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Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the known JAK2 (V617F) somatic variant. The role of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, of which one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 when investigating patients with myeloproliferative neoplasms the patient did not have the JAK2 (V617F) variant. Influence of CALR had not been discovered at this time
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, 26 members from five families sequenced with at least two members affected by MPN. A proband who had primary myelofibrosis phenotype had the E208Q SH2B3 variant and a CALR variant (p.L367fs*46) were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and the JAK2 (V617F) variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the E208Q SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 27716218 also identified variant E208Q in SH2B3 and concluded it as a germline variant. Two unrelated families each had two family members with MPNs and the E208Q in SH2B3 variant. Only 2/4 with MPNs had thrombocythaemia all had the JAK2 (V617F) variant, the authors concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Amber as although germline variants have been discovered the Thromobcythaemia phenotype has only been observed when accompanied with additional known somatic variants in JAK2/CALR
Intellectual disability v3.355 INTS6 Arina Puzriakova Classified gene: INTS6 as Red List (low evidence)
Intellectual disability v3.355 INTS6 Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.355 INTS6 Arina Puzriakova Gene: ints6 has been classified as Red List (Low Evidence).
Intellectual disability v3.354 CPD Arina Puzriakova Classified gene: CPD as Red List (low evidence)
Intellectual disability v3.354 CPD Arina Puzriakova Added comment: Comment on list classification: The Red review by Konstantinos Varvagiannis supports the current Red rating of CPD. There is currently no evidence to support this gene-disease association, and therefore have kept rating as Red.
Intellectual disability v3.354 CPD Arina Puzriakova Gene: cpd has been classified as Red List (Low Evidence).
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype with these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow changed review comment from: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; to: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities is Essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.
Thrombocythaemia v0.8 SH2B3 Catherine Snow Deleted their comment
Thrombocythaemia v0.8 SH2B3 Catherine Snow edited their review of gene: SH2B3: Added comment: Limited evidence of SH2B3 (alson known as LNK) variants associated with Thrombocythaemia. Most reporting on Thrombocythaemia are in adjacent to work on Myeloproliferative neoplasms (MPNs) - these are a heterogenous group of malignant haematological disorder, one of the seven diagnostic entities of it is essential Thrombocythaemia.
• PMID: 27237057 Aimed to discover new variants associated with familial forms of MPN's, sequenced 26 members from five families with at least two members affected by MPN. The proband had primary myelofibrosis phenotype a SH2B3 variant and a CALR variant were identified. The probands daughter had a thrombocythaemia phenotype with the same SH2B3 variant and a JAK2V617F variant. Three additional family members had the SH2B3 variant but no reported associated phenotypes. Although the SH2B3 variant is germline there is not sufficient evidence that this variant causes a thrombocythaemia phenotype.
• PMID 20404132 identifies a patient with thrombocythaemia with a somatic variant (E208Q) in SH2B3 again when investigating patients with myeloproliferative neoplasms.
• PMID 27716218 identified a germline variant in SH2B3 in two families affected members had MPNs but not all had thrombocythaemia and concluded that it appears unlikely that SH2B3 alterations may act as driver mutations in MPNs.
Therefore rating SH2B3 as Red as although germline variants have been discovered there is no conclusive association of a thrombocythaemia phenotype and these variants.; Changed publications: 20404132, 27716218, 27237057
Thrombocythaemia v0.8 SH2B3 Catherine Snow reviewed gene: SH2B3: Rating: RED; Mode of pathogenicity: None; Publications: 20404132, 27716218; Phenotypes: ; Mode of inheritance: Other
Cytopenia - NOT Fanconi anaemia v1.16 DDX41 Arina Puzriakova Phenotypes for gene: DDX41 were changed from 616871 Susceptibility to myeloid neoplasms to Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to, 616871
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Classified gene: DDX41 as Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Added comment: Comment on list classification: The rating of this gene should be re-evaluated by the GMS Haematology Specialist Test Group in context of the recent review by Zornitza Stark (added for-review tag)
Cytopenia - NOT Fanconi anaemia v1.15 DDX41 Arina Puzriakova Gene: ddx41 has been classified as Red List (Low Evidence).
Cytopenia - NOT Fanconi anaemia v1.14 DDX41 Arina Puzriakova Tag for-review tag was added to gene: DDX41.
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Classified gene: SRP54 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 28 unrelated cases with congenital neutropenia due to variants in SRP54
Cytopenia - NOT Fanconi anaemia v1.14 SRP54 Arina Puzriakova Gene: srp54 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.13 SRP54 Arina Puzriakova Added comment: Comment on publications: Added publications to support association with this phenotype.
Cytopenia - NOT Fanconi anaemia v1.13 SRP54 Arina Puzriakova Publications for gene: SRP54 were set to 28972538
Cytopenia - NOT Fanconi anaemia v1.12 SRP54 Arina Puzriakova Tag for-review tag was added to gene: SRP54.
Cytopenia - NOT Fanconi anaemia v1.12 SRP54 Arina Puzriakova Phenotypes for gene: SRP54 were changed from Syndromic neutropenia with Shwachman-Diamond-like features to Neutropenia, severe congenital, 8, autosomal dominant, 618752
Cytopenia - NOT Fanconi anaemia v1.11 NPM1 Arina Puzriakova Mode of inheritance for gene: NPM1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to Unknown
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Classified gene: NPM1 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Added comment: Comment on list classification: Rated Amber as additional cases required to corroborate causality and better define the phenotype. Both variants currently classified VUS - no information regarding segregation or zygosity.
Cytopenia - NOT Fanconi anaemia v1.10 NPM1 Arina Puzriakova Gene: npm1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.97 ATP1A2 Rhiannon Mellis reviewed gene: ATP1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31608932; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.9 NPM1 Arina Puzriakova reviewed gene: NPM1: Rating: ; Mode of pathogenicity: None; Publications: 31570891; Phenotypes: Dyskeratosis congenita; Mode of inheritance: Unknown
Cytopenia - NOT Fanconi anaemia v1.9 AK2 Arina Puzriakova Phenotypes for gene: AK2 were changed from Reticular dysgenesis, MIM# 267500 to Reticular dysgenesis, 267500
Cytopenia - NOT Fanconi anaemia v1.8 AK2 Arina Puzriakova Added comment: Comment on publications: Added publications to support association with this phenotype.
Cytopenia - NOT Fanconi anaemia v1.8 AK2 Arina Puzriakova Publications for gene: AK2 were set to 19043416
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Classified gene: AK2 as Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - >3 unrelated cases with reticular dysgenesis (leukopenia is part of the phenotype) due to biallelic variants in AK2.
