
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Kour et al. 2021 (PMID: 33963192) report 30 individuals from 22 unrelated families with biallelic variants in the GEMIN5 gene. All affected individuals displayed predominantly motor DD, although cognitive and speech delays were also seen in most patients (18/19). 23/30 had central hypotonia, and variable appendicular spasticity was observed in 13/30 cases. 8 individuals were nonambulatory, while all ambulatory patients (19) had a gait ataxia. Brain MRI in all cases showed cerebellar atrophy.

Variants perturbed the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners, and disrupted snRNP complex assembly formation in patient iPSC-derived neurons, suggesting a LoF mechanism. Knockdown in Drosophila lead to developmental defects, motor dysfunction, and a reduced lifespan

GEMIN5 is associated with a relevant phenotype in OMIM (Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333) but is not yet listed in G2P.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Gene: gemin5 has been classified as Amber List (Moderate Evidence).
White matter disorders - adult onset v1.22 COL4A2 Ivone Leong Phenotypes for gene: COL4A2 were changed from Brain small vessel disease 2, 614483 to Brain small vessel disease 2, OMIM:614483
White matter disorders and cerebral calcification - narrow panel v1.182 AUH Ivone Leong Entity copied from White matter disorders - adult onset v1.21
White matter disorders and cerebral calcification - narrow panel v1.182 AUH Ivone Leong gene: AUH was added
gene: AUH was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list,Expert Review Amber
Q2_21_rating tags were added to gene: AUH.
Mode of inheritance for gene: AUH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AUH were set to 20855850; 17130438
Phenotypes for gene: AUH were set to 3-methylglutaconic aciduria, type I, OMIM:250950
Hereditary ataxia - adult onset v2.77 AUH Ivone Leong Entity copied from White matter disorders - adult onset v1.21
Hereditary ataxia - adult onset v2.77 AUH Ivone Leong gene: AUH was added
gene: AUH was added to Hereditary ataxia - adult onset. Sources: Expert list,Expert Review Amber
Q2_21_rating tags were added to gene: AUH.
Mode of inheritance for gene: AUH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AUH were set to 20855850; 17130438
Phenotypes for gene: AUH were set to 3-methylglutaconic aciduria, type I, OMIM:250950
White matter disorders - adult onset v1.21 AUH Ivone Leong Tag Q2_21_rating tag was added to gene: AUH.
White matter disorders - adult onset v1.21 AUH Ivone Leong Classified gene: AUH as Amber List (moderate evidence)
White matter disorders - adult onset v1.21 AUH 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. The age of onset is between 1 to 52 years of age. Childhood onset patients have psychomotor retardation and white matter changes. There are 3 cases of adult onset of this phenotype. Patients presented with ataxia (3/3), dementia (2/3) and spasticity (2/3) and all had white matter changes. This gene should be rated Green at the next review.
White matter disorders - adult onset v1.21 AUH Ivone Leong Gene: auh has been classified as Amber List (Moderate Evidence).
White matter disorders - adult onset v1.20 AUH Ivone Leong Phenotypes for gene: AUH were changed from 3-methylglutaconic aciduria, type I, MIM# 250950 to 3-methylglutaconic aciduria, type I, OMIM:250950
White matter disorders - adult onset v1.19 AUH Ivone Leong Publications for gene: AUH were set to 20855850
Intellectual disability v3.1144 GEMIN5 Arina Puzriakova Phenotypes for gene: GEMIN5 were changed from Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333 to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, OMIM:619333
Hereditary spastic paraplegia - childhood onset v2.41 BCAS3 Arina Puzriakova Entity copied from Intellectual disability v3.1143
Hereditary spastic paraplegia - childhood onset v2.41 BCAS3 Arina Puzriakova gene: BCAS3 was added
gene: BCAS3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: BCAS3.
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Tag Q2_21_rating tag was added to gene: BCAS3.
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Classified gene: BCAS3 as Amber List (moderate evidence)
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
-----
Hengel et al. 2021 (PMID: 34022130) report 8 unrelated families, all with different biallelic variants in the BCAS3 gene. All affected individuals (15 total, +1 additional proband but with unphased variants but consistent phenotype) had severe GDD and ID, with 10 subjects having minimal vocabulary and 4 never learning to speak. All probands had a severe motor disorder with pyramidal tract involvement resulting in hyperreflexia and spasticity of the lower limbs (15/15). Other variable features observed in the cohort include microcephaly, short stature, seizures, and dysmorphic facial features.
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Gene: bcas3 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.18 DISP1 Sarah Leigh Phenotypes for gene: DISP1 were changed from Holoprosencephaly to holoprosencephaly MONDO:0016296
Holoprosencephaly v2.17 DISP1 Sarah Leigh reviewed gene: DISP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders - adult onset v1.18 ASPA Ivone Leong Classified gene: ASPA as Red List (low evidence)
White matter disorders - adult onset v1.18 ASPA 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. Age of onset for Canavan disease is reported range from congenital, infantile to childhood onset. PMID: 2512436 indicated that there are late-onset forms of Canavan disease; however, I cannot access this article. There is enough evidence to support a gene-disease association; however, due to lack of evidence about age of onset being in adulthood, this gene has been given a Red rating on this panel.

This gene is Green on White matter disorders and cerebral calcification - narrow panel (Version 1.181).
White matter disorders - adult onset v1.18 ASPA Ivone Leong Gene: aspa has been classified as Red List (Low Evidence).
Hypogonadotropic hypogonadism idiopathic v1.43 CPE Arina Puzriakova Entity copied from Intellectual disability v3.1142
Hypogonadotropic hypogonadism idiopathic v1.43 CPE Arina Puzriakova gene: CPE was added
gene: CPE was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: CPE.
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
Intellectual disability v3.1142 CPE Arina Puzriakova Tag watchlist tag was added to gene: CPE.
Intellectual disability v3.1142 CPE Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag); to: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature to date with different homozygous variants in the CPE gene (PMIDs: 26120850; 32936766). Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability v3.1142 CPE Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.39 CPE Arina Puzriakova Added comment: Comment on phenotypes: CPE is now associated with a relevant phenotype in OMIM - Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Severe early-onset obesity v2.39 CPE Arina Puzriakova Phenotypes for gene: CPE were changed from obesity to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
Intellectual disability v3.1141 CPE Arina Puzriakova Phenotypes for gene: CPE were changed from Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326 to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
White matter disorders - adult onset v1.17 ASPA Ivone Leong Phenotypes for gene: ASPA were changed from to Canavan disease, OMIM:271900
Paroxysmal central nervous system disorders v1.15 ATP1A4 Ivone Leong Classified gene: ATP1A4 as Red List (low evidence)
Paroxysmal central nervous system disorders v1.15 ATP1A4 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.
Paroxysmal central nervous system disorders v1.15 ATP1A4 Ivone Leong Gene: atp1a4 has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v1.14 ATP1A4 Ivone Leong Phenotypes for gene: ATP1A4 were changed from Hemiplegic migraine to familial hemiplegic migraine, MONDO:0000700
Congenital myopathy v2.28 TNNC2 Dmitrijs Rots reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33755597; Phenotypes: Myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hydrocephalus v2.114 ERF Ivone Leong Tag Q2_21_expert_review tag was added to gene: ERF.
Hydrocephalus v2.114 TNFRSF11A Ivone Leong Phenotypes for gene: TNFRSF11A were changed from Osteopetrosis, autosomal recessive 7, MIM# 612301 to Osteopetrosis, autosomal recessive 7, OMIM:612301
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: POU4F1.
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Classified gene: POU4F1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update - sufficient number of unrelated cases (>3), supported by an animal model (see details below)
-----
Webb et al. 2021 (PMID:33783914) identified four unrelated individuals with different de novo POU4F1 variants. All presented with ataxia, hypotonia, and intention tremor. 3/4 also had strabismus and a history of paroxysmal tonic upgaze. Pou4f1−/− mice are known to have uncoordinated movements consistent with the ataxia phenotype seen in this patient cohort.

POU4F1 is associated with a relevant phenotype in OMIM (Ataxia, intention tremor, and hypotonia syndrome, childhood-onset, MIM# 619352) but is not yet listed in G2P.
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Gene: pou4f1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.434 OAS1 Boaz Palterer reviewed gene: OAS1: 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: 34145065; Phenotypes: recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, hypogammaglobulinemia.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency v2.434 IKZF3 Boaz Palterer gene: IKZF3 was added
gene: IKZF3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IKZF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IKZF3 were set to B cell deficiency; EBV inefctions suspectibility; hypogammaglobulinemia
Penetrance for gene: IKZF3 were set to unknown
Review for gene: IKZF3 was set to RED
Added comment: Motoi Yamashita et al. ( https://www.nature.com/articles/s41590-021-00951-z ) identified 3 patients from a kindred harboring the missense G159R variant in AIOLOS, encoded by the IKZF3 gene. They demonstrated that the variant acts as a dominant-negative mutation through heterodimeric interference by disrupting IKAROS (IKZF1) function.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.209 POU4F1 Arina Puzriakova Phenotypes for gene: POU4F1 were changed from Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) , MIM#619352 to Ataxia, intention tremor, and hypotonia syndrome, childhood-onset, OMIM:619352
Ataxia and cerebellar anomalies - narrow panel v2.208 Arina Puzriakova removed gene:POU1F1 from the panel
Skeletal dysplasia v2.104 RPL13 Arina Puzriakova Added comment: Comment on phenotypes: RPL13 is now associated with a relevant phenotype in OMIM - Spondyloepimetaphyseal dysplasia, Isidor-Toutain type, MIM# 618728
Skeletal dysplasia v2.104 RPL13 Arina Puzriakova Phenotypes for gene: RPL13 were changed from Spondyloepimetaphyseal Dysplasia with Severe Short Stature to Spondyloepimetaphyseal dysplasia, Isidor-Toutain type, OMIM:618728
Fetal anomalies v1.679 CELSR1 Arina Puzriakova Phenotypes for gene: CELSR1 were changed from hereditary lymphedema to Lymphatic malformation 9, OMIM:619319
Primary lymphoedema v2.13 CELSR1 Arina Puzriakova Phenotypes for gene: CELSR1 were changed from hereditary lymphedema to Lymphatic malformation 9, OMIM:619319
Intellectual disability v3.1140 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Developmental and epileptic encephalopathy 80, OMIM:618580
Hereditary neuropathy NOT PMP22 copy number v1.28 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from intellectual disability; developmental delay; epilepsy; axonal neuropathy to Developmental and epileptic encephalopathy 80, OMIM:618580
Genetic epilepsy syndromes v2.377 PIGB Arina Puzriakova Phenotypes for gene: PIGB were changed from Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Developmental and epileptic encephalopathy 80, OMIM:618580
Skeletal dysplasia v2.103 FZD2 Arina Puzriakova Phenotypes for gene: FZD2 were changed from Autosomal dominant omodysplasia type 2 164745; Autosomal dominant omodysplasia 164745 to Omodysplasia 2, OMIM:164745; Robinow syndrome
Limb disorders v2.43 FZD2 Arina Puzriakova Phenotypes for gene: FZD2 were changed from Omodysplasia 2, 164745; Robinow syndrome to Omodysplasia 2, OMIM:164745; Robinow syndrome
Mitochondrial disorders v2.45 SLC25A10 Arina Puzriakova Mode of inheritance for gene: SLC25A10 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.44 SLC25A10 Arina Puzriakova Phenotypes for gene: SLC25A10 were changed from to ?Mitochondrial DNA depletion syndrome 19, OMIM:618972
Inborn errors of metabolism v2.143 MRM2 Arina Puzriakova Phenotypes for gene: MRM2 were changed from ?Mitochondrial DNA depletion syndrome 17, 618567 to ?Mitochondrial DNA depletion syndrome 17, OMIM:618567
Possible mitochondrial disorder - nuclear genes v1.47 MRM2 Arina Puzriakova Phenotypes for gene: MRM2 were changed from No OMIM phenotype to ?Mitochondrial DNA depletion syndrome 17, OMIM:618567
Mitochondrial disorders v2.43 MRM2 Arina Puzriakova Phenotypes for gene: MRM2 were changed from No OMIM phenotype to ?Mitochondrial DNA depletion syndrome 17, OMIM:618567
Severe hypertriglyceridaemia v1.13 CREB3L3 Arina Puzriakova Phenotypes for gene: CREB3L3 were changed from monogenic dominant hypertriglyceridemia associated with CREB3L3 to Hypertriglyceridemia 2, OMIM:619324
Lipoprotein lipase deficiency v1.16 CREB3L3 Arina Puzriakova Added comment: Comment on phenotypes: CREB3L3 is now associated with a relevantly phenotype in OMIM - Hypertriglyceridemia 2, MIM# 619324
Lipoprotein lipase deficiency v1.16 CREB3L3 Arina Puzriakova Phenotypes for gene: CREB3L3 were changed from hypertriglyceridemia (disease) MONDO:0005347 to Hypertriglyceridemia 2, OMIM:619324; Hypertriglyceridemia (disease) MONDO:0005347
Genetic epilepsy syndromes v2.376 ALKBH8 Arina Puzriakova Phenotypes for gene: ALKBH8 were changed from Intellectual developmental disorder, autosomal recessive 71, 618504; Global developmental delay; Seizures; Intellectual Disability; Developmental Delay; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Intellectual disability v3.1139 ALKBH8 Arina Puzriakova Phenotypes for gene: ALKBH8 were changed from Global developmental delay; Seizures; Intellectual disability to Intellectual developmental disorder, autosomal recessive 71, OMIM:618504
Ataxia and cerebellar anomalies - narrow panel v2.207 SLC17A5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SLC17A5.
Ataxia and cerebellar anomalies - narrow panel v2.207 SLC17A5 Arina Puzriakova Publications for gene: SLC17A5 were set to 26171070
Ataxia and cerebellar anomalies - narrow panel v2.206 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Sialic acid storage disorder, infantile, MIM# 269920 to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
Ataxia and cerebellar anomalies - narrow panel v2.205 SLC17A5 Arina Puzriakova Classified gene: SLC17A5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.205 SLC17A5 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). There is enough evidence to promote this gene to Green at the next GMS panel update.