Cytopenia - NOT Fanconi anaemia v1.7 AK2 Arina Puzriakova Gene: ak2 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.6 AK2 Arina Puzriakova Tag for-review tag was added to gene: AK2.
Intellectual disability v3.353 KDM6B Arina Puzriakova Classified gene: KDM6B as Amber List (moderate evidence)
Intellectual disability v3.353 KDM6B Arina Puzriakova Added comment: Comment on list classification: Sufficient number of patients to rate this gene GREEN at the next major review - psychomotor delay was consistently reported and was the key indication for clinical investigation in several cases.
Intellectual disability v3.353 KDM6B Arina Puzriakova Gene: kdm6b has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505 to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.352 KDM6B Arina Puzriakova Phenotypes for gene: KDM6B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505
Intellectual disability v3.351 KDM6B Arina Puzriakova Publications for gene: KDM6B were set to 21937992
Intellectual disability v3.350 KDM6B Arina Puzriakova Mode of inheritance for gene: KDM6B was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 KDM6B Arina Puzriakova Tag for-review tag was added to gene: KDM6B.
Intellectual disability v3.349 KDM6B Arina Puzriakova reviewed gene: KDM6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31124279; Phenotypes: Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, 618505; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.349 HADH Arina Puzriakova Classified gene: HADH as Green List (high evidence)
Intellectual disability v3.349 HADH Arina Puzriakova Added comment: Comment on list classification: As ID is a secondary finding, reported in only a subset of patients, this gene should be downgraded from Green to Amber/Red at the next major review.
Intellectual disability v3.349 HADH Arina Puzriakova Gene: hadh has been classified as Green List (High Evidence).
Intellectual disability v3.348 HADH Arina Puzriakova Phenotypes for gene: HADH were changed from 3-HYDROXYACYL-COENZYME A DEHYDROGENASE DEFICIENCY to Hyperinsulinemic hypoglycemia, familial, 4, 609975; 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530
Intellectual disability v3.347 HADH Arina Puzriakova Tag for-review tag was added to gene: HADH.
Intellectual disability v3.347 HADH Arina Puzriakova reviewed gene: HADH: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 4, 609975, 3-hydroxyacyl-CoA dehydrogenase deficiency, 231530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.16 SH2B3 Catherine Snow reviewed gene: SH2B3: Rating: RED; Mode of pathogenicity: None; Publications: 23812944, 20843259; Phenotypes: Hereditary Erythrocytosis; Mode of inheritance: Other
Neurodegenerative disorders - adult onset v2.16 SS18L1 Zornitza Stark reviewed gene: SS18L1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25888396, 24360741, 23708140, 30976389; Phenotypes: Amyotrophic lateral sclerosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Neurodegenerative disorders - adult onset v2.16 SPG7 Zornitza Stark reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16765570, 19364936; Phenotypes: Spastic paraplegia 7, autosomal recessive MIM#607259; Mode of inheritance: None; Current diagnostic: yes
Neurodegenerative disorders - adult onset v2.16 NEK1 Zornitza Stark reviewed gene: NEK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31768050, 26945885, 27455347, 29929116; Phenotypes: Amyotrophic lateral sclerosis, susceptibility to, 24 MIM#617892; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Neurodegenerative disorders - adult onset v2.16 GLT8D1 Zornitza Stark gene: GLT8D1 was added
gene: GLT8D1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GLT8D1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GLT8D1 were set to 30811981
Phenotypes for gene: GLT8D1 were set to Amyotrophic lateral sclerosis
Review for gene: GLT8D1 was set to GREEN
gene: GLT8D1 was marked as current diagnostic
Added comment: 14 ALS cases with heterozygous missense (10 cases with p.R92C), and supporting in vitro functional assays and zebrafish model.
Sources: Expert list
Neurodegenerative disorders - adult onset v2.16 GBE1 Zornitza Stark gene: GBE1 was added
gene: GBE1 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 20301758; 26194201
Phenotypes for gene: GBE1 were set to Polyglucosan body disease, adult form MIM#263570
Review for gene: GBE1 was set to GREEN
Added comment: APBD can have upper and lower motor neuron involvement, and at least 5 cases in a cohort of 30 were misdiagnosed with ALS.
Sources: Expert list
Neurodegenerative disorders - adult onset v2.16 ERBB4 Zornitza Stark reviewed gene: ERBB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28889094; Phenotypes: Amyotrophic lateral sclerosis 19, 615515; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurodegenerative disorders - adult onset v2.16 DNAJB2 Zornitza Stark gene: DNAJB2 was added
gene: DNAJB2 was added to Neurodegenerative disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: DNAJB2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJB2 were set to Spinal muscular atrophy, distal, autosomal recessive, 5, 614881
Review for gene: DNAJB2 was set to GREEN
Added comment: Young adult onset, progressive neurological disorder, phenotype resembles ALS.
Sources: Expert list
Intellectual disability v3.347 ADGRG6 Arina Puzriakova Phenotypes for gene: ADGRG6 were changed from LETHAL CONGENITAL CONTRACTURE SYNDROME 9 to Lethal congenital contracture syndrome 9, 616503
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Classified gene: ADGRG6 as Red List (low evidence)
Intellectual disability v3.346 ADGRG6 Arina Puzriakova Gene: adgrg6 has been classified as Red List (Low Evidence).
Intellectual disability v3.345 AGL Arina Puzriakova Classified gene: AGL as Red List (low evidence)
Intellectual disability v3.345 AGL Arina Puzriakova Gene: agl has been classified as Red List (Low Evidence).
Intellectual disability v3.344 ALDOB Arina Puzriakova Classified gene: ALDOB as Red List (low evidence)
Intellectual disability v3.344 ALDOB Arina Puzriakova Gene: aldob has been classified as Red List (Low Evidence).
Intellectual disability v3.343 ADCY5 Arina Puzriakova Classified gene: ADCY5 as Red List (low evidence)
Intellectual disability v3.343 ADCY5 Arina Puzriakova Gene: adcy5 has been classified as Red List (Low Evidence).
Intellectual disability v3.342 ABAT Arina Puzriakova Classified gene: ABAT as Amber List (moderate evidence)
Intellectual disability v3.342 ABAT Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team), it has been agreed that this gene should be upgraded from Amber to Green at the next major review.
Intellectual disability v3.342 ABAT Arina Puzriakova Gene: abat has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.341 ABAT Arina Puzriakova Tag for-review tag was added to gene: ABAT.
Intellectual disability v3.341 ABAT Arina Puzriakova reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GABA-transaminase deficiency, 613163; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.341 ACADSB Arina Puzriakova Phenotypes for gene: ACADSB were changed from to 2-methylbutyrylglycinuria, 610006
Intellectual disability v3.340 ACADSB Arina Puzriakova Mode of inheritance for gene: ACADSB was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.339 ACADSB Arina Puzriakova Classified gene: ACADSB as Amber List (moderate evidence)
Intellectual disability v3.339 ACADSB Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as DD has been reported, but only in a subset of symptomatic cases.

Metabolic abnormalities should be a sufficient indication for testing, for which this gene is already rated Green.
Intellectual disability v3.339 ACADSB Arina Puzriakova Gene: acadsb has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.338 ACADSB Arina Puzriakova reviewed gene: ACADSB: Rating: ; Mode of pathogenicity: None; Publications: 30730842; Phenotypes: 2-methylbutyrylglycinuria, 610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.22 AHCY Arina Puzriakova Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids
Undiagnosed metabolic disorders v1.422 AHCY Arina Puzriakova Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids
Undiagnosed metabolic disorders v1.421 AHCY Arina Puzriakova Publications for gene: AHCY were set to 27604308
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Undiagnosed metabolic disorders v1.420 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Tag for-review tag was added to gene: AHCY.
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Undiagnosed metabolic disorders v1.419 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Mode of inheritance for gene: AHCY was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Deleted their comment
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Inborn errors of metabolism v2.21 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder due to variants in AHCY.
Inborn errors of metabolism v2.20 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987
Inborn errors of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987
Inborn errors of metabolism v2.19 AHCY Arina Puzriakova Publications for gene: AHCY were set to 27604308
Intellectual disability v3.338 AHCY Arina Puzriakova Publications for gene: AHCY were set to 15024124
Inborn errors of metabolism v2.18 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Tag for-review tag was added to gene: AHCY.
Inborn errors of metabolism v2.18 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Inborn errors of metabolism v2.18 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.23 AHCY Arina Puzriakova Classified gene: AHCY as Green List (high evidence)
Fetal hydrops v1.23 AHCY Arina Puzriakova Added comment: Comment on list classification: Updated rating from Amber to Green based on additional 2020 paper (PMID:31957987) which reports an infant with foetal hydrops - taking the total number of families to three.
Fetal hydrops v1.23 AHCY Arina Puzriakova Gene: ahcy has been classified as Green List (High Evidence).
Fetal hydrops v1.22 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.97 AHCY Arina Puzriakova Publications for gene: AHCY were set to 30121674; 20852937
Fetal anomalies v1.96 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Fetal anomalies v1.96 AHCY Arina Puzriakova Added comment: Comment on list classification: With addition of the recent publication (PMID:31957987) describing a patient with foetal hydrops, among other features, there is now sufficient evidence to rate this gene GREEN at the next major review.
Fetal anomalies v1.96 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.95 AHCY Arina Puzriakova Tag for-review tag was added to gene: AHCY.
Fetal anomalies v1.95 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.337 AHCY Arina Puzriakova Classified gene: AHCY as Amber List (moderate evidence)
Intellectual disability v3.337 AHCY Arina Puzriakova Added comment: Comment on list classification: DD may occasionally be mild, however is an early and consistent finding amongst surviving patients. Inclusion on this panel may benefit detection of patients who would otherwise not be considered for testing via other routes (e.g. where metabolic abnormalities become apparent later).