Associated with relevant phenotypes in OMIM and has a 'confirmed' disease confidence rating in G2P. At least 6 variants reported in at least 6 cases of Sialic acid storage disorder, infantile (MIM# 269920) and at least 2 variants reported in at least 5 cases of Salla disease (MIM# 604369). Cerebellar ataxia is a main presenting feature of this disorder, typically arising within the first year of life.
Ataxia and cerebellar anomalies - narrow panel v2.205 SLC17A5 Arina Puzriakova Gene: slc17a5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1138 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Salla disease, 604369Sialic acid storage disorder, infantile, 269920; SALLA DISEASE (SD) to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
Inborn errors of metabolism v2.142 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Salla disease, 604369; Sialic acid storage disorder, infantile, 269920 to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
Undiagnosed metabolic disorders v1.461 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Salla disease 604369; Sialic acid storage disorder, infantile 269920 to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
Skeletal dysplasia v2.102 SLC17A5 Arina Puzriakova Phenotypes for gene: SLC17A5 were changed from Sialic acid storage disorder, infantile 269920 to Salla disease, OMIM:604369; Sialic acid storage disorder, infantile, OMIM:269920
Hydrocephalus v2.113 TCIRG1 Ivone Leong Phenotypes for gene: TCIRG1 were changed from Osteopetrosis, autosomal recessive 1, MIM# 259700 to Osteopetrosis, autosomal recessive 1, OMIM:259700
Hydrocephalus v2.112 TBC1D7 Ivone Leong Classified gene: TBC1D7 as Red List (low evidence)
Hydrocephalus v2.112 TBC1D7 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. Currently, there is no evidence to support this gene-disease association.
Hydrocephalus v2.112 TBC1D7 Ivone Leong Gene: tbc1d7 has been classified as Red List (Low Evidence).
Hydrocephalus v2.111 TBC1D7 Ivone Leong Tag watchlist was removed from gene: TBC1D7.
Segmental overgrowth disorders v2.14 TBC1D7 Ivone Leong Phenotypes for gene: TBC1D7 were changed from Macrocephaly/megalencephaly syndrome, autosomal recessive, 248000; MGCPH to Macrocephaly/megalencephaly syndrome, autosomal recessive, OMIM:248000
Hereditary ataxia v1.228 SCN8A Arina Puzriakova changed review comment from: SCN8A is associated with a range of phenotypes including epilepsy, neurodevelopmental defects, and movement disorders. Some individuals with deleterious SCN8A variants develop ataxia - at least 14 individuals with ataxia reported in literature (see publications list). Variable age of onset including both childhood-onset and adult-onset cases. Mouse Scn8a mutants exhibit movement disorders including ataxia, tremor and dystonia.; to: SCN8A is associated with a range of phenotypes including epilepsy, neurodevelopmental defects, and movement disorders. Some individuals with deleterious SCN8A variants develop ataxia - at least 14 individuals with ataxia reported in literature (see publications list). Variable age of onset - mostly during childhood but adult-onset cases have also been described. Mouse Scn8a mutants exhibit movement disorders including ataxia, tremor and dystonia.
Ataxia and cerebellar anomalies - narrow panel v2.204 SCN8A Arina Puzriakova changed review comment from: SCN8A is associated with a range of phenotypes including epilepsy, neurodevelopmental defects, and movement disorders. Some individuals with deleterious SCN8A variants develop ataxia - at least 14 individuals with ataxia reported in literature (see publications list). Variable age of onset including both childhood-onset and adult-onset cases.

Several patients with the other phenotypes (although not including ataxia) have been reported as having cerebellar abnormalities. Mouse Scn8a mutants exhibit movement disorders including ataxia, tremor and dystonia.; to: SCN8A is associated with a range of phenotypes including epilepsy, neurodevelopmental defects, and movement disorders. Some individuals with deleterious SCN8A variants develop ataxia - at least 14 individuals with ataxia reported in literature (see publications list). Variable age of onset - mostly during childhood but adult-onset cases have also been described.

Several patients with the other phenotypes (although not including ataxia) have been reported as having cerebellar abnormalities. Mouse Scn8a mutants exhibit movement disorders including ataxia, tremor and dystonia.
Hereditary ataxia - adult onset v2.76 SCN8A Arina Puzriakova Publications for gene: SCN8A were set to 26677014
Hereditary ataxia v1.228 SCN8A Arina Puzriakova Publications for gene: SCN8A were set to
Hereditary ataxia v1.227 SCN8A Arina Puzriakova Classified gene: SCN8A as Green List (high evidence)
Hereditary ataxia v1.227 SCN8A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green - there is now a sufficient number of unrelated cases (>3) presenting ataxia in association with variants in the gene, supported by an animal model.
Hereditary ataxia v1.227 SCN8A Arina Puzriakova Gene: scn8a has been classified as Green List (High Evidence).
Hereditary ataxia v1.226 SCN8A Arina Puzriakova reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16236810, 22365152, 25725044, 28702509, 31675620, 31887642; Phenotypes: Cognitive impairment with or without cerebellar ataxia, OMIM:614306, Developmental and epileptic encephalopathy 13, OMIM:614558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ataxia and cerebellar anomalies - narrow panel v2.204 SCN8A Arina Puzriakova Classified gene: SCN8A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.204 SCN8A 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.
Ataxia and cerebellar anomalies - narrow panel v2.204 SCN8A Arina Puzriakova Gene: scn8a has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.203 SCN8A Arina Puzriakova Tag Q2_21_rating tag was added to gene: SCN8A.
Ataxia and cerebellar anomalies - narrow panel v2.203 SCN8A Arina Puzriakova Publications for gene: SCN8A were set to
Ataxia and cerebellar anomalies - narrow panel v2.202 SCN8A Arina Puzriakova reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 16236810, 22365152, 25725044, 28702509, 31675620, 31887642; Phenotypes: Cognitive impairment with or without cerebellar ataxia, OMIM:614306, Developmental and epileptic encephalopathy 13, OMIM:614558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hydrocephalus v2.111 SEC24D Ivone Leong reviewed gene: SEC24D: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.202 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, 614306 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Hereditary ataxia - adult onset v2.75 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from epilepsy; paroxysmal kinesigenic dyskinesias; Epileptic encephalopathy 13, 614558; Benign familial infantile seizures 5, 617080; Cognitive impairment with or without cerebellar ataxia, 614306 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Hereditary ataxia v1.226 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from Cognitive impairment with or without cerebellar ataxia, 614306 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Paroxysmal central nervous system disorders v1.13 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from Epileptic encephalopathy, early infantile, 13, 614558; Seizures, benign familial infantile, 5, 617080; paroxysmal kinesigenic dyskinesias to Seizures, benign familial infantile, 5, OMIM:617080; Paroxysmal kinesigenic dyskinesias; ?Myoclonus, familial, 2, OMIM:618364
Brain channelopathy v1.60 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from epilepsy; paroxysmal kinesigenic dyskinesias to Seizures, benign familial infantile, 5, OMIM:617080; Paroxysmal kinesigenic dyskinesias
Intellectual disability v3.1137 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080 to Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558
Childhood onset dystonia or chorea or related movement disorder v1.131 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from paroxysmal kinesigenic dyskinesias; epilepsy, Seizures, benign familial infantile, 5, 617080 to Seizures, benign familial infantile, 5, OMIM:617080; Paroxysmal kinesigenic dyskinesias
Genetic epilepsy syndromes v2.375 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from ?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080 to Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364
DDG2P v2.29 SCN8A Arina Puzriakova Phenotypes for gene: SCN8A were changed from COGNITIVE IMPAIRMENT WITH OR WITHOUT CEREBELLAR ATAXIA 614306; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 13 614558 to EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 13, 614558
Hydrocephalus v2.111 MPDZ Ivone Leong reviewed gene: MPDZ: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hydrocephalus v2.111 MPDZ Ivone Leong Tag watchlist was removed from gene: MPDZ.
Tag Q2_21_rating tag was added to gene: MPDZ.
Hydrocephalus v2.111 MPDZ Ivone Leong Publications for gene: MPDZ were set to 23240096; 28460636
Hydrocephalus v2.110 KIF7 Ivone Leong Added comment: Comment on publications: New publication added PMID:26174511
Hydrocephalus v2.110 KIF7 Ivone Leong Publications for gene: KIF7 were set to 21552264
Cytopenia - NOT Fanconi anaemia v1.37 ACD Zornitza Stark reviewed gene: ACD: Rating: RED; Mode of pathogenicity: None; Publications: 25205116, 25233904; Phenotypes: Dyskeratosis congenita, MIM# 616553; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tumour predisposition - childhood onset v2.20 MAX Arina Puzriakova Classified gene: MAX as Red List (low evidence)
Tumour predisposition - childhood onset v2.20 MAX Arina Puzriakova Added comment: Comment on list classification: Overall there is some evidence to suggest pertinence of this panel to some MAX variant carriers; however, inclusion could risk potential incidental findings in others. Therefore, this gene will be flagged for review by the GMS specialist working group to establish consensus on whether MAX should be included on this panel.
Tumour predisposition - childhood onset v2.20 MAX Arina Puzriakova Gene: max has been classified as Red List (Low Evidence).
Tumour predisposition - childhood onset v2.19 MAX Arina Puzriakova gene: MAX was added
gene: MAX was added to Tumour predisposition - childhood onset. Sources: NHS GMS
Q2_21_expert_review tags were added to gene: MAX.
Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAX were set to 33367756; 32508744; 22452945
Phenotypes for gene: MAX were set to {Pheochromocytoma, susceptibility to}, OMIM:171300
Review for gene: MAX was set to AMBER
Added comment: This gene was flagged internally by a GLH following identification of a pathogenic germline variant in a patient with paediatric neuroblastoma. The variant was initially classified as tier 3 as the gene was not included on any panels applied for variant prioritisation - but was on a different cancer susceptibility panel (Adult solid tumours cancer susceptibility v2.2).
-----
There is a well-established link between MAX variants and pheochromocytoma (PCC; MIM# 171300). Typically, age of diagnosis is in adulthood.

Literature search for MAX-related paediatric onset cases did reveal a large family with multiple individuals with PCCs including one female (III.5) diagnosed with PCC at 14 years (Seabrook et al. 2021, PMID: 33367756). The same family also had 2 children without PCC at time of reporting but with different malignancies - paravertebral ganglioneuroma (III.8, aged 5 years) and abdominal neuroblastoma (III.9, aged 6 months), respectively.

Pozza et al. 2020 (PMID: 32508744) also reported on an unrelated female who was diagnosed with pelvic ganglioneuroblastoma with lumbar–aortic lymph node metastases at 11 months and later with right composite adrenal PCC-ganglioneuroma at 15 years.

Another study (PMID: 22452945) investigating contribution of MAX variants to PCC stated the age of diagnosis ranged between 13-58 years in a cohort of 23 probands.
Sources: NHS GMS
Adult solid tumours cancer susceptibility v2.11 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Familial Pheochromocytoma, adrenal to {Pheochromocytoma, susceptibility to}, OMIM:171300; Familial Pheochromocytoma, adrenal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.16 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from {Pheochromocytoma, susceptibility to}, 171300; Hereditary Paraganglioma-Pheochromocytoma Syndrome; pheochromocytomas (PHEOs), paragangliomas (PGLs) to {Pheochromocytoma, susceptibility to}, OMIM:171300; Hereditary Paraganglioma-Pheochromocytoma Syndrome
Multiple endocrine tumours v1.10 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Endocrine Cancer to {Pheochromocytoma, susceptibility to}, OMIM:171300
Adult solid tumours for rare disease v1.23 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Familial Pheochromocytoma, adrenal to {Pheochromocytoma, susceptibility to}, OMIM:171300
Neuroendocrine cancer pertinent cancer susceptibility v1.1 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Neuroendocrine cancer to {Pheochromocytoma, susceptibility to}, OMIM:171300
Hydrocephalus v2.109 TRIM71 Ivone Leong Tag Q2_21_rating tag was added to gene: TRIM71.
Hydrocephalus v2.109 TRIM71 Ivone Leong Classified gene: TRIM71 as Amber List (moderate evidence)
Hydrocephalus v2.109 TRIM71 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. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hydrocephalus v2.109 TRIM71 Ivone Leong Gene: trim71 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.108 TRIM71 Ivone Leong Added comment: Comment on publications: PMID: 33077954. 3 additional cases with different variants.
Hydrocephalus v2.108 TRIM71 Ivone Leong Publications for gene: TRIM71 were set to 29983323; 32168371; 30975633
Hydrocephalus v2.107 TRIM71 Ivone Leong Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1, MIM# 618667 to Hydrocephalus, congenital communicating, 1, OMIM:618667
Proteinuric renal disease v2.50 CD151 Natalie Forrester reviewed gene: CD151: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15265795, 29138120, 17015618, 32641585, 22338088, 18787104, 22201679; Phenotypes: Nephropathy with pretibial epidermolysis bullosa and deafness #609057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Limb girdle muscular dystrophy v2.18 POPDC3 Agnese Zarina gene: POPDC3 was added
gene: POPDC3 was added to Limb girdle muscular dystrophy. Sources: Literature
Mode of inheritance for gene: POPDC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POPDC3 were set to https://doi.org/10.1002/ana.25620
Phenotypes for gene: POPDC3 were set to Muscular dystrophy, limb-girdle, autosomal recessive 26
Review for gene: POPDC3 was set to AMBER
Added comment: Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 SQSTM1 Agnese Zarina gene: SQSTM1 was added
gene: SQSTM1 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: SQSTM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SQSTM1 were set to doi:10.1001/archneurol.2011.250
Phenotypes for gene: SQSTM1 were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Penetrance for gene: SQSTM1 were set to Complete
Review for gene: SQSTM1 was set to AMBER
Added comment: The gene is included in other panels, but one of the phenotypes is also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 SPG11 Agnese Zarina gene: SPG11 was added
gene: SPG11 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: SPG11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPG11 were set to https://doi.org/10.1093/brain/awp325
Phenotypes for gene: SPG11 were set to Amyotrophic lateral sclerosis 5, juvenile
Penetrance for gene: SPG11 were set to Complete
Review for gene: SPG11 was set to AMBER
Added comment: The gene is included in other panels (e.g., spastic paraplegia), but one of the phenotypes could be also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 ANXA11 Agnese Zarina gene: ANXA11 was added
gene: ANXA11 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to DOI: 10.1126/scitranslmed.aad9157
Phenotypes for gene: ANXA11 were set to Amyotrophic lateral sclerosis 23
Penetrance for gene: ANXA11 were set to Complete
Review for gene: ANXA11 was set to AMBER
Added comment: gene is added to "Neurodegenerative disorders - adult onset" panel, but one of the phenotype is also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 TUBA4A Agnese Zarina gene: TUBA4A was added
gene: TUBA4A was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA4A were set to https://doi.org/10.1016/j.neuron.2014.09.027
Phenotypes for gene: TUBA4A were set to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia
Penetrance for gene: TUBA4A were set to Complete
Review for gene: TUBA4A was set to AMBER
Added comment: Gene is added to "Neurodegenerative disorders - adult onset" panel, but the phenotype can be also amyotrophic lateral sclerosis with or without frontotemporal dementia
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 MATR3 Agnese Zarina gene: MATR3 was added
gene: MATR3 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: MATR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MATR3 were set to https://doi.org/10.1038/nn.3688 https://doi.org/10.1002/ana.24255
Phenotypes for gene: MATR3 were set to Amyotrophic lateral sclerosis 21
Penetrance for gene: MATR3 were set to Complete
Review for gene: MATR3 was set to AMBER
Added comment: Gene is added to the "Neuromuscular diseases" super panel and "Dystal myopathies" sub-panel, but it should be added also to the "ALS" panel.
Sources: Literature
Hearing loss v2.176 ADGRV1 Ivone Leong Publications for gene: ADGRV1 were set to PMID:10234513; 10976914; 11545713; 11606593; 12095917; 12402266; 14740321; 15820310; 18854872; 19357116; 19357117; 20440071; 22147658; 9598305; 9734811
Intellectual disability v3.1136 RUBCN Arina Puzriakova edited their review of gene: RUBCN: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1136 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: ; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1136 RUBCN Arina Puzriakova Tag founder-effect tag was added to gene: RUBCN.
Intellectual disability v3.1136 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to 20826435
Genetic epilepsy syndromes v2.374 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: RED; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.225 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to PMID: 20826435
Hereditary ataxia - adult onset v2.74 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from Autosomal recessive spinocerebellar ataxia 15, 615705 to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Hereditary ataxia v1.224 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: RED; Mode of pathogenicity: None; Publications: 20826435, 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.201 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to PMID: 20826435
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Classified gene: RUBCN as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Added comment: Comment on list classification: Gene was reassessed following a Green review by Zornitza Stark. Five individuals from two consanguineous Saudi families have been identified (PMID: 20826435; 32450808) who presented with early-onset ataxia, dysarthria, and developmental delay. All harboured the same c.2624delC variant, which was confirmed to be a founder variant by autozygosity mapping. Limited functional data showing the variant results in mislocalisation of the mutant protein from the late endosome and lysosomes to diffuse cytosolic distribution.