Therefore, recommending a GREEN rating at the next major review.
Intellectual disability v3.337 AHCY Arina Puzriakova Gene: ahcy has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.336 AHCY Arina Puzriakova Tag for-review tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova commented on gene: AHCY: Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)
Intellectual disability v3.336 AHCY Arina Puzriakova Tag treatable tag was added to gene: AHCY.
Intellectual disability v3.336 AHCY Arina Puzriakova reviewed gene: AHCY: Rating: GREEN; Mode of pathogenicity: None; Publications: 15024124, 16435181, 16736098, 20852937, 22959829, 26095522, 26527160, 28779239, 30121674, 31957987; Phenotypes: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.16 JAK2 Arina Puzriakova Mode of pathogenicity for gene: JAK2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary Erythrocytosis v1.15 JAK2 Arina Puzriakova Mode of inheritance for gene: JAK2 was changed from Unknown to Other
Hereditary Erythrocytosis v1.14 JAK2 Arina Puzriakova reviewed gene: JAK2: Rating: RED; 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: 27389715; Phenotypes: Erythrocytosis, somatic, 133100; Mode of inheritance: Other
Neurodegenerative disorders - adult onset v2.16 SPG21 Zornitza Stark reviewed gene: SPG21: Rating: GREEN; Mode of pathogenicity: None; Publications: 14564668, 24451228, 28752238, 26978163; Phenotypes: Mast syndrome, MIM# 248900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegenerative disorders - adult onset v2.16 C19orf12 Zornitza Stark reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278385, 21981780, 23269600; Phenotypes: Neurodegeneration with brain iron accumulation 4, MIM# 614298; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.94 COL2A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type I #108300 (AD) in OMIM.

PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 showed hearing loss.

PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss.; to: Associated with Stickler syndrome, type I #108300 (AD) in OMIM.

PMID: 23110709 - Acke et al 2012 - review the literature to give an overview of hearing loss in Stickler syndrome, correlated with the genotype. 313 patients from 102 families were reviewed. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

PMID: 27408751 - Kondo et al 2016 - report 21 cases (some familial, most sporadic) with COL2A1 variants. 4/21 (20%) showed hearing loss.

PMID: 20179744 - Hoornaert et al 2010 - identified 77 different heterozygous COL2A1 mutations in 100 affected individuals out of a group of 188 individuals referred with a potential diagnosis of Stickler syndrome. 30% of COL2A1-variant positive patients had sensorineural hearing loss. However, over a higher percentage (50%) of patients without a COL2A1 mutation have sensorineural hearing loss.
Hearing loss v2.94 COL11A1 Eleanor Williams Classified gene: COL11A1 as Amber List (moderate evidence)
Hearing loss v2.94 COL11A1 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it has been decided that this gene has sufficient cases with hearing loss to be promoted to green. Therefore this gene should be reviewed at the next GMS update.
Hearing loss v2.94 COL11A1 Eleanor Williams Gene: col11a1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.93 COL11A1 Eleanor Williams edited their review of gene: COL11A1: Changed rating: GREEN
Intellectual disability v3.336 DDOST Eleanor Williams Classified gene: DDOST as Green List (high evidence)
Intellectual disability v3.336 DDOST Eleanor Williams Added comment: Comment on list classification: Leaving Green until the next major review, but the evidence does not support a green rating; this gene should be demoted to amber or red.
Intellectual disability v3.336 DDOST Eleanor Williams Gene: ddost has been classified as Green List (High Evidence).
Intellectual disability v3.335 DDOST Eleanor Williams Tag for-review tag was added to gene: DDOST.
Intellectual disability v3.335 DDOST Eleanor Williams reviewed gene: DDOST: Rating: AMBER; Mode of pathogenicity: None; Publications: 22305527; Phenotypes: ?Congenital disorder of glycosylation, type Ir, 614507, CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thrombocythaemia v0.8 JAK2 Arina Puzriakova Tag somatic tag was added to gene: JAK2.
Thrombocythaemia v0.8 JAK2 Arina Puzriakova edited their review of gene: JAK2: Added comment: Most cases are typically associated with somatic JAK2 variants; however, some hereditary cases (at least 4 families) with different germline heterozygous variants have also been reported.; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 22397670, 23535062, 24381227, 24398328; Changed phenotypes: Thrombocythemia 3, 614521
Thrombocythaemia v0.8 CALR Eleanor Williams changed review comment from: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM.

PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL.

PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers.

PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.; to: Associated with Myelofibrosis, somatic MIM#254450 and Thrombocythemia, somatic MIM#187950 in OMIM.

2 papers report somatic mutations. No germline mutations reported to date.

PMID: 24325356 - Klampfl et al 2013 - performed WES to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Two patients had somatic deletions in exon 9 of CALR, and the remaining 4 had a recurrent 5-bp insertion. They then screened 382 patients with polycythemia vera, 311 with essential thrombocythemia, and 203 with primary myelofibrosis for alterations in CALR. 78 patients with essential thrombocythemia (25%) and 72 with primary myelofibrosis (35%) had mutations in CALR. All patients with mutated CALR had nonmutated JAK2 and MPL.

PMID: 24325359 - Nangalia et al 2013 - performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers.

PMID: 31778606 - Jan and Choi 2020 - review of molecular basis of myeloproliferative neoplasms - only somatic mutations mentioned, no germline.
Thrombocythaemia v0.8 CALR Eleanor Williams Phenotypes for gene: CALR were changed from Thrombocythemia, somatic, 187950 to Thrombocythemia, somatic, 187950; Myelofibrosis, somatic, 254450
Thrombocythaemia v0.7 CALR Eleanor Williams Publications for gene: CALR were set to
Thrombocythaemia v0.6 CALR Eleanor Williams reviewed gene: CALR: Rating: AMBER; Mode of pathogenicity: None; Publications: 24325356, 24325359, 31778606; Phenotypes: Myelofibrosis, somatic, 254450, Thrombocythemia, somatic, 187950; Mode of inheritance: Unknown
Intellectual disability v3.335 CYP2U1 Eleanor Williams reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.335 AGPS Arina Puzriakova Phenotypes for gene: AGPS were changed from RHIZOMELIC CHONDRODYSPLASIA PUNCTATA TYPE 3 (RCDP3) to Rhizomelic chondrodysplasia punctata, type 3, 600121
Intellectual disability v3.334 AGPS Arina Puzriakova Publications for gene: AGPS were set to 7807941; 11152660
Intellectual disability v3.333 AGPS Arina Puzriakova Classified gene: AGPS as Green List (high evidence)
Intellectual disability v3.333 AGPS Arina Puzriakova Added comment: Comment on list classification: Though some relevant phenotypic features have been reported, the relationship with ID is not clear from literature. Patients are more likely to be recognised in context of the skeletal phenotype.