*Note the third publication identified by Zornitza (PMID:30237576) refers to the same sib pair as in PMID:32450808. The variants appeared distinct as the two papers refer to different reference sequences (NM_014687 vs NM_001145642.2) but the variant/case are in fact the same.
-----
Overall as there is only a single variant in a single population with only limited in vitro functional support, maintaining Red rating on this panel until further evidence on the gene/variants emerges.
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Gene: rubcn has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.199 RUBCN Arina Puzriakova Tag founder-effect tag was added to gene: RUBCN.
Hearing loss v2.175 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Hearing loss v2.175 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Hearing loss. Sources: Literature,Expert Review Red
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Optic neuropathy v2.44 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Optic neuropathy v2.44 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Optic neuropathy. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Hydrocephalus v2.106 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Hydrocephalus v2.106 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Hydrocephalus. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Retinal disorders v2.187 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Retinal disorders v2.187 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Retinal disorders. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Severe microcephaly v2.208 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Severe microcephaly v2.208 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Severe microcephaly. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Growth failure in early childhood v1.70 ZPR1 Ivone Leong Classified gene: ZPR1 as Red List (low evidence)
Growth failure in early childhood v1.70 ZPR1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Growth failure in early childhood v1.70 ZPR1 Ivone Leong Gene: zpr1 has been classified as Red List (Low Evidence).
Growth failure in early childhood v1.69 ZPR1 Ivone Leong Tag founder-effect tag was added to gene: ZPR1.
Growth failure in early childhood v1.69 ZPR1 Ivone Leong Added comment: Comment on publications: PMID: 29851065. 4 affected individuals from 3 families of New Mexican Hispanic heritage, residing in the middle Rio Grande Valley. 3/4 died at ages 12-33 months. 2/4 severe microcephaly at birth (<-3SD, other 2 have moderate microcephaly -2SD), 4/4 severe microcephaly postnatal (-4SD to -6.5 SD), 4/4 growth restriction, 4/4 alopecia, 4/4 hypopigmented porcelain-like skin at birth, 4/4 hypoplastic kidneys, 3/4 optic atrophy, 1/4 retinal dystrophy and night blindness, 4/4 distinctive facial features, 4/4 congenital sensorineural hearing loss, 4/4 joint contractures or congenital hip dislocation, 1/4 diabetes (1 other patient has sparse hypotrophic islets of Langerhans), 3/4 acquired increased adiposity, 3/3 hydrocephalus.
Growth failure in early childhood v1.69 ZPR1 Ivone Leong Publications for gene: ZPR1 were set to 29851065
Growth failure in early childhood v1.68 ZPR1 Ivone Leong Phenotypes for gene: ZPR1 were changed from Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies 619321 to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Thoracic aortic aneurysm or dissection v1.118 COL5A1 Ivone Leong Publications for gene: COL5A1 were set to 26188975; 10946364; 28868310; 25845371; 239975631; 2180144; 29543232
Thoracic aortic aneurysm or dissection v1.117 COL5A1 Ivone Leong reviewed gene: COL5A1: Rating: ; Mode of pathogenicity: None; Publications: 32938213; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1135 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm or dissection v1.117 COL5A1 Ivone Leong Phenotypes for gene: COL5A1 were changed from Ehlers-Danlos syndrome vascular type; Ehlers-Danlos syndrome, classic type, 130000 to Ehlers-Danlos syndrome, classic type, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329
Genetic epilepsy syndromes v2.374 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from ?Spinocerebellar ataxia, autosomal recessive 15 615705 to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm and dissection v1.12 COL5A1 Ivone Leong Added comment: Comment on phenotypes: Added Fibromuscular dysplasia, multifocal, OMIM:619329
Thoracic aortic aneurysm and dissection v1.12 COL5A1 Ivone Leong Phenotypes for gene: COL5A1 were changed from Ehlers-Danlos syndrome, classic type, 130000; Ehlers-Danlos syndrome vascular type to Ehlers-Danlos syndrome, classic type, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329
Hereditary ataxia v1.224 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Ataxia and cerebellar anomalies - narrow panel v2.199 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm or dissection v1.116 IPO8 Ivone Leong Classified gene: IPO8 as Green List (high evidence)
Thoracic aortic aneurysm or dissection v1.116 IPO8 Ivone Leong Gene: ipo8 has been classified as Green List (High Evidence).
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong Tag Q2_21_rating was removed from gene: IPO8.
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong Entity copied from Thoracic aortic aneurysm and dissection v1.11
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong gene: IPO8 was added
gene: IPO8 was added to Thoracic aortic aneurysm or dissection. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: IPO8.
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604; 34010605
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Thoracic aortic aneurysm and dissection v1.11 IPO8 Ivone Leong Tag Q2_21_rating tag was added to gene: IPO8.
Primary immunodeficiency v2.434 IPO8 Ivone Leong changed review comment from: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8):

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"; to: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8) panel:

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Hereditary neuropathy NOT PMP22 copy number v1.27 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Ataxia, spasticity, and demyelinating neuropathy to POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Thoracic aortic aneurysm and dissection v1.11 IPO8 Ivone Leong commented on gene: IPO8: Boaz Palterer also left a Green review on the Primary immunodeficiency panel (Version 2.434):

"Ziegler et al. reported 12 individuals from 9 unrelated kindreds with bi-allelic loss-of-function variants in IPO8 presenting with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation. IPO8 is involved in the TGFbeta/SMAD signaling, which is a known pathway in Loeys-Dietz syndrome. Functional data in a zebrafish model. Sources: Literature
Boaz Palterer (University of Florence), 24 May 2021"
Ataxia and cerebellar anomalies - narrow panel v2.198 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381; POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Primary immunodeficiency v2.434 IPO8 Ivone Leong commented on gene: IPO8: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8):

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Primary immunodeficiency v2.434 IPO8 Ivone Leong Added comment: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype.
Primary immunodeficiency v2.434 IPO8 Ivone Leong Publications for gene: IPO8 were set to 34010604; 34010605
Thoracic aortic aneurysm and dissection v1.11 IPO8 Ivone Leong Publications for gene: IPO8 were set to 34010604; 34010605
Primary immunodeficiency v2.433 IPO8 Ivone Leong Publications for gene: IPO8 were set to 34010604
Thoracic aortic aneurysm and dissection v1.10 IPO8 Ivone Leong changed review comment from: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients.; to: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype.
Thoracic aortic aneurysm and dissection v1.10 IPO8 Ivone Leong Classified gene: IPO8 as Amber List (moderate evidence)
Thoracic aortic aneurysm and dissection v1.10 IPO8 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 v1.10 IPO8 Ivone Leong Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1134 POLR3B Arina Puzriakova Publications for gene: POLR3B were set to
Thoracic aortic aneurysm and dissection v1.9 IPO8 Ivone Leong Added comment: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients.
Thoracic aortic aneurysm and dissection v1.9 IPO8 Ivone Leong Publications for gene: IPO8 were set to 34010604
Intellectual disability v3.1133 POLR3B Arina Puzriakova Added comment: Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ID. There is enough evidence for a Green rating for both allelic requirements, so POLR3B has been tagged Q2_21_MOI to change the MOI from biallelic to both biallelic/monoallelic at the next GMS review.
-----
Biallelic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy (OMIM:614381), associated with variable ID.

Recently, heterozygous variants were also linked to ID. Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. The majority had some degree of DD, with 5/6 participants being diagnosed with intellectual disability ranging from mild to moderate severity. Four individuals required assistance with basic activities of daily living, however none had developmental regression. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Intellectual disability v3.1133 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1132 POLR3B Arina Puzriakova Tag Q2_21_MOI tag was added to gene: POLR3B.
Intellectual disability v3.1132 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381; POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Hereditary neuropathy NOT PMP22 copy number v1.26 POLR3B Arina Puzriakova Classified gene: POLR3B as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.26 POLR3B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. EMG/NCSs for 5/6 individuals revealed predominantly demyelinating sensory and motor neuropathy. Other features included ID, ataxia, spasticity.

POLR3B is listed in G2P with a 'probable' disease confidence rating for this phenotype (POLR3B-related neurodevelopmental disorder - monoallelic), but is not yet in OMIM.

Overall, there is sufficient evidence to warrant a Green rating on this panel.
Hereditary neuropathy NOT PMP22 copy number v1.26 POLR3B Arina Puzriakova Gene: polr3b has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy NOT PMP22 copy number v1.25 POLR3B Arina Puzriakova Tag Q2_21_rating tag was added to gene: POLR3B.
Ataxia and cerebellar anomalies - narrow panel v2.197 POLR3B Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Progressive childhood-onset cerebellar ataxia is a feature in a subset of cases with biallelic variants in this gene. There are sufficient unrelated families in literature to warrant a Green rating on this panel (>10 individuals reported with ataxia)

Recently, heterozygous variants were also linked to ataxia, with different de novo POLR3B variants identified in 6 unrelated individuals presenting (PMID:33417887). All had had a variable degree of gait dysfunction - 5/6 had truncal and/or appendicular ataxia with wide-based ataxic gait, inability to perform tandem gait, or gait instability. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.


Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ataxia - enough evidence for a Green rating for both allelic requirements; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Progressive childhood-onset cerebellar ataxia is a feature in a subset of cases with biallelic variants in this gene. There are sufficient unrelated families in literature to warrant a Green rating on this panel (>10 individuals reported with ataxia)

Recently, heterozygous variants were also linked to ataxia, with different de novo POLR3B variants identified in 6 unrelated individuals (PMID:33417887). All had had a variable degree of gait dysfunction - 5/6 had truncal and/or appendicular ataxia with wide-based ataxic gait, inability to perform tandem gait, or gait instability. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.


Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ataxia - enough evidence for a Green rating for both allelic requirements
Ataxia and cerebellar anomalies - narrow panel v2.197 POLR3B Arina Puzriakova edited their review of gene: POLR3B: Changed rating: GREEN; Changed publications to: 22036171, 18851904, 22036172, 24190003, 25339210, 26204956, 27159321, 32319736, 33417887; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.197 POLR3B Arina Puzriakova Tag Q2_21_rating tag was added to gene: POLR3B.
Ataxia and cerebellar anomalies - narrow panel v2.197 POLR3B Arina Puzriakova Publications for gene: POLR3B were set to 22036171; 22036172
Ataxia and cerebellar anomalies - narrow panel v2.196 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.195 POLR3B Arina Puzriakova Classified gene: POLR3B as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.195 POLR3B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Progressive childhood-onset cerebellar ataxia is a feature in a subset of cases with biallelic variants in this gene. There are sufficient unrelated families in literature to warrant a Green rating on this panel (>10 individuals reported with ataxia)

Recently, heterozygous variants were also linked to ataxia, with different de novo POLR3B variants identified in 6 unrelated individuals presenting (PMID:33417887). All had had a variable degree of gait dysfunction - 5/6 had truncal and/or appendicular ataxia with wide-based ataxic gait, inability to perform tandem gait, or gait instability. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.


Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ataxia - enough evidence for a Green rating for both allelic requirements
Ataxia and cerebellar anomalies - narrow panel v2.195 POLR3B Arina Puzriakova Gene: polr3b has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.101 ARCN1 Andžela Lazdāne edited their review of gene: ARCN1: Changed rating: GREEN
IUGR and IGF abnormalities v1.35 ARCN1 Andžela Lazdāne edited their review of gene: ARCN1: Changed rating: GREEN
DDG2P v2.28 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM 607694; AUTOSOMAL RECESSIVE MENTAL RETARDATION to Autosomal recessive mental retardation; Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism; POLR3B-related neurodevelopmental disorder
Intellectual disability v3.1131 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropichypogonadism, 614381; LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Fetal anomalies v1.678 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Inherited white matter disorders v1.126 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
White matter disorders - adult onset v1.16 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Ataxia and cerebellar anomalies - narrow panel v2.194 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
White matter disorders and cerebral calcification - narrow panel v1.181 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Intellectual disability v3.1130 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures, intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Genetic epilepsy syndromes v2.373 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Intellectual disability v3.1129 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Developmental and epileptic encephalopathy 70, OMIM:618298
Genetic epilepsy syndromes v2.372 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures to Developmental and epileptic encephalopathy 70, OMIM:618298
Intellectual disability v3.1128 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Genetic epilepsy syndromes v2.371 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Intellectual disability v3.1127 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior to Developmental and epileptic encephalopathy 67, OMIM:618141; Seizures; Intellectual disability; Autistic behaviour
Genetic epilepsy syndromes v2.370 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy to Developmental and epileptic encephalopathy 67, OMIM:618141; Infantile onset myoclonic epileptic encephalopathy
Skeletal dysplasia v2.101 FAM46A Arina Puzriakova Phenotypes for gene: FAM46A were changed from Osteogenesis imperfecta, type XVIII 617952 to Osteogenesis imperfecta, type XVIII, OMIM:617952
Osteogenesis imperfecta v2.14 FAM46A Arina Puzriakova Phenotypes for gene: FAM46A were changed from osteogenesis imperfecta to Osteogenesis imperfecta, type XVIII, OMIM:617952
Fetal anomalies v1.677 SPTBN5 Arina Puzriakova Phenotypes for gene: SPTBN5 were changed from Multicystic kidney; Oligohydramnios to Multicystic kidney; Oligohydramnios; Sacral agenesis
Fetal anomalies v1.676 SPTBN5 Arina Puzriakova Publications for gene: SPTBN5 were set to 32732226
Fetal anomalies v1.675 SPTBN5 Arina Puzriakova Mode of inheritance for gene: SPTBN5 was changed from BIALLELIC, autosomal or pseudoautosomal to Unknown
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: PITRM1.
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Classified gene: PITRM1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for PITRM1 to be classified as Green at the next GMS panel update. Three unrelated families including 2 consanguineous Palestinian families each with 2 affected boys (PMID: 29764912) and a consanguineous Norwegian family also with 2 affected sibs (PMID: 26697887). Phenotypes include ataxia although severity is variable. Supported by functional work and mouse model also exhibiting progressive ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Gene: pitrm1 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm and dissection v1.8 COL5A1 Ivone Leong Publications for gene: COL5A1 were set to
Fetal hydrops v1.29 SLC30A5 Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.45
Fetal hydrops v1.29 SLC30A5 Ivone Leong gene: SLC30A5 was added
gene: SLC30A5 was added to Fetal hydrops. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: SLC30A5.
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919
Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy; cardiomyopathy, MONDO:0004994
Cardiomyopathies - including childhood onset v1.45 SLC30A5 Ivone Leong Classified gene: SLC30A5 as Amber List (moderate evidence)
Cardiomyopathies - including childhood onset v1.45 SLC30A5 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.
Cardiomyopathies - including childhood onset v1.45 SLC30A5 Ivone Leong Gene: slc30a5 has been classified as Amber List (Moderate Evidence).
Cardiomyopathies - including childhood onset v1.44 SLC30A5 Ivone Leong Tag watchlist tag was added to gene: SLC30A5.
Cardiomyopathies - including childhood onset v1.44 SLC30A5 Ivone Leong Phenotypes for gene: SLC30A5 were changed from Perinatal lethal cardiomyopathy to Perinatal lethal cardiomyopathy; cardiomyopathy, MONDO:0004994
Stickler syndrome v2.22 BMP4 Ivone Leong Added comment: Comment on publications: Added publication and removed PMID: 25663169; 30362103, which were for LOXL3 and not BMP4
Stickler syndrome v2.22 BMP4 Ivone Leong Publications for gene: BMP4 were set to 30568244
Stickler syndrome v2.21 BMP4 Ivone Leong Publications for gene: BMP4 were set to 25663169; 30362103; 30568244
Stickler syndrome v2.20 LOXL3 Ivone Leong Publications for gene: LOXL3 were set to 25663169
Stickler syndrome v2.19 BMP4 Ivone Leong Publications for gene: BMP4 were set to 25663169; 30362103
Hearing loss v2.174 COL9A3 Ivone Leong reviewed gene: COL9A3: Rating: ; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: ; Mode of inheritance: None
Stickler syndrome v2.18 COL9A3 Ivone Leong changed review comment from: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.; to: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 variant associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong changed review comment from: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with Stickler syndrome, the MOI will be kept as "Biallelic" until more evidence is available.; to: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong Added comment: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with Stickler syndrome, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong Mode of inheritance for gene: COL9A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Stickler syndrome v2.17 COL9A3 Ivone Leong Publications for gene: COL9A3 were set to 24273071 and unpublished observation; 30450842
Structural eye disease v1.73 KIF17 Ivone Leong Classified gene: KIF17 as Red List (low evidence)
Structural eye disease v1.73 KIF17 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 gene-disease association. This gene has been given a Red rating.
Structural eye disease v1.73 KIF17 Ivone Leong Gene: kif17 has been classified as Red List (Low Evidence).
Structural eye disease v1.72 KIF17 Ivone Leong Phenotypes for gene: KIF17 were changed from Microphthalmia; Coloboma to Microphthalmia, MONDO:0021129; Coloboma, MONDO:0001476
Primary immunodeficiency v2.432 MYOF Arina Puzriakova Penetrance for gene MYOF was set from to None
IUGR and IGF abnormalities v1.35 ARCN1 Andžela Lazdāne gene: ARCN1 was added
gene: ARCN1 was added to IUGR and IGF abnormalities. Sources: Literature
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARCN1 were set to PMID: 27476655; PMID: 33154040
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
Penetrance for gene: ARCN1 were set to Complete
Review for gene: ARCN1 was set to AMBER
Added comment: Pathogenic loss-of-function variants in ARCN1 represent an emerging disorder of developmental delay and skeletal manifestations. Phenotype corresponds to IUGR such as craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, cleft palate, microcephalic dwarfism and mild developmental delay.
Sources: Literature
Skeletal dysplasia v2.100 ARCN1 Andžela Lazdāne gene: ARCN1 was added
gene: ARCN1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARCN1 were set to PMID: 27476655
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
Penetrance for gene: ARCN1 were set to Complete
Review for gene: ARCN1 was set to AMBER
Added comment: Clinical features like short stature, rhizomelia, laxity of the small joints, cleft palete and developmental delay also tend to occur in Skeletal dysplasia.