Therefore, suggesting a rating downgrade from Green to Amber at the next major review.
Intellectual disability v3.333 AGPS Arina Puzriakova Gene: agps has been classified as Green List (High Evidence).
Intellectual disability v3.332 AGPS Arina Puzriakova Tag for-review tag was added to gene: AGPS.
Intellectual disability v3.332 AGPS Arina Puzriakova reviewed gene: AGPS: Rating: AMBER; Mode of pathogenicity: None; Publications: 7807941, 11152660, 11152660, 21990100; Phenotypes: Rhizomelic chondrodysplasia punctata, type 3, 600121; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy NOT PMP22 copy number v1.8 C1orf194 Arina Puzriakova changed review comment from: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; to: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.
Hereditary neuropathy NOT PMP22 copy number v1.8 C1orf194 Arina Puzriakova edited their review of gene: C1orf194: Added comment: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; Changed publications: 32592472; Changed phenotypes: Charcot-Marie-Tooth
Hereditary neuropathy NOT PMP22 copy number v1.8 C1orf194 Arina Puzriakova Publications for gene: C1orf194 were set to 31199454
Hereditary neuropathy NOT PMP22 copy number v1.7 C1orf194 Arina Puzriakova Classified gene: C1orf194 as Amber List (moderate evidence)
Hereditary neuropathy NOT PMP22 copy number v1.7 C1orf194 Arina Puzriakova Added comment: Comment on list classification: This is has been added with an Amber rating, in accordance with the expert review by Zornitza Stark.
Hereditary neuropathy NOT PMP22 copy number v1.7 C1orf194 Arina Puzriakova Gene: c1orf194 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.332 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic epilepsy syndromes v2.154 MECP2 Arina Puzriakova reviewed gene: MECP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32469049; Phenotypes: Rett syndrome, 312750; 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 v3.332 UPF3B Arina Puzriakova reviewed gene: UPF3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32667670; Phenotypes: Mental retardation, X-linked, syndromic 14, 300676; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Parkinson Disease and Complex Parkinsonism v1.68 XPR1 Zornitza Stark gene: XPR1 was added
gene: XPR1 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: XPR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: XPR1 were set to 25938945
Phenotypes for gene: XPR1 were set to Basal ganglia calcification, idiopathic, 6, MIM# 616413
Review for gene: XPR1 was set to GREEN
gene: XPR1 was marked as current diagnostic
Added comment: Idiopathic basal ganglia calcification is an autosomal dominant neurodegenerative disorder characterised by adult onset of progressive neuropsychiatric and movement disorders, although some patients remain asymptomatic. Clinical features can include dystonia, parkinsonism, gait abnormalities, psychosis, dementia, and chorea. Brain imaging shows calcifications of the basal ganglia and other brain regions. At least 5 unrelated families reported.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 VPS13C Zornitza Stark gene: VPS13C was added
gene: VPS13C was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: VPS13C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS13C were set to 26942284; 30452786; 28862745
Phenotypes for gene: VPS13C were set to Parkinson disease 23, autosomal recessive, early onset MIM#616840
Review for gene: VPS13C was set to GREEN
gene: VPS13C was marked as current diagnostic
Added comment: >3 individuals with biallelic variants.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 TWNK Zornitza Stark gene: TWNK was added
gene: TWNK was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: TWNK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TWNK were set to 24076137; 22949510; 22580846; 19353676
Phenotypes for gene: TWNK were set to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 MIM#609286
Review for gene: TWNK was set to GREEN
gene: TWNK was marked as current diagnostic
Added comment: Greater than three cases reported with parkinsonism as a feature of the condition.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 SLC20A2 Zornitza Stark gene: SLC20A2 was added
gene: SLC20A2 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: SLC20A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A2 were set to 22327515; 23334463
Phenotypes for gene: SLC20A2 were set to Basal ganglia calcification, idiopathic, 1, MIM# 213600
Review for gene: SLC20A2 was set to GREEN
gene: SLC20A2 was marked as current diagnostic
Added comment: Over 50 families reported. Affected individuals can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, dystonia, tremor, ataxia, dementia, psychosis, seizures, and chronic headache.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDGFRB Zornitza Stark gene: PDGFRB was added
gene: PDGFRB was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRB were set to 23255827; 30979360
Phenotypes for gene: PDGFRB were set to Basal ganglia calcification, idiopathic, 4, MIM# 615007
Review for gene: PDGFRB was set to GREEN
gene: PDGFRB was marked as current diagnostic
Added comment: Idiopathic basal ganglia calcification-4 is an autosomal dominant condition characterized by the accumulation of calcium deposits in various brain regions, most commonly in the basal ganglia. Presentation is with parkinsonism and impaired cognitive function.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDGFB Zornitza Stark gene: PDGFB was added
gene: PDGFB was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDGFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFB were set to 23913003
Phenotypes for gene: PDGFB were set to Basal ganglia calcification, idiopathic, 5, MIM# 615483
Review for gene: PDGFB was set to GREEN
gene: PDGFB was marked as current diagnostic
Added comment: Progressive disorder characterised by neurologic symptoms that are associated with brain calcifications mainly affecting the basal ganglia. Calcifications may also occur in the thalamus, cerebellum, or white matter. Affected individuals have motor symptoms, such as dyskinesias or parkinsonism, headache, cognitive impairment, and psychiatric manifestations, including apathy and depression. More than 10 families reported.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 PDE8B Zornitza Stark gene: PDE8B was added
gene: PDE8B was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: PDE8B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDE8B were set to 20085714; 26769607; 26475694
Phenotypes for gene: PDE8B were set to Striatal degeneration, autosomal dominant, MIM#609161
Review for gene: PDE8B was set to GREEN
Added comment: Movement disorder due to basal ganglia abnormalities, at least three families reported with heterozygous variants in this gene.
Sources: Expert list
Primary immunodeficiency v2.199 NLRP1 Eleanor Williams Phenotypes for gene: NLRP1 were changed from Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammatory Disorders; Autoinflammation with arthritis and dyskeratosis to Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammatory Disorders; Autoinflammation with arthritis and dyskeratosis, 617388
Primary immunodeficiency v2.198 TREX1 Eleanor Williams Phenotypes for gene: TREX1 were changed from Aicardi-Goutieres syndrome 1, dominant and recessive; Type 1 interferonopathies; Classical AGS, SLE, FCL; Autoinflammatory Disorders to Aicardi-Goutieres syndrome 1, dominant and recessive, 225750; Type 1 interferonopathies; Classical AGS, SLE, FCL; Autoinflammatory Disorders
Primary immunodeficiency v2.197 STK4 Eleanor Williams Phenotypes for gene: STK4 were changed from Hypergammaglobulinaemia, lymphopenia, combined immunodeficiency, congenital heart disease, autoimmunity; T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations; AR hyperimmunoglobulin E syndrome; Combined immunodeficiency; Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease; Immunodeficiencies affecting cellular and humoral immunity to Hypergammaglobulinaemia, lymphopenia, combined immunodeficiency, congenital heart disease, autoimmunity; T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations, 614868; AR hyperimmunoglobulin E syndrome; Combined immunodeficiency; Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency v2.196 DOCK8 Eleanor Williams Phenotypes for gene: DOCK8 were changed from Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity to Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity
Primary immunodeficiency v2.195 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853 to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation
Primary immunodeficiency v2.194 MAGT1 Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853
Intellectual disability v3.332 STAT1 Arina Puzriakova Classified gene: STAT1 as Red List (low evidence)
Intellectual disability v3.332 STAT1 Arina Puzriakova Gene: stat1 has been classified as Red List (Low Evidence).
Intellectual disability v3.331 STAT1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 RASA1 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Intellectual disability v3.331 ABCC6 Arina Puzriakova Classified gene: ABCC6 as Red List (low evidence)
Intellectual disability v3.331 ABCC6 Arina Puzriakova Gene: abcc6 has been classified as Red List (Low Evidence).
Intellectual disability v3.330 ABCC6 Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis
Hereditary Erythrocytosis v1.14 Sarah Leigh Panel types changed to Rare Disease 100K; GMS Rare Disease
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Classified gene: SH2B3 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to SH2B3, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.13 SH2B3 Sarah Leigh Gene: sh2b3 has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.12 SH2B3 Sarah Leigh Tag for-review tag was added to gene: SH2B3.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Tag for-review tag was added to gene: JAK2.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Classified gene: JAK2 as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Added comment: Comment on list classification: An amber rating has been given to JAK2, as only somatic variants in this gene have been reported to be associated with Erythrocytosis, somatic 133100.
Hereditary Erythrocytosis v1.12 JAK2 Sarah Leigh Gene: jak2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.193 PTEN Arina Puzriakova reviewed gene: PTEN: Rating: ; Mode of pathogenicity: None; Publications: 32588888; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Disorders of sex development v2.11 TCF12 Arina Puzriakova changed review comment from: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).; to: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered. Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Disorders of sex development v2.11 TCF12 Arina Puzriakova Tag watchlist tag was added to gene: TCF12.
Disorders of sex development v2.11 TCF12 Arina Puzriakova Classified gene: TCF12 as Amber List (moderate evidence)
Disorders of sex development v2.11 TCF12 Arina Puzriakova Added comment: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Disorders of sex development v2.11 TCF12 Arina Puzriakova Gene: tcf12 has been classified as Amber List (Moderate Evidence).
Disorders of sex development v2.10 TCF12 Arina Puzriakova gene: TCF12 was added
gene: TCF12 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: TCF12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TCF12 were set to 32620954
Phenotypes for gene: TCF12 were set to Kallmann syndrome
Review for gene: TCF12 was set to AMBER
Added comment: Note monoallelic variants in this gene are a well-established cause of craniosynostosis.
--------------------------------------------------------------------------------------------------------------------