ARCN1 gene encodes the coatomer subunit delta of COPI which is a coatomer protein complex responsible for intracellular protein transport. The importance of this mechanisms is underscored by various skeletal disorders. COPI-mediated transport is important in human development, including skeletogenesis and brain growth.
Sources: Literature
Intellectual disability v3.1126 CTC1 Zornitza Stark reviewed gene: CTC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency v2.431 MYOF Arina Puzriakova Classified gene: MYOF as Red List (low evidence)
Primary immunodeficiency v2.431 MYOF Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as only a single family has been reported at this time. Likely incomplete penetrance as one unaffected family member also carried the variant (PMID:32542751)
Primary immunodeficiency v2.431 MYOF Arina Puzriakova Gene: myof has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.430 MYOF Arina Puzriakova Phenotypes for gene: MYOF were changed from Hereditary angioedema-7 (HAE7), MIM#619366 to ?Angioedema, hereditary, 7, OMIM:619366
Primary immunodeficiency v2.429 HS3ST6 Arina Puzriakova Phenotypes for gene: HS3ST6 were changed from Hereditary angioedema-8 (HAE8), MIM#619367 to ?Angioedema, hereditary, 8, OMIM:619367
Primary immunodeficiency v2.428 HS3ST6 Arina Puzriakova Classified gene: HS3ST6 as Red List (low evidence)
Primary immunodeficiency v2.428 HS3ST6 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Rating Red as only a single family has been reported at this time (PMID:33508266)
Primary immunodeficiency v2.428 HS3ST6 Arina Puzriakova Gene: hs3st6 has been classified as Red List (Low Evidence).
IUGR and IGF abnormalities v1.35 KANSL1 Andžela Lazdāne gene: KANSL1 was added
gene: KANSL1 was added to IUGR and IGF abnormalities. Sources: Expert list,Literature
Mode of inheritance for gene: KANSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KANSL1 were set to PMID: 22544363
Phenotypes for gene: KANSL1 were set to Koolen-De Vries syndrome; Facial features; Delayed psychomotor development; Intellectual disability
Penetrance for gene: KANSL1 were set to Complete
Review for gene: KANSL1 was set to GREEN
Added comment: Region: ISCA-37420-Loss wich is in IUGR and IGF abnormalities panel includes KANSL1 gene.
Based on the literature de novo heterozygous truncating mutations in the KANSL1 gene causes symptoms like characteristic facial features, including broad forehead, long face, developmental delay, cleft lip/palate and tubular nose with bulbous nasal tip may manifest also in IUGR.
Sources: Expert list, Literature
Skeletal dysplasia v2.100 MYO18B Andžela Lazdāne gene: MYO18B was added
gene: MYO18B was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MYO18B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO18B were set to PMID: 32637634
Phenotypes for gene: MYO18B were set to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism
Penetrance for gene: MYO18B were set to Complete
Review for gene: MYO18B was set to AMBER
Added comment: Truncating mutations of MYO18B have been found to cause nemaline myopathy with cardiomyopathy or Klippel-Feil syndrome (KFS). Other KFS genes such as GDF3, GDF6, MEOX1, and RIPPLY2 are include in Skeletal dysplasia panel. KFS patients may have symptoms like spinal instability, disc degeneration, scoliosis, short neck, cleft palate, facial dysmorphism, and limb and hand abnormalities which may also be present in Skeletal dysplasia.
Sources: Literature
Hereditary ataxia - adult onset v2.73 VPS41 Arina Puzriakova Publications for gene: VPS41 were set to 32367058; 33875678
Hereditary ataxia - adult onset v2.72 VPS41 Arina Puzriakova Classified gene: VPS41 as Amber List (moderate evidence)
Hereditary ataxia - adult onset v2.72 VPS41 Arina Puzriakova Added comment: Comment on list classification: New gene added by James Polke (North Thames GLH). There are sufficient unrelated families with ataxia (9/11 patients) and VPS41 variants to rate Green - but this appears to be a childhood-onset condition. There is one older subject (22-year-old male - PMID:33764426) for whom the age of onset is not indicated but can probably be inferred by comparison with other cases.

Inclusion may allow for identification of edge cases, but overall VPS41 will be flagged for GMS review to assess whether this is justified.
Hereditary ataxia - adult onset v2.72 VPS41 Arina Puzriakova Gene: vps41 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia - adult onset v2.71 VPS41 Arina Puzriakova Tag Q2_21_rating was removed from gene: VPS41.
Tag Q2_21_expert_review tag was added to gene: VPS41.
Hereditary ataxia - adult onset v2.71 VPS41 Arina Puzriakova Tag Q2_21_rating tag was added to gene: VPS41.
Hereditary ataxia - adult onset v2.71 VPS41 Arina Puzriakova reviewed gene: VPS41: Rating: AMBER; Mode of pathogenicity: None; Publications: 32808683, 33764426, 33851776; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset movement disorder v1.121 VPS41 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: VPS41.
Adult onset movement disorder v1.121 VPS41 Arina Puzriakova Publications for gene: VPS41 were set to 32808683; 33764426
Adult onset movement disorder v1.120 VPS41 Arina Puzriakova Classified gene: VPS41 as Amber List (moderate evidence)
Adult onset movement disorder v1.120 VPS41 Arina Puzriakova Added comment: Comment on list classification: New gene added by James Polke (North Thames GLH). There are sufficient unrelated families with a movement disorder and VPS41 variants to rate Green - but this appears to be a childhood-onset condition. There is one older subject (22-year-old male - PMID:33764426) for whom the age of onset is not indicated but can probably be inferred by comparison with other cases.

Inclusion may allow for identification of edge cases, but overall VPS41 will be flagged for GMS review to assess whether this is justified.
Adult onset movement disorder v1.120 VPS41 Arina Puzriakova Gene: vps41 has been classified as Amber List (Moderate Evidence).
Adult onset movement disorder v1.119 VPS41 Arina Puzriakova reviewed gene: VPS41: Rating: AMBER; Mode of pathogenicity: None; Publications: 32808683, 33764426, 33851776; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1126 VPS41 Arina Puzriakova Entity copied from Childhood onset dystonia or chorea or related movement disorder v1.130
Intellectual disability v3.1126 VPS41 Arina Puzriakova gene: VPS41 was added
gene: VPS41 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: VPS41.
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426; 33851776
Phenotypes for gene: VPS41 were set to Dystonia; Intellectual disability
Childhood onset dystonia or chorea or related movement disorder v1.130 VPS41 Arina Puzriakova Phenotypes for gene: VPS41 were changed from Dystonia; intellectual disability to Dystonia; Intellectual disability
Childhood onset dystonia or chorea or related movement disorder v1.129 VPS41 Arina Puzriakova Publications for gene: VPS41 were set to 32808683
Childhood onset dystonia or chorea or related movement disorder v1.128 VPS41 Arina Puzriakova Classified gene: VPS41 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.128 VPS41 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GSM panel update.
Childhood onset dystonia or chorea or related movement disorder v1.128 VPS41 Arina Puzriakova Gene: vps41 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.127 VPS41 Arina Puzriakova Tag Q2_21_rating tag was added to gene: VPS41.
Childhood onset dystonia or chorea or related movement disorder v1.127 VPS41 Arina Puzriakova reviewed gene: VPS41: Rating: GREEN; Mode of pathogenicity: None; Publications: 32808683, 33764426, 33851776; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.192 VPS41 Arina Puzriakova Publications for gene: VPS41 were set to 32808683; 33764426
Ataxia and cerebellar anomalies - narrow panel v2.191 VPS41 Arina Puzriakova Classified gene: VPS41 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.191 VPS41 Arina Puzriakova Added comment: Comment on list classification: New gene added by James Polke (North Thames GLH). There is sufficient evidence to promote this gene to Green at the next GSM panel update - cerebellar ataxia was evident in 9/11 patients reported to date.
Ataxia and cerebellar anomalies - narrow panel v2.191 VPS41 Arina Puzriakova Gene: vps41 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.190 VPS41 Arina Puzriakova Tag Q2_21_rating tag was added to gene: VPS41.
Ataxia and cerebellar anomalies - narrow panel v2.190 VPS41 Arina Puzriakova reviewed gene: VPS41: Rating: GREEN; Mode of pathogenicity: None; Publications: 32808683, 33764426, 33851776; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thrombophilia v1.19 ADAMTS13 Kate Downes reviewed gene: ADAMTS13: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.26 ADAMTS13 Kate Downes reviewed gene: ADAMTS13: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: Other
White matter disorders and cerebral calcification - narrow panel v1.180 PTEN Ivone Leong Classified gene: PTEN as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.180 PTEN 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. There is enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.180 PTEN Ivone Leong Gene: pten has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.179 PTEN Ivone Leong Publications for gene: PTEN were set to 29720545; 29152901; 30664625
Inherited white matter disorders v1.125 SDHA Ivone Leong Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, MIM#252011 to Mitochondrial respiratory chain complex II deficiency, OMIM:252011
Inherited white matter disorders v1.124 SDHA Ivone Leong Added comment: Comment on publications: PMID: 24781757. 4 unrelated patients. 1/4 had leukodystrophy, 1/4 had cerebral atrophy and 1/4 had both leukodystrophy and cerebral atrophy. PMID: 22972948. 2 unrelated patients both had leukodystrophy.
Inherited white matter disorders v1.124 SDHA Ivone Leong Publications for gene: SDHA were set to 22972948
Inherited white matter disorders v1.123 SDHA Ivone Leong Classified gene: SDHA as Green List (high evidence)
Inherited white matter disorders v1.123 SDHA Ivone Leong Gene: sdha has been classified as Green List (High Evidence).
Inherited white matter disorders v1.122 SDHA Ivone Leong Classified gene: SDHA as Red List (low evidence)
Inherited white matter disorders v1.122 SDHA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.122 SDHA Ivone Leong Gene: sdha has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.178 SDHA Ivone Leong Classified gene: SDHA as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.178 SDHA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. 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 promoted to Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.178 SDHA Ivone Leong Gene: sdha has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.177 SDHA Ivone Leong Tag Q2_21_rating tag was added to gene: SDHA.
White matter disorders and cerebral calcification - narrow panel v1.177 SDHA Ivone Leong Added comment: Comment on publications: PMID: 24781757. 4 unrelated patients. 1/4 had leukodystrophy, 1/4 had cerebral atrophy and 1/4 had both leukodystrophy and cerebral atrophy.

PMID: 22972948. 2 unrelated patients both had leukodystrophy.
White matter disorders and cerebral calcification - narrow panel v1.177 SDHA Ivone Leong Publications for gene: SDHA were set to 22972948
Lysosomal storage disorder v1.74 VPS16 Arina Puzriakova Phenotypes for gene: VPS16 were changed from Mucopolysaccharidosis-like syndrome (biallelic); Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities (monoallelic) to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291
Lysosomal storage disorder v1.73 VPS16 Arina Puzriakova changed review comment from: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion on this panel for this allelic requirement.

Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases.

VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic); to: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion for this allelic requirement.

Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases.

VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)
Lysosomal storage disorder v1.73 VPS16 Arina Puzriakova Classified gene: VPS16 as Amber List (moderate evidence)
Lysosomal storage disorder v1.73 VPS16 Arina Puzriakova Gene: vps16 has been classified as Amber List (Moderate Evidence).
Lysosomal storage disorder v1.72 VPS16 Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion on this panel for this allelic requirement.

Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases.

VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)
Lysosomal storage disorder v1.72 VPS16 Arina Puzriakova Mode of inheritance for gene: VPS16 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Lysosomal storage disorder v1.71 VPS16 Arina Puzriakova gene: VPS16 was added
gene: VPS16 was added to Lysosomal storage disorder. Sources: Literature
Q2_21_rating, Q2_21_MOI tags were added to gene: VPS16.
Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS16 were set to 33938619; 34013567
Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities (monoallelic)
Review for gene: VPS16 was set to GREEN
Added comment: Four individuals from three families were identified (PMIDs: 33938619; 34013567) exhibiting a mucopolysaccharidosis (MPS)-like lysosomal storage phenotype with short stature, coarse facies, DD or regression, peripheral neuropathy, skeletal dysplasia, neutropenia, and high-normal glycosaminoglycan excretion. All harboured homozygous variants in VPS16 which segregated with disease, including a missense variant in a sib pair (c.540G>T; p.Trp180Cys) and a recurrent intronic variant (c.2272‐18C>A) in two supposedly unrelated patients (although both of Middle Eastern descent).

Fibroblasts of the two patients with the intronic variant showed accumulation of lysosomal compartments and autophagosomes with significantly decreased VPS16 mRNA and protein levels, as well as HOPS/CORVET complexes. Cellular phenotypes were rescued upon re-expression of wild-type VPS16.

-----
Heterozygous variants, as well as a homozygous missense variant (c.156C>A) found in a consanguineous Chinese family (PMID:27174565), have been found to cause dystonia with variable onset (OMIM:619291). It has been suggested that the discrepancies in patient phenotypes are due to different mechanisms of pathogenicity, where variants causing dystonia do not affect the levels of endolysosomal tethering (HOPS/CORVET) complexes.

More research is needed to clarify the mechanisms underlying VPS16-related dystonia as only limited functional data is currently available - Steel et al. 2020 (PMID:32808683) did perform electron microscopic studies of lymphocytes and fibroblasts derived from 2 unrelated patients, which showed vacuolar abnormalities suggestive of impaired lysosomal function.
Sources: Literature
Ehlers Danlos syndromes v2.57 LTBP1 Andžela Lazdāne edited their review of gene: LTBP1: Changed phenotypes to: Cutis laxa, Craniofacial dysmorphism, Altered skeletal development, including short stature, Brachydactyly, Clinodactyly
Ehlers Danlos syndromes v2.57 LTBP1 Andžela Lazdāne changed review comment from: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae.
Sources: Literature; to: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae.
Sources: Literature
Ehlers Danlos syndromes v2.57 LTBP1 Andžela Lazdāne gene: LTBP1 was added
gene: LTBP1 was added to Ehlers Danlos syndromes. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to PMID: 33991472
Phenotypes for gene: LTBP1 were set to Cutis laxa; craniofacial dysmorphism; altered skeletal development, including short stature; brachydactyly; clinodactyly
Penetrance for gene: LTBP1 were set to Complete
Review for gene: LTBP1 was set to GREEN
Added comment: Based on the literature homozygous premature truncating LTBP1 variants was reported in eight affected individuals with connective tissue features. In vivo validation with two independent zebrafish lines carrying mutations in LTBP1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.127 VPS16 Arina Puzriakova Penetrance for gene VPS16 was set from to None
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova commented on gene: VPS16: Penetrance for gene VPS16 was set from None to Incomplete - some variants transmitted from an unaffected parent and heterozygous LoF variants are observed in presumably healthy individuals in gnomAD
Adult onset movement disorder v1.119 VPS16 Arina Puzriakova commented on gene: VPS16: Penetrance for gene VPS16 was set from None to Incomplete - some variants transmitted from an unaffected parent and heterozygous LoF variants are observed in presumably healthy individuals in gnomAD
Adult onset movement disorder v1.119 VPS16 Arina Puzriakova Penetrance for gene VPS16 was set from to None
Congenital myopathy v2.28 TPM2 Zornitza Stark reviewed gene: TPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32092148, 27726070; Phenotypes: Congenital myopathy, Multiple pterygium syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Structural eye disease v1.71 KIF17 Zornitza Stark gene: KIF17 was added
gene: KIF17 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: KIF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF17 were set to 33922911; 30458707; 28341548
Phenotypes for gene: KIF17 were set to Microphthalmia; Coloboma
Review for gene: KIF17 was set to RED
Added comment: Two siblings reported with MAC spectrum and homozygous missense variant in this gene. Some pre-existing data linking KIF17 to eye development.
Sources: Literature
Primary immunodeficiency v2.427 SASH3 Zornitza Stark reviewed gene: SASH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33876203; Phenotypes: Combined immunodeficiency, immune dysregulation; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pain syndromes v1.9 PLEKHN1 Zornitza Stark gene: PLEKHN1 was added
gene: PLEKHN1 was added to Pain syndromes. Sources: Literature
Mode of inheritance for gene: PLEKHN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHN1 were set to 33884296
Phenotypes for gene: PLEKHN1 were set to Sensory neuropathy
Review for gene: PLEKHN1 was set to RED
Added comment: Hom missense variant in single patient with severely reduced/absent pain and temperature sensation
Sources: Literature
Pain syndromes v1.9 SMPDL3A Zornitza Stark changed review comment from: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature; to: Hom missense variant in twin sisters with severely reduced pain and temperature sensation
Sources: Literature
Pain syndromes v1.9 SMPDL3A Zornitza Stark gene: SMPDL3A was added
gene: SMPDL3A was added to Pain syndromes. Sources: Literature
Mode of inheritance for gene: SMPDL3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPDL3A were set to 33884296
Phenotypes for gene: SMPDL3A were set to Sensory neuropathy
Review for gene: SMPDL3A was set to RED
Added comment: Hom missense variant in twin sisters with deverely reduced pain and temperature sensation
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.126 EIF2AK2 Zornitza Stark reviewed gene: EIF2AK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33236446, 33866603; Phenotypes: Early onset dystonia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital disorders of glycosylation v2.70 SLC37A4 Zornitza Stark edited their review of gene: SLC37A4: Changed rating: GREEN
Intellectual disability v3.1125 PGM2L1 Zornitza Stark gene: PGM2L1 was added
gene: PGM2L1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PGM2L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGM2L1 were set to 33979636
Phenotypes for gene: PGM2L1 were set to Neurodevelopmental disorder
Review for gene: PGM2L1 was set to GREEN
Added comment: PMID: 33979636:
- Bi-allelic PTVs in 4 unrelated individuals. All four affected individuals had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals.
- Studies on patient fibroblasts and cell lines indicated that PGM2L1 deficiency causes a decrease, but not a disappearance, of the sugar bisphosphates needed for the formation of NDP-sugars and that there is no evidence that this leads to a glycosylation defect.
Sources: Literature
Craniosynostosis v2.23 LTBP1 Zornitza Stark gene: LTBP1 was added
gene: LTBP1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to Craniosynostosis; cutis laxa; intelectual disability
Review for gene: LTBP1 was set to GREEN
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Cardiomyopathies - including childhood onset v1.43 SLC30A5 Zornitza Stark gene: SLC30A5 was added
gene: SLC30A5 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919
Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy
Review for gene: SLC30A5 was set to AMBER
Added comment: Four affected children from two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. 2 different homozygous PTCs variants found. Knockout of SLC30A5 in mouse models showed reduced body growth and reduced bone density. About 60% of the mice died due to bradyarrhythmia.
Sources: Literature
Intellectual disability v3.1125 ATXN2L Zornitza Stark gene: ATXN2L was added
gene: ATXN2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ATXN2L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN2L were set to 33283965; 33057194
Phenotypes for gene: ATXN2L were set to Intellectual disability; Macrocephaly
Review for gene: ATXN2L was set to AMBER
Added comment: Combined data from three large exome groups identified several de novo variants, including frameshift and missense, in ATXN2L in patients with developmental delay (Kaplanis et al., 2020). pLI=1.0 Limited other data available.
Single case report of a novel de novo missense variant in a child with macrocephaly and developmental delay. No functional work.
Sources: Literature
Stickler syndrome v2.16 COL9A3 Zornitza Stark reviewed gene: COL9A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: Stickler syndrome, AR, Deafness, AD, Peripheral vitreoretinal degeneration and retinal detachment, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.25 CADM3 Zornitza Stark gene: CADM3 was added
gene: CADM3 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CADM3 were set to 33889941
Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease
Review for gene: CADM3 was set to AMBER
Added comment: Three families reported with the same missense variant in CADM3, p.Tyr172Cys (one family de novo), with functional work in mice to show reduced expression of the mutant protein in axons and abnormal axonal organization.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova edited their review of gene: VPS16: Changed rating: GREEN
Adult onset movement disorder v1.118 VPS16 Arina Puzriakova edited their review of gene: VPS16: Changed rating: GREEN
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova Tag Q2_21_rating tag was added to gene: VPS16.
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova Classified gene: VPS16 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 19 unrelated families reported with progressive dystonia (both multifocal and generalised types described) in association with variants in this gene (publications updated with relevant literature). Variable age of onset ranging from 3 to 50 years.
Childhood onset dystonia or chorea or related movement disorder v1.126 VPS16 Arina Puzriakova Gene: vps16 has been classified as Amber List (Moderate Evidence).
Adult onset movement disorder v1.118 VPS16 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: VPS16.
Childhood onset dystonia or chorea or related movement disorder v1.125 VPS16 Arina Puzriakova Added comment: Comment on mode of inheritance: While most cases of VPS16-related dystonia have been due to heterozygous variants, one Chinese consanguineous family with dystonia has been found to harbour a homozygous missense variant (PMID:27174565). In view of only one biallelic case, MOI has been set as 'Monoallelic' - patients with biallelic variants would still be picked up by the Genomics England pipeline.

Furthermore, biallelic VPS16 variants have been linked to a mucopolysaccharidosis‐like disease - reviewed on the 'Lysosomal storage disorder' (R276) panel.
Childhood onset dystonia or chorea or related movement disorder v1.125 VPS16 Arina Puzriakova Mode of inheritance for gene: VPS16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.124 VPS16 Arina Puzriakova Phenotypes for gene: VPS16 were changed from Dystonia to Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities
Childhood onset dystonia or chorea or related movement disorder v1.123 VPS16 Arina Puzriakova Publications for gene: VPS16 were set to 32808683
Adult onset movement disorder v1.118 VPS16 Arina Puzriakova Publications for gene: VPS16 were set to 32808683
Adult onset movement disorder v1.117 VPS16 Arina Puzriakova Phenotypes for gene: VPS16 were changed from Dystonia; Dystonia Associated with Lysosomal Abnormalities; Dystonia 30; OMIM #619291 to Dystonia 30, OMIM:619291; Dystonia Associated with Lysosomal Abnormalities
Adult onset movement disorder v1.116 VPS16 Arina Puzriakova Tag Q2_21_rating tag was added to gene: VPS16.
Adult onset movement disorder v1.116 VPS16 Arina Puzriakova Classified gene: VPS16 as Amber List (moderate evidence)
Adult onset movement disorder v1.116 VPS16 Arina Puzriakova Added comment: Comment on list classification: New gene added by James Polke (North Thames GLH). There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 19 unrelated families reported with progressive dystonia (both multifocal and generalised types described) in association with variants in this gene (publications updated with relevant literature). Variable age of onset ranging from 3 to 50 years.
Adult onset movement disorder v1.116 VPS16 Arina Puzriakova Gene: vps16 has been classified as Amber List (Moderate Evidence).
Adult onset movement disorder v1.115 VPS16 Arina Puzriakova Added comment: Comment on mode of inheritance: While most cases of VPS16-related dystonia have been due to heterozygous variants, one Chinese consanguineous family with dystonia has been found to harbour a homozygous missense variant (PMID:27174565). In view of only one biallelic case, MOI has been set as 'Monoallelic' - patients with biallelic variants would still be picked up by the Genomics England pipeline.

Furthermore, biallelic VPS16 variants have been linked to a mucopolysaccharidosis‐like disease - reviewed on the 'Lysosomal storage disorder' (R276) panel.
Adult onset movement disorder v1.115 VPS16 Arina Puzriakova Mode of inheritance for gene: VPS16 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v1.176 SDHA Ivone Leong Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, OMIM:252011 to Mitochondrial respiratory chain complex II deficiency, OMIM:252011
White matter disorders and cerebral calcification - narrow panel v1.176 SDHA Ivone Leong Phenotypes for gene: SDHA were changed from Mitochondrial respiratory chain complex II deficiency, MIM#252011 to Mitochondrial respiratory chain complex II deficiency, OMIM:252011
White matter disorders and cerebral calcification - narrow panel v1.175 SNORD118 Ivone Leong Classified gene: SNORD118 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.175 SNORD118 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene is also Green on the Inherited white matter disorders (Version 1.121) and White matter disorders - adult onset (Version 1.15) panels. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.175 SNORD118 Ivone Leong Gene: snord118 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.174 SNORD118 Ivone Leong Tag Q2_21_rating tag was added to gene: SNORD118.
White matter disorders and cerebral calcification - narrow panel v1.174 SNORD118 Ivone Leong Phenotypes for gene: SNORD118 were changed from 614561 to Leukoencephalopathy, brain calcifications, and cysts, OMIM:614561
Inherited white matter disorders v1.121 SPART Ivone Leong Classified gene: SPART as Green List (high evidence)
Inherited white matter disorders v1.121 SPART Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant disorder in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene is also recommended for Green status in the White matter disorders and cerebral calcification - narrow panel (Version 1.173).
Inherited white matter disorders v1.121 SPART Ivone Leong Gene: spart has been classified as Green List (High Evidence).
Inherited white matter disorders v1.120 SPART Ivone Leong Phenotypes for gene: SPART were changed from Troyer syndrome, MIM#275900 to Troyer syndrome, OMIM:275900
Inherited white matter disorders v1.119 SPART Ivone Leong Publications for gene: SPART were set to 27112432, 18413476, 26003402, 12134148
White matter disorders and cerebral calcification - narrow panel v1.173 SPART Ivone Leong Classified gene: SPART as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.173 SPART Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant disorder in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.173 SPART Ivone Leong Gene: spart has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.172 SPART Ivone Leong Tag Q2_21_rating tag was added to gene: SPART.
Intellectual disability v3.1125 SIN3B Arina Puzriakova Tag Q2_21_rating tag was added to gene: SIN3B.
Intellectual disability v3.1125 SIN3B Arina Puzriakova Classified gene: SIN3B as Amber List (moderate evidence)
Intellectual disability v3.1125 SIN3B Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed by Zornitza Stark (Green) and Konstantinos Varvagiannis (Green/Amber). Overall there are sufficient unrelated cases (>3) of ID associated with SNVs in this gene to warrant a Green rating on this panel at the next GMS review. Deletions of the region containing SIN3B have also been linked to ID, lending further support to this gene-disease association.
Intellectual disability v3.1125 SIN3B Arina Puzriakova Gene: sin3b has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.369 EMC10 Arina Puzriakova Entity copied from Intellectual disability v3.1124
Genetic epilepsy syndromes v2.369 EMC10 Arina Puzriakova gene: EMC10 was added
gene: EMC10 was added to Genetic epilepsy syndromes. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: EMC10.
Mode of inheritance for gene: EMC10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EMC10 were set to 32869858; 33531666
Phenotypes for gene: EMC10 were set to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1124 EMC10 Arina Puzriakova Classified gene: EMC10 as Amber List (moderate evidence)
Intellectual disability v3.1124 EMC10 Arina Puzriakova Added comment: Comment on list classification: There is now enough evidence to warrant a Green rating at the next GMS panel update.
Intellectual disability v3.1124 EMC10 Arina Puzriakova Gene: emc10 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1123 EMC10 Arina Puzriakova Tag Q2_21_rating tag was added to gene: EMC10.
Intellectual disability v3.1123 EMC10 Arina Puzriakova edited their review of gene: EMC10: Added comment: There are now at least 15 individuals from 8 families reported with biallelic variants in the EMC10 gene associated with disease. One variant found in a single population is likely to be a founder variant; however, the identification of a different variant in a family presenting with a similar phenotype corroborates causality. Both variants were shown to significantly reduce EMC10 RNA expression. All affected individuals show a core phenotype of GDD/ID with variable severity. Seizures were noted in 7/15 individuals, typically during childhood or in the neonatal period, and included multifocal as well as generalized tonic–clonic seizures.; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1123 BCAS3 Zornitza Stark gene: BCAS3 was added
gene: BCAS3 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Review for gene: BCAS3 was set to GREEN
Added comment: 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. Patient fibroblasts confirmed absence of BCAS3 protein.
Sources: Literature
Intellectual disability v3.1123 SRCAP Zornitza Stark reviewed gene: SRCAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33909990; Phenotypes: Neurodevelopmental disorder, non-Floating Harbor; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ehlers Danlos syndromes v2.57 ADAMTSL2 Zornitza Stark gene: ADAMTSL2 was added
gene: ADAMTSL2 was added to Ehlers Danlos syndromes. Sources: Literature
Mode of inheritance for gene: ADAMTSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTSL2 were set to 33369194; 26879370
Phenotypes for gene: ADAMTSL2 were set to Dermatosparaxic Ehlers Danlos syndrome
Review for gene: ADAMTSL2 was set to AMBER
Added comment: Six families reported with same variant. However, in five, no further segregation studies were performed and overall it is unclear whether this is a founder variant or a recurrent variant. No functional data.

Note association between bi-allelic variants and geleophysic dysplasia is well established.
Sources: Literature
Primary immunodeficiency v2.427 HS3ST6 Zornitza Stark gene: HS3ST6 was added
gene: HS3ST6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: HS3ST6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HS3ST6 were set to 33508266
Phenotypes for gene: HS3ST6 were set to Hereditary angioedema-8 (HAE8), MIM#619367
Review for gene: HS3ST6 was set to RED
Added comment: Three affected individuals from a single family reported, missense variant, no functional data.
Sources: Literature
Primary immunodeficiency v2.427 MYOF Zornitza Stark gene: MYOF was added
gene: MYOF was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MYOF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYOF were set to 32542751
Phenotypes for gene: MYOF were set to Hereditary angioedema-7 (HAE7), MIM#619366
Review for gene: MYOF was set to RED
Added comment: Three individuals from one family reported, onset of recurrent episodic swelling of the face, lips, and oral mucosa was in the second decade. Variant was also present in another unaffected family member. Some functional data.
Sources: Literature
Primary immunodeficiency v2.427 PLG Zornitza Stark reviewed gene: PLG: Rating: GREEN; Mode of pathogenicity: None; Publications: 28795768, 29548426, 29987869; Phenotypes: Hereditary angioedema-4 (HAE4), MIM#619360; Mode of inheritance: None
Fetal anomalies v1.674 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907, 32817298, 25713110, 33919081; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364, Congenital heart disease, autosomal recessive; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.190 POU4F1 Zornitza Stark gene: POU4F1 was added
gene: POU4F1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: POU4F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU4F1 were set to 33783914; 8876243
Phenotypes for gene: POU4F1 were set to Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) , MIM#619352
Review for gene: POU4F1 was set to GREEN
gene: POU4F1 was marked as current diagnostic
Added comment: 4 unrelated probands presenting with paediatric onset ataxia, intention tremor, and hypotonia, with de novo loss of function variants, and supporting null mouse model.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.190 POU1F1 Zornitza Stark Deleted their review
Ataxia and cerebellar anomalies - narrow panel v2.190 POU1F1 Zornitza Stark gene: POU1F1 was added
gene: POU1F1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: POU1F1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POU1F1 were set to 33783914; 8876243
Phenotypes for gene: POU1F1 were set to Childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS) , MIM#619352
Review for gene: POU1F1 was set to GREEN
gene: POU1F1 was marked as current diagnostic
Added comment: 4 unrelated probands presenting with paediatric onset ataxia, intention tremor, and hypotonia, with de novo loss of function variants, and supporting null mouse model.
Sources: Literature
Intellectual disability v3.1123 EMC10 Arina Puzriakova Publications for gene: EMC10 were set to 32869858
Intellectual disability v3.1122 EMC10 Arina Puzriakova Added comment: Comment on phenotypes: EMC10 is now associated with a relevant phenotype in OMIM - 'Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264' and is listed in G2P with a 'probable' disease confidence rating for 'EMC10-related neurodevelopmental disorder'
Intellectual disability v3.1122 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264 to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1121 EMC10 Arina Puzriakova Phenotypes for gene: EMC10 were changed from Intellectual disability to Neurodevelopmental disorder with dysmorphic facies and variable seizures, OMIM:619264
Intellectual disability v3.1120 GEMIN5 Zornitza Stark gene: GEMIN5 was added
gene: GEMIN5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GEMIN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GEMIN5 were set to 33963192
Phenotypes for gene: GEMIN5 were set to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333
Review for gene: GEMIN5 was set to GREEN
gene: GEMIN5 was marked as current diagnostic
Added comment: Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) is an autosomal recessive disorder characterized by global developmental delay with prominent motor abnormalities, mainly axial hypotonia, gait ataxia, and appendicular spasticity. Affected individuals have cognitive impairment and speech delay; brain imaging shows cerebellar atrophy.

30 individuals from 22 unrelated families reported.
Sources: Literature
Thoracic aortic aneurysm and dissection v1.7 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to GREEN
gene: IPO8 was marked as current diagnostic
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Literature
Intellectual disability v3.1120 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Intellectual disability. Sources: Literature
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
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Intellectual disability v3.1120 MYCN Zornitza Stark reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21224895, 8470948; Phenotypes: Feingold syndrome 1, Megalencephaly, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm and dissection v1.7 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32938213; Phenotypes: Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital disorders of glycosylation v2.70 SLC37A4 Zornitza Stark edited their review of gene: SLC37A4: Added comment: PMID 33964207: 7 patients from 4 families, additional to the two reported previously, described with the same recurrent c.1267C>T (p.R423*) variant with liver dysfunction multifactorial coagulation deficiency and cardiac issues. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans. Hepatoma cell-line studies support the pathogenicity of the variant.; Changed publications to: 32884905, 33964207
Intellectual disability v3.1120 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Literature
Intellectual disability v3.1120 SMARCA5 Zornitza Stark reviewed gene: SMARCA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33980485; Phenotypes: Neurodevelopmental disorder, microcephaly, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure in early childhood v1.67 ZPR1 Zornitza Stark gene: ZPR1 was added
gene: ZPR1 was added to Growth failure in early childhood. Sources: Literature
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to Growth restriction, hypoplastic kidneys, alpecia, and distinctive facies 619321
Review for gene: ZPR1 was set to RED
Added comment: 3 families reported with growth restriction, hypoplastic kidneys, alopecia, and distinctive facies (GKAF). All were Hispanic families from the middle Rio Grande Valley. Homozygous missense identified in one family, p. Ile196Thr. Others unavailable for testing, founder effect postulated.
Sources: Literature
Skeletal ciliopathies v1.10 INTU Zornitza Stark gene: INTU was added
gene: INTU was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: INTU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTU were set to 27158779; 29451301; 20067783
Phenotypes for gene: INTU were set to Orofaciodigital syndrome XVII MIM#617926; Short-rib thoracic dysplasia 20 with polydactyly MIM#617925
Review for gene: INTU was set to GREEN
Added comment: Three families and a mouse model:

PMID: 27158779 - 1 hom (PTC) and 1 compound het (PTC/missense) patients with OFD or Short-rib thoracic dysplasia

PMID: 20067783 - null mouse model exhibits severe polydactyly, lethal midgestation, exhibiting multiple defects including neural tube closure defects, abnormal dorsal/ventral patterning of the central nervous system

PMID: 29451301 - 1 compound het patient (missense/CNV) with OFD and polydactyly
Sources: Literature
Fetal anomalies v1.674 SPTBN5 Zornitza Stark reviewed gene: SPTBN5: Rating: RED; Mode of pathogenicity: None; Publications: 28007035; Phenotypes: Sacral agenesis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.674 WDR91 Zornitza Stark reviewed gene: WDR91: Rating: AMBER; Mode of pathogenicity: None; Publications: 34028500, 28860274; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1120 CAPN15 Arina Puzriakova Classified gene: CAPN15 as Amber List (moderate evidence)
Intellectual disability v3.1120 CAPN15 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of cases presenting with DD/ID (5/7 individuals from 3 unrelated families - PMIDs: 33410501; 32885237) to warrant a Green rating on this panel.
Intellectual disability v3.1120 CAPN15 Arina Puzriakova Gene: capn15 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1119 CAPN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAPN15.
Intellectual disability v3.1119 CAPN15 Arina Puzriakova Phenotypes for gene: CAPN15 were changed from Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318 to Oculogastrointestinal neurodevelopmental syndrome, OMIM:619318
Structural eye disease v1.71 CAPN15 Arina Puzriakova Added comment: Comment on publications: Mor-Shaked et al. 2021 (PMID:33410501) report a fifth family with 2 sibs who harboured a homozygous 47 base-pair deletion in a minimal intron of CAPN15. Both patients presented with microphthalmia, and one individual also had a right iris coloboma and bilateral optic gliosis
Structural eye disease v1.71 CAPN15 Arina Puzriakova Publications for gene: CAPN15 were set to 32885237
Structural eye disease v1.70 CAPN15 Arina Puzriakova Added comment: Comment on phenotypes: CAPN15 is now associated with a relevant phenotype in OMIM - 'Oculogastrointestinal neurodevelopmental syndrome', MIM# 619318
Structural eye disease v1.70 CAPN15 Arina Puzriakova Phenotypes for gene: CAPN15 were changed from microphthalmia HP:0000568; coloboma HP:0000589 to Oculogastrointestinal neurodevelopmental syndrome, OMIM:619318; Microphthalmia, HP:0000568; Coloboma, HP:0000589
Anophthalmia or microphthalmia v1.40 CAPN15 Arina Puzriakova edited their review of gene: CAPN15: Changed rating: GREEN
Anophthalmia or microphthalmia v1.40 CAPN15 Arina Puzriakova Added comment: Comment on publications: Mor-Shaked et al. 2021 (PMID:33410501) report a fifth family with 2 sibs who harboured a homozygous 47 base-pair deletion in a minimal intron of CAPN15. Both patients presented with microphthalmia, and one individual also had a right iris coloboma and bilateral optic gliosis
Anophthalmia or microphthalmia v1.40 CAPN15 Arina Puzriakova Publications for gene: CAPN15 were set to 32885237
Anophthalmia or microphthalmia v1.39 CAPN15 Arina Puzriakova Added comment: Comment on phenotypes: CAPN15 is now associated with a relevant phenotype in OMIM - 'Oculogastrointestinal neurodevelopmental syndrome', MIM# 619318
Anophthalmia or microphthalmia v1.39 CAPN15 Arina Puzriakova Phenotypes for gene: CAPN15 were changed from microphthalmia HP:0000568; coloboma HP:0000589 to Oculogastrointestinal neurodevelopmental syndrome, OMIM:619318; Microphthalmia, HP:0000568; Coloboma, HP:0000589
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Classified gene: ANKRD17 as Amber List (moderate evidence)
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to rate this gene Green at the next GMS panel update.

Chopra et al. 2021 (PMID: 33909992) report 34 individuals from 32 families with a heterozygous variant or microdeletion of ANKRD17. GDD/ID was the most common feature, affecting 31/33 individuals with variable severity - 7 severe, 12 moderate, 5 mild, 7 borderline. Deletions of the region containing ANKRD17 have also been associated with ID.
Intellectual disability v3.1118 ANKRD17 Arina Puzriakova Gene: ankrd17 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1117 ANKRD17 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ANKRD17.
Stickler syndrome v2.16 BMP4 Dmitrijs Rots reviewed gene: BMP4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30568244; Phenotypes: Microphthalmia, Micrognathia, Retrognathia, Midface hypoplasia, Cleft palate, hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Hearing loss v2.174 GREB1L Eleanor Williams Classified gene: GREB1L as Amber List (moderate evidence)
Hearing loss v2.174 GREB1L Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. 4 cases with non-syndromic hearing loss now reported.
Hearing loss v2.174 GREB1L Eleanor Williams Gene: greb1l has been classified as Amber List (Moderate Evidence).
Hearing loss v2.173 GREB1L Eleanor Williams Tag Q2_21_rating tag was added to gene: GREB1L.
Hearing loss v2.173 GREB1L Eleanor Williams Phenotypes for gene: GREB1L were changed from Deafness, autosomal dominant 80, MIM# 619274 to Deafness, autosomal dominant 80 OMIM:619274; deafness, autosomal dominant 80, MONDO:0030998
Hearing loss v2.172 GREB1L Eleanor Williams Publications for gene: GREB1L were set to 29955957; 32585897
Hearing loss v2.171 GREB1L Eleanor Williams edited their review of gene: GREB1L: Changed rating: GREEN; Changed publications to: 29955957, 32585897, 29100090; Changed phenotypes to: Deafness, autosomal dominant 80 OMIM:619274, deafness, autosomal dominant 80, MONDO:0030998; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.171 GREB1L Eleanor Williams commented on gene: GREB1L
Hearing loss v2.171 CRYM Eleanor Williams Classified gene: CRYM as Red List (low evidence)
Hearing loss v2.171 CRYM Eleanor Williams Added comment: Comment on list classification: Leaving rating as red but with green recommendation following GMS review. 3 cases now reported, 1 in a family of significant size. Expression data to show that this protein is express in the ear.
Hearing loss v2.171 CRYM Eleanor Williams Gene: crym has been classified as Red List (Low Evidence).
Hearing loss v2.170 CRYM Eleanor Williams Tag Q2_21_rating tag was added to gene: CRYM.
Hearing loss v2.170 CRYM Eleanor Williams Phenotypes for gene: CRYM were changed from hearing loss; Deafness, autosomal dominant 40 to Deafness, autosomal dominant 40, OMIM:616357; autosomal dominant nonsyndromic deafness 40, MONDO:0014603
Hearing loss v2.169 CRYM Eleanor Williams Publications for gene: CRYM were set to 12471561; 1384048; 1478656; 16740909; 9328354
Hearing loss v2.168 CRYM Eleanor Williams edited their review of gene: CRYM: Added comment: Associated with Deafness, autosomal dominant 40 #616357 (AD) in OMIM.

PMID: 32742378 - Wang et al 2020 - report a 4 generation Chinese family with 31 members, of which 7 have hearing loss. WES identified a heterozygous missense mutation in CRYM (c.152C>T; Pro51Leu) which segregated with the phenotype in the family. As Zornitza Stark reports gnomad (3.1.1) has 2 hets reported (allele freq of 1.32e-5).

PMID: 12471561 - Abe et al 2003 - used genome-wide cDNA microarray analysis to investigate gene-expression profiles in human cochlea and vestibule and identified CRYM as a candidate gene. They then screened CRYM, among 192 patients with nonsyndromic deafness. Two unrelated Japanese patients were identified with variants in CRYM; one with a de novo change (c.945A→T, p.X315Y) which results in an extended protein in a patient with unaffected parents, and the other was a missense mutation (c.941A→C;p.K314T) that segregated dominantly in the proband’s family.

PMID: 16740909 - Oshima et al 2006 - looked at the effect of the two variants found by Abe et al, X315Y and K314T by looking at T3 binding activity of the mutant μ‐crystallin (product of CRYM) proteins. They found the K314T mutation impaired the NADPH dependent T3 binding (but did not find this for the X315Y variant). They also showed that μ‐crystallin protein localisation in mouse cochlea using immunocytochemical methods.

PMID: 18448257 - Usami et al 2009 - showed that Crym protein localizes in type II fibrocytes of the spiral ligament in the cochlea in mice and rats

PMID: 24676347 - Yoshimura et al 2014 - show a gradient of gene expression of CRYM in mouse cochlea

PMID: 26915689 - Hosoya et al 2016 - immunohistochemical analysis of expression of CRYM in cochlea of a non-human primate, the common marmoset and found a different expression pattern compared to mouse, with expression not only in the lateral wall spiral ligament and the spiral limbus, but also in both inner and outer hair cells, supporting cells.; Changed publications to: 32742378, 12471561, 16740909, 18448257, 24676347, 26915689; Changed phenotypes to: Deafness, autosomal dominant 40, OMIM:616357, autosomal dominant nonsyndromic deafness 40, MONDO:0014603; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.168 CLRN2 Eleanor Williams Classified gene: CLRN2 as Amber List (moderate evidence)
Hearing loss v2.168 CLRN2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber as there is one extended family reported with variants in this gene, plus some supporting functional data.
Hearing loss v2.168 CLRN2 Eleanor Williams Gene: clrn2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.167 CLRN2 Eleanor Williams Phenotypes for gene: CLRN2 were changed from Non-syndromic hearing loss to ?Deafness, autosomal recessive 117, OMIM:619174; deafness, autosomal recessive 117, MONDO:0030905
Hearing loss v2.166 CLRN2 Eleanor Williams reviewed gene: CLRN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33496845; Phenotypes: Deafness, autosomal recessive 117, OMIM:619174, deafness, autosomal recessive 117, MONDO:0030905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova Tag Q2_21_NHS_review was removed from gene: SMARCA5.
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova changed review comment from: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Regarding cognition, four probands had mild ID and one had severe ID. Although relatively mild in most patients, the number of unrelated families presenting ID is sufficient for a Green rating and inclusion on this panel should increase the likelihood of detecting cases.; to: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Postnatal microcephaly [HC ranging between -2.33 and -6.21 SD] was evident in 10/12 individuals, and three had a birth HC less than −2.5 SD. Overall sufficient number of unrelated families presenting microcephaly of relevant severity to warrant a Green rating on this panel.
Skeletal Muscle Channelopathies v1.31 CACNA1A Eleanor Williams Classified gene: CACNA1A as Green List (high evidence)
Skeletal Muscle Channelopathies v1.31 CACNA1A Eleanor Williams Added comment: Comment on list classification: Changing back from red to green, to await advice from Genomics England clinical team as to the appropriateness of this gene for the panel given potential phenotypic overlap with other skeletal muscle channelopathies
Skeletal Muscle Channelopathies v1.31 CACNA1A Eleanor Williams Gene: cacna1a has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.30 ATP1A2 Eleanor Williams Classified gene: ATP1A2 as Green List (high evidence)
Skeletal Muscle Channelopathies v1.30 ATP1A2 Eleanor Williams Added comment: Comment on list classification: Changing back from red to green, to await advice from Genomics England clinical team as to the appropriateness of this gene for the panel given potential phenotypic overlap with other skeletal muscle channelopathies
Skeletal Muscle Channelopathies v1.30 ATP1A2 Eleanor Williams Gene: atp1a2 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.30 PYGM Eleanor Williams Tag Q2_21_phenotype tag was added to gene: PYGM.
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova Entity copied from Intellectual disability v3.1117
Severe microcephaly v2.207 SMARCA5 Arina Puzriakova gene: SMARCA5 was added
gene: SMARCA5 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_21_rating, Q2_21_NHS_review tags were added to gene: SMARCA5.
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Skeletal muscle channelopathy v1.30 SLC2A1 Eleanor Williams Classified gene: SLC2A1 as Green List (high evidence)
Skeletal muscle channelopathy v1.30 SLC2A1 Eleanor Williams Added comment: Comment on list classification: Leaving this gene green but with a recommendation for a red rating following GMS review as to whether it is useful to have this gene on panel although variants seem to result in a brain channelopathy rather than a skeletal muscle one
Skeletal muscle channelopathy v1.30 SLC2A1 Eleanor Williams Gene: slc2a1 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.29 SLC2A1 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC2A1.
Tag Q2_21_phenotype tag was added to gene: SLC2A1.
Skeletal muscle channelopathy v1.29 SLC2A1 Eleanor Williams reviewed gene: SLC2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SMARCA5.
Tag Q2_21_NHS_review tag was added to gene: SMARCA5.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Classified gene: SMARCA5 as Amber List (moderate evidence)
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Added comment: Comment on list classification: New gene added and reviewed Green by Julia Baptista (RD&E NHS FT). SMARCA5 should be promoted to Green at the next GMS panel update.

Variants have been associated with a variable neurodevelopmental phenotype including predominantly mild DD, short stature, and microcephaly (PMID:33980485). Regarding cognition, four probands had mild ID and one had severe ID. Although relatively mild in most patients, the number of unrelated families presenting ID is sufficient for a Green rating and inclusion on this panel should increase the likelihood of detecting cases.
Intellectual disability v3.1117 SMARCA5 Arina Puzriakova Gene: smarca5 has been classified as Amber List (Moderate Evidence).
Skeletal muscle channelopathy v1.29 SLC1A3 Eleanor Williams Classified gene: SLC1A3 as Green List (high evidence)
Skeletal muscle channelopathy v1.29 SLC1A3 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as Green but with a recommendation for red rating following GMS review as to whether it is useful to have this gene on panel although variants seem to result in a brain channelopathy rather than a skeletal muscle one.
Skeletal muscle channelopathy v1.29 SLC1A3 Eleanor Williams Gene: slc1a3 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.28 SLC1A3 Eleanor Williams Phenotypes for gene: SLC1A3 were changed from Episodic ataxia, type 6, 612656 to Episodic ataxia, type 6, OMIM:612656; episodic ataxia type 6, MONDO:0012982
Skeletal muscle channelopathy v1.27 SLC1A3 Eleanor Williams Publications for gene: SLC1A3 were set to 19139306
Skeletal muscle channelopathy v1.26 SLC1A3 Eleanor Williams Tag Q2_21_phenotype tag was added to gene: SLC1A3.
Skeletal muscle channelopathy v1.26 SLC1A3 Eleanor Williams Tag Q2_21_rating tag was added to gene: SLC1A3.
Skeletal muscle channelopathy v1.26 SLC1A3 Eleanor Williams reviewed gene: SLC1A3: Rating: RED; Mode of pathogenicity: None; Publications: 16116111, 19139306, 25497598; Phenotypes: Episodic ataxia, type 6, OMIM:612656, episodic ataxia type 6, MONDO:0012982; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v1.172 SPART Ivone Leong Phenotypes for gene: SPART were changed from Troyer syndrome, MIM#275900 to Troyer syndrome, OMIM:275900
White matter disorders and cerebral calcification - narrow panel v1.171 SPART Ivone Leong Publications for gene: SPART were set to 27112432; 18413476; 26003402; 12134148; 28875386; 15372254
Primary immunodeficiency v2.427 CSF2 Arina Puzriakova Classified gene: CSF2 as Red List (low evidence)
Primary immunodeficiency v2.427 CSF2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Relevant phenotype but currently only a single family reported (PMID:33349924). Rating Red, awaiting further cases/clinical evidence to support pathogenicity.
Primary immunodeficiency v2.427 CSF2 Arina Puzriakova Gene: csf2 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.170 SPART Ivone Leong Publications for gene: SPART were set to 27112432, 18413476, 26003402, 12134148
Primary immunodeficiency v2.426 LRRC32 Arina Puzriakova Classified gene: LRRC32 as Red List (low evidence)
Primary immunodeficiency v2.426 LRRC32 Arina Puzriakova Added comment: Comment on list classification: Novel candidate gene added by Boaz Palterer. Rating Red as currently there is not enough evidence to support this gene-disease association.

Lehmkuhl et al. 2021 (PMID: 34059789) - 2 unrelated patients with immunodeficiency were found to harbour two rare heterozygous missense variants each in the LRRC32 gene (p.Arg312Cys (recurring), p.Trp247Ter, p.Arg421Gln) - variants were in cis in one patient, but in trans in the other.

Note that a different homozygous founder variant was also found in 2 families with GDD, cleft palate, and proliferative retinopathy (PMID: 30976112) - none of these features were evident in the two cases discussed here.
Primary immunodeficiency v2.426 LRRC32 Arina Puzriakova Gene: lrrc32 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Tag Q2_21_rating tag was added to gene: SPG11.
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Classified gene: SPG11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. 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 Green in the next review.
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Gene: spg11 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.168 SPG11 Ivone Leong Added comment: Comment on publications: PMID: 33581793. A total of 339 patients were analysed, their mean age at onset was 13.10 +/- 3.65 years.
White matter disorders and cerebral calcification - narrow panel v1.168 SPG11 Ivone Leong Publications for gene: SPG11 were set to 14745065; 18067136
Intellectual disability v3.1116 LRRC32 Arina Puzriakova Phenotypes for gene: LRRC32 were changed from Intellectual disability; cleft palate; proliferative retinopathy to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
White matter disorders and cerebral calcification - narrow panel v1.167 SPG11 Ivone Leong Phenotypes for gene: SPG11 were changed from Spastic paralplegia 11, autosomal recessive, MIM#604360 to Spastic paralplegia 11, autosomal recessive, OMIM:604360
White matter disorders and cerebral calcification - narrow panel v1.166 SPG11 Ivone Leong Publications for gene: SPG11 were set to 14745065
Inborn errors of metabolism v2.141 NAXD Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.165
Inborn errors of metabolism v2.141 NAXD Ivone Leong gene: NAXD was added
gene: NAXD was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 33224489; 31755961
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321
Hearing loss v2.166 STXBP3 Arina Puzriakova Entity copied from Primary immunodeficiency v2.425
Hearing loss v2.166 STXBP3 Arina Puzriakova gene: STXBP3 was added
gene: STXBP3 was added to Hearing loss. Sources: Expert Review Amber,Expert Review
Mode of inheritance for gene: STXBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STXBP3 were set to 33346580; https://doi.org/10.1053/j.gastro.2017.11.120; 33891011
Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Sensorineural hearing loss
Penetrance for gene: STXBP3 were set to unknown
Primary immunodeficiency v2.425 STXBP3 Arina Puzriakova Classified gene: STXBP3 as Amber List (moderate evidence)
Primary immunodeficiency v2.425 STXBP3 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of cases presenting a relevant phenotype with some functional data. However, given that several families carried potentially contributory variants in other genes, going to maintain an Amber rating at this time in anticipation of further cases/clinical evidence to validate the pathogenicity of this gene.
Primary immunodeficiency v2.425 STXBP3 Arina Puzriakova Gene: stxbp3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.424 STXBP3 Arina Puzriakova changed review comment from: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families.

* Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4/5 of the families from PMID:33891011; to: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families.

* Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4 of the families from PMID:33891011
Primary immunodeficiency v2.424 STXBP3 Arina Puzriakova reviewed gene: STXBP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 33891011; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.165 NAXD Ivone Leong commented on gene: NAXD: Affected individuals show normal early development followed by acute psychomotor regression with ataxia, hypotonia, and sometimes seizures triggered by acute fever. The affected infants usually die in the first few years of life. Brain imaging shows multiple abnormalities, including brain edema and white matter abnormalities. The infants also present with skin lesions/rash.
Mitochondrial disorders v2.42 NAXD Ivone Leong Tag Q2_21_rating tag was added to gene: NAXD.
Mitochondrial disorders v2.42 NAXD Ivone Leong Classified gene: NAXD as Amber List (moderate evidence)
Mitochondrial disorders v2.42 NAXD Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There are 2 additional cases reported. This gene should be promoted to Green at the next review.
Mitochondrial disorders v2.42 NAXD Ivone Leong Gene: naxd has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.41 NAXD Ivone Leong Publications for gene: NAXD were set to 29903433; 30576410
White matter disorders and cerebral calcification - narrow panel v1.165 NAXD Ivone Leong Tag Q2_21_rating tag was added to gene: NAXD.
White matter disorders and cerebral calcification - narrow panel v1.165 NAXD Ivone Leong Classified gene: NAXD as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.165 NAXD 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. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.165 NAXD Ivone Leong Gene: naxd has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.164 NAXD Ivone Leong Added comment: Comment on publications: PMID: 31755961 and 33224489 are 2 additional cases. PMID: 31755961 did not mention anything about the patient's brain.
White matter disorders and cerebral calcification - narrow panel v1.164 NAXD Ivone Leong Publications for gene: NAXD were set to 30576410
Primary immunodeficiency v2.424 STXBP3 Arina Puzriakova Publications for gene: STXBP3 were set to 33346580; https://doi.org/10.1053/j.gastro.2017.11.120
Skeletal muscle channelopathy v1.26 PYGM Eleanor Williams changed review comment from: Comment on list classification: Leaving the rating as green, but with a recommendation for a red rating following GMS review because this gene encodes an enzyme not a channel.; to: Comment on list classification: Leaving the rating as green, but with a recommendation for a red rating following GMS review because this gene encodes an enzyme not a channel. However, the phenotype may overlap with channelopathies.
Skeletal muscle channelopathy v1.26 PYGM Eleanor Williams Classified gene: PYGM as Green List (high evidence)
Skeletal muscle channelopathy v1.26 PYGM Eleanor Williams Added comment: Comment on list classification: Leaving the rating as green, but with a recommendation for a red rating following GMS review because this gene encodes an enzyme not a channel.
Skeletal muscle channelopathy v1.26 PYGM Eleanor Williams Gene: pygm has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.29 CACNA1A Eleanor Williams Classified gene: CACNA1A as Red List (low evidence)
Skeletal Muscle Channelopathies v1.29 CACNA1A Eleanor Williams Added comment: Comment on list classification: Demoting this gene from green to red as variants in this gene are associated with a brain channelopathy rather than a skeletal muscle channelopathy/
Skeletal Muscle Channelopathies v1.29 CACNA1A Eleanor Williams Gene: cacna1a has been classified as Red List (Low Evidence).
Skeletal muscle channelopathy v1.25 PYGM Eleanor Williams Tag Q2_21_rating tag was added to gene: PYGM.
Skeletal muscle channelopathy v1.25 ATP1A2 Eleanor Williams Tag Q2_21_phenotype tag was added to gene: ATP1A2.
Skeletal muscle channelopathy v1.25 CACNA1A Eleanor Williams Classified gene: CACNA1A as Green List (high evidence)
Skeletal muscle channelopathy v1.25 CACNA1A Eleanor Williams Added comment: Comment on list classification: Leaving rating as green but with a recommendation for red rating following GMS review. As reported by Zornitza Stark variants in this gene appear to be associated with brain channelopathies rather than skeletal muscle.
Skeletal muscle channelopathy v1.25 CACNA1A Eleanor Williams Gene: cacna1a has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.24 CACNA1A Eleanor Williams Tag Q2_21_rating tag was added to gene: CACNA1A.
Tag Q2_21_phenotype tag was added to gene: CACNA1A.
Skeletal muscle channelopathy v1.24 CACNA1A Eleanor Williams reviewed gene: CACNA1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v1.163 NAXD Ivone Leong Phenotypes for gene: NAXD were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321
Skeletal Muscle Channelopathies v1.28 ATP1A2 Eleanor Williams Classified gene: ATP1A2 as Red List (low evidence)
Skeletal Muscle Channelopathies v1.28 ATP1A2 Eleanor Williams Added comment: Comment on list classification: Demoting this gene from green to red as only one case reported with a skeletal muscle channelopathy.
Skeletal Muscle Channelopathies v1.28 ATP1A2 Eleanor Williams Gene: atp1a2 has been classified as Red List (Low Evidence).
Skeletal Muscle Channelopathies v1.27 ATP1A2 Eleanor Williams commented on gene: ATP1A2
Skeletal muscle channelopathy v1.24 ATP1A2 Eleanor Williams Classified gene: ATP1A2 as Green List (high evidence)
Skeletal muscle channelopathy v1.24 ATP1A2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as Green but with a recommendation of a red rating following GMS review, as there is only one case reported associated with a skeletal muscle phenotype.
Skeletal muscle channelopathy v1.24 ATP1A2 Eleanor Williams Gene: atp1a2 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v1.23 ATP1A2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ATP1A2.
Skeletal muscle channelopathy v1.23 ATP1A2 Eleanor Williams Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2, 602481; Alternating hemiplegia of childhood 1, 104290; Hypokalaemic periodic paralysis to hypokalaemic periodic paralysis MONDO:0008223
Skeletal muscle channelopathy v1.22 ATP1A2 Eleanor Williams Publications for gene: ATP1A2 were set to 30423015; 15286158; 18056581
Skeletal muscle channelopathy v1.21 ATP1A2 Eleanor Williams reviewed gene: ATP1A2: Rating: RED; Mode of pathogenicity: None; Publications: 30423015; Phenotypes: hypokalaemic periodic paralysis MONDO:0008223; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Following confirmation from the Genomics England clinical team that progressive microcephaly (to the severe range) is within scope of this panel, recommending a green rating for this gene at the next review.
Severe microcephaly v2.206 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.205 MPLKIP Ivone Leong Phenotypes for gene: MPLKIP were changed from Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149 to microcephaly (disease), MONDO:0001149
Severe microcephaly v2.204 MPLKIP Ivone Leong Classified gene: MPLKIP as Amber List (moderate evidence)
Severe microcephaly v2.204 MPLKIP Ivone Leong Gene: mplkip has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.203 MPLKIP Ivone Leong gene: MPLKIP was added
gene: MPLKIP was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MPLKIP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPLKIP were set to 25655951; 25290684; 26518168; 25606444; 26880286; 29421601; 30580289; 30598092; 16977596; 33043633; 33729667
Phenotypes for gene: MPLKIP were set to Trichothiodystrophy 4, nonphotosensitive, OMIM:234050; microcephaly (disease), MONDO:0001149
Review for gene: MPLKIP was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Microcephaly has been reported for 6/20 cases (2 cases <-3SD), growth retardation 15/20 and 7/20 had gonadal dysfunction. There is not enough evidence to support a gene-disease association, this gene has been given an Amber rating.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.162 MPLKIP Ivone Leong Phenotypes for gene: MPLKIP were changed from Non-photosensitive trichothiodystrophy 4; Trichothiodystrophy, nonphotosensitive to Trichothiodystrophy 4, nonphotosensitive, OMIM:234050
White matter disorders and cerebral calcification - narrow panel v1.161 MPLKIP Ivone Leong commented on gene: MPLKIP: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is no reported cases of this gene associated with white matter changes, therefore, it is recommended that this gene be demoted to Red.
White matter disorders and cerebral calcification - narrow panel v1.161 MPLKIP Ivone Leong Deleted their comment
White matter disorders and cerebral calcification - narrow panel v1.161 MPLKIP Ivone Leong reviewed gene: MPLKIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v1.161 MPLKIP Ivone Leong Tag Q2_21_rating tag was added to gene: MPLKIP.
Tag Q2_21_expert_review tag was added to gene: MPLKIP.
White matter disorders and cerebral calcification - narrow panel v1.161 MPLKIP Ivone Leong Publications for gene: MPLKIP were set to 25655951; 25290684; 26518168; 25606444; 26880286; 2942160; 30580289; 30598092; 16977596; 33043633; 33729667
White matter disorders and cerebral calcification - narrow panel v1.160 MPLKIP Ivone Leong Publications for gene: MPLKIP were set to 25655951
Primary immunodeficiency v2.423 PLG Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: PLG.
Paediatric motor neuronopathies v1.62 AR_CAG Dmitrijs Rots STR: AR_CAG was added
STR: AR_CAG was added to Paediatric motor neuronopathies. Sources: Literature
Mode of inheritance for STR: AR_CAG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for STR: AR_CAG were set to spinal and bulbar muscular atrophy; gynecomastia; muscular weakness
Penetrance for STR: AR_CAG were set to Complete
Review for STR: AR_CAG was set to GREEN
STR: AR_CAG was marked as current diagnostic
Added comment: Sources: Literature
Paediatric motor neuronopathies v1.62 AR Dmitrijs Rots reviewed gene: AR: Rating: RED; Mode of pathogenicity: Other; Publications: ; Phenotypes: SBMA; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Primary immunodeficiency v2.423 CSF2 Boaz Palterer gene: CSF2 was added
gene: CSF2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CSF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSF2 were set to 33349924
Phenotypes for gene: CSF2 were set to Behcet-like disease; Pathergy
Penetrance for gene: CSF2 were set to unknown
Mode of pathogenicity for gene: CSF2 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: CSF2 was set to RED
Added comment: Rösler et al. described a kindred with two patients affected by a Behcet-like disease characterized by marked pathergy and absent inflammation. They identified a heterozygous variant in the GM-CSF gene CSF2 (c.130A>C, p.N44H) resulting in disruption of an N-glycosylation site. They show that de-glycosylated GM-CSF enhances STAT-5 phosphorylation, and therefore the variant acts as a gain-of-function.
Sources: Literature
Primary immunodeficiency v2.423 LRRC32 Boaz Palterer gene: LRRC32 was added
gene: LRRC32 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to Unknown
Publications for gene: LRRC32 were set to 34059789
Phenotypes for gene: LRRC32 were set to Common variable immunodeficiency; Enteropathy; Lymphopenia; Reduced Tregs
Penetrance for gene: LRRC32 were set to unknown
Review for gene: LRRC32 was set to RED
Added comment: Lehmkuhl et al. described two patients with immune dysregulation and mutations of LRRC32. Both patients carried two rare variants, however, patient 1 has both variants in cis, while patient 2 was a compound heterozygote. Reduced protein expression ex-vivo was demonstrated. Conditional mice KO model recapitulated the phenotype.
Sources: Literature
Inherited white matter disorders v1.118 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to MIM#270800
Inherited white matter disorders v1.117 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
White matter disorders - adult onset v1.15 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to 24117163; 19439420; 19187859
White matter disorders - adult onset v1.14 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
White matter disorders - adult onset v1.14 CYP7B1 Arina Puzriakova Added comment: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether the phenotype is appropriate and there is enough potential clinical value to rate as Green on this panel.
White matter disorders - adult onset v1.14 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
White matter disorders - adult onset v1.13 CYP7B1 Arina Puzriakova reviewed gene: CYP7B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19187859, 19439420, 24117163; Phenotypes: Spastic paraplegia 5A, autosomal recessive , OMIM:270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.159 CYP7B1 Arina Puzriakova changed review comment from: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.; to: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether the phenotype is appropriate and there is enough potential clinical value to rate as Green on this panel.
White matter disorders - adult onset v1.13 CYP7B1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: CYP7B1.
White matter disorders and cerebral calcification - narrow panel v1.159 CYP7B1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: CYP7B1.
White matter disorders and cerebral calcification - narrow panel v1.159 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to MIM#270800
White matter disorders and cerebral calcification - narrow panel v1.158 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
White matter disorders and cerebral calcification - narrow panel v1.158 CYP7B1 Arina Puzriakova Added comment: Comment on list classification: CYP7B1 will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.
White matter disorders and cerebral calcification - narrow panel v1.158 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.157 CYP7B1 Arina Puzriakova reviewed gene: CYP7B1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19187859, 19439420, 24117163; Phenotypes: Spastic paraplegia 5A, autosomal recessive , OMIM:270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.157 KIF5A Ivone Leong Tag Q2_21_rating tag was added to gene: KIF5A.
White matter disorders and cerebral calcification - narrow panel v1.157 KIF5A Ivone Leong Classified gene: KIF5A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.157 KIF5A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.157 KIF5A Ivone Leong Gene: kif5a has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia v1.226 CYP7B1 Arina Puzriakova Publications for gene: CYP7B1 were set to Tsaousidou et al. (2008) i
Hereditary spastic paraplegia - childhood onset v2.40 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive, 270800 to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
Hereditary spastic paraplegia v1.225 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
White matter disorders - adult onset v1.13 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive, MIM# 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
White matter disorders and cerebral calcification - narrow panel v1.156 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
Intellectual disability v3.1115 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive 270800 to Spastic paraplegia 5A, autosomal recessive , OMIM:270800
White matter disorders and cerebral calcification - narrow panel v1.155 KIF5A Ivone Leong Phenotypes for gene: KIF5A were changed from Myoclonus, intractable, neonatal, MIM# 617235 to Myoclonus, intractable, neonatal, OMIM:617235
Optic neuropathy v2.43 ISCA2 Ivone Leong Classified gene: ISCA2 as Amber List (moderate evidence)
Optic neuropathy v2.43 ISCA2 Ivone Leong Gene: isca2 has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.42 ISCA2 Ivone Leong gene: ISCA2 was added
gene: ISCA2 was added to Optic neuropathy. Sources: Literature
Q2_21_rating tags were added to gene: ISCA2.
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29297947; 29122497; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4, OMIM:616370; optic atrophy, MONDO:0003608
Review for gene: ISCA2 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There are >3 unrelated cases. Patients usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Intellectual disability v3.1114 CYP7B1 Arina Puzriakova Mode of inheritance for gene: CYP7B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Classified gene: CYP7B1 as Red List (low evidence)
Intellectual disability v3.1113 CYP7B1 Arina Puzriakova Gene: cyp7b1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.154 ISCA2 Ivone Leong Classified gene: ISCA2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.154 ISCA2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene is also Green on the Inherited white matter disorders (Version 1.113) panel. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.154 ISCA2 Ivone Leong Gene: isca2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.153 ISCA2 Ivone Leong Tag founder-effect tag was added to gene: ISCA2.
Tag Q2_21_rating tag was added to gene: ISCA2.
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Classified gene: CNTNAP1 as Green List (high evidence)
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green - sufficient cases of white matter disease from unrelated families to warrant a Green rating.

At least 10 unrelated families reported in literature (PMIDs: 28374019; 29511323; 29882456) . Brain imaging in all affected patients shows marked brain hypomyelination/demyelination, as well as variably reduced white matter volume and cerebral atrophy.
Inherited white matter disorders v1.116 CNTNAP1 Arina Puzriakova Gene: cntnap1 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.153 CNTNAP1 Arina Puzriakova changed review comment from: Comment on list classification: There are sufficient cases of white matter defects from unrelated families to warrant a Green rating at the next GMS panel update.; to: Comment on list classification: There are sufficient cases of white matter disease from unrelated families to warrant a Green rating at the next GMS panel update.
Inherited white matter disorders v1.115 CNTNAP1 Arina Puzriakova Publications for gene: CNTNAP1 were set to 29882456
Inherited white matter disorders v1.114 CNTNAP1 Arina Puzriakova Phenotypes for gene: CNTNAP1 were changed from to Hypomyelinating neuropathy, congenital, 3, OMIM:618186
White matter disorders and cerebral calcification - narrow panel v1.153 CNTNAP1 Arina Puzriakova Phenotypes for gene: CNTNAP1 were changed from to Hypomyelinating neuropathy, congenital, 3, OMIM:618186
White matter disorders and cerebral calcification - narrow panel v1.152 CNTNAP1 Arina Puzriakova Publications for gene: CNTNAP1 were set to 29882456
White matter disorders and cerebral calcification - narrow panel v1.151 CNTNAP1 Arina Puzriakova Classified gene: CNTNAP1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.151 CNTNAP1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of white matter defects from unrelated families to warrant a Green rating at the next GMS panel update.
White matter disorders and cerebral calcification - narrow panel v1.151 CNTNAP1 Arina Puzriakova Gene: cntnap1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.150 CNTNAP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: CNTNAP1.
White matter disorders and cerebral calcification - narrow panel v1.150 CNTNAP1 Arina Puzriakova reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29511323, 29882456; Phenotypes: Hypomyelinating neuropathy, congenital, 3, OMIM:618186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.150 ISCA2 Ivone Leong Phenotypes for gene: ISCA2 were changed from to Multiple mitochondrial dysfunctions syndrome 4, OMIM:616370
White matter disorders and cerebral calcification - narrow panel v1.149 CLPP Ivone Leong changed review comment from: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families (1 - 3), with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.; to: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families, with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
White matter disorders and cerebral calcification - narrow panel v1.149 CLPP Ivone Leong Added comment: Comment on publications: PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families (1 - 3), with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
White matter disorders and cerebral calcification - narrow panel v1.149 CLPP Ivone Leong Publications for gene: CLPP were set to 27899912
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova commented on gene: APOPT1: Added new-gene-name tag, new approved HGNC gene symbol for APOPT1 is COA8
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova Tag new-gene-name tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Classified gene: APOPT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of white matter disease from unrelated families to warrant a Green rating at the next GMS panel update.
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Gene: apopt1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.146 APOPT1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - narrow panel v1.146 APOPT1 Arina Puzriakova reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.165 APOPT1 Arina Puzriakova Publications for gene: APOPT1 were set to
Cardiomyopathies - including childhood onset v1.43 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Mitochondrial disorders v2.40 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Hearing loss v2.164 APOPT1 Arina Puzriakova Mode of inheritance for gene: APOPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1112 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Hearing loss v2.163 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial Complex IV Deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Inborn errors of metabolism v2.140 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Possible mitochondrial disorder - nuclear genes v1.46 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Undiagnosed metabolic disorders v1.460 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Mitochondrial disorder with complex IV deficiency v1.12 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Inherited white matter disorders v1.113 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 23472759; 17525174; 25925986
White matter disorders and cerebral calcification - narrow panel v1.146 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 25925986; 17525174; 23472759
White matter disorders and cerebral calcification - narrow panel v1.145 LAMB1 Arina Puzriakova reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23472759, 25925986, 29888467; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.25 PIGB Dmitrijs Rots gene: PIGB was added
gene: PIGB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to intellectual disability; developmental delay; epilepsy; axonal neuropathy
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
gene: PIGB was marked as current diagnostic
Added comment: Murakami et al., reported 10 cases with biallelic PIGB variants with complex and severe phenotype, of whom 4 had peripheral neuropathy.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.145 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191; Cystic leukoencephalopathy
Intellectual disability v3.1111 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from COBBLESTONE BRAIN MALFORMATION WITHOUT MUSCULAR OR OCULAR ABNORMALITIES to Lissencephaly 5, OMIM:615191
Inherited white matter disorders v1.112 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191
White matter disorders - adult onset v1.12 LAMB1 Arina Puzriakova Classified gene: LAMB1 as Red List (low evidence)
White matter disorders - adult onset v1.12 LAMB1 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only a single adult-onset case of leukoencephalopathy reported (PMID: 32548278). Additional cases required prior to inclusion on this panel. All other publications to date report congenital or infantile- to childhood-onset leukoencephalopathy.
White matter disorders - adult onset v1.12 LAMB1 Arina Puzriakova Gene: lamb1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.144 CLPP Ivone Leong Phenotypes for gene: CLPP were changed from Perrault syndrome 3, MIM# 614129 to Perrault syndrome 3, OMIM:614129
Hydrocephalus v2.105 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Fetal anomalies v1.674 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Rare anaemia v1.23 SLC19A1 Arina Puzriakova Phenotypes for gene: SLC19A1 were changed from Megaloblastic anemia, folate-responsive, MIM# 601775 to Megaloblastic anemia, folate-responsive, OMIM:601775
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Classified gene: SLC19A1 as Red List (low evidence)
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as only a single case reported at this time. Additional cases required to validate pathogenicity of variants in this gene.
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Gene: slc19a1 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.423 SPI1 Arina Puzriakova Classified gene: SPI1 as Amber List (moderate evidence)
Primary immunodeficiency v2.423 SPI1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (6) presenting a relevant phenotype, supported by some functional data (PMID: 33951726). However, only able to access the publication abstract at this time - Rating Amber with a watchlist tag until the full text becomes available (on 2022-01-0