- PMID: 32620954 (2020) - 13 unrelated kindreds (11 de novo, 1 AD and 1 AR) comprising 14 affected individuals with an anosmic form of isolated GnRH deficiency (IGD) (Kallman syndrome) due to different LoF variants in TCF12.

Clinical manifestation included anosmia and pubertal failure (with reproductive phenotypes such as micropenis, bilateral cryptorchidism, hypospadias). Two unrelated individuals within the cohort additionally exhibited craniosynostosis, and a further two pedigrees had a family history of craniosynostosis (that did not affect the index cases). Multiplex cases typically presented incomplete penetrance.

Loss of tcf12 in a mutant zebrafish model perturbed GnRH neuronal patterning, with concomitant expression attenuation of tcf3a/b and stub1 (latter mutated in other syndromic forms of IGD). Furthermore, restored STUB1 expression rescued loss of tcf12 in vivo.
Sources: Literature
Disorders of sex development v2.9 DHX37 Arina Puzriakova Tag for-review tag was added to gene: DHX37.
Disorders of sex development v2.9 DHX37 Arina Puzriakova Publications for gene: DHX37 were set to 31337883; 31745530
Disorders of sex development v2.8 DHX37 Arina Puzriakova Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46, XY sex reversal 11, 273250
Primary immunodeficiency v2.193 SLC7A7 Arina Puzriakova reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 32504080; Phenotypes: Lysinuric protein intolerance, 222700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.20 TNFRSF11A Sarah Leigh Added comment: Comment on mode of inheritance: It is suggested that the mode of inheritance for TNFRSF11A should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review.
Skeletal dysplasia v2.20 TNFRSF11A Sarah Leigh Mode of inheritance for gene: TNFRSF11A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.19 TNFRSF11A Sarah Leigh Tag for-review tag was added to gene: TNFRSF11A.
Parkinson Disease and Complex Parkinsonism v1.68 DNAJC5 Zornitza Stark gene: DNAJC5 was added
gene: DNAJC5 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC5 were set to 22978711; 21820099; 22235333
Phenotypes for gene: DNAJC5 were set to Ceroid lipofuscinosis, neuronal, 4, Parry type, MIM# 162350
Review for gene: DNAJC5 was set to GREEN
Added comment: Parkinsonism has been described in some individuals with this progressive adult-onset neurodegenerative disorder. The (346_348delCTC) variant is recurrent, without evidence of founder effect.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 DNAJC12 Zornitza Stark gene: DNAJC12 was added
gene: DNAJC12 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: DNAJC12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNAJC12 were set to Hyperphenylalaninemia, mild, non-BH4-deficient, MIM#617384
Review for gene: DNAJC12 was set to GREEN
Added comment: Highly variable neurological phenotype, including ID, dystonia, parkinsonism.
Sources: Expert list
Parkinson Disease and Complex Parkinsonism v1.68 CP Zornitza Stark gene: CP was added
gene: CP was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: CP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CP were set to 28012953
Phenotypes for gene: CP were set to Hemosiderosis, systemic, due to aceruloplasminemia MIM#604290
Review for gene: CP was set to GREEN
Added comment: Parkinsonism is a prominent feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 WDR45B Zornitza Stark reviewed gene: WDR45B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 TFG Zornitza Stark reviewed gene: TFG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 SPART Zornitza Stark reviewed gene: SPART: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 SLC25A15 Zornitza Stark gene: SLC25A15 was added
gene: SLC25A15 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: SLC25A15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A15 were set to 16376511; 22465082; 28592010
Phenotypes for gene: SLC25A15 were set to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome MIM#238970
Review for gene: SLC25A15 was set to GREEN
Added comment: At least four unrelated cases reported with an adult onset spastic paraparesis as a feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 SLC1A4 Zornitza Stark reviewed gene: SLC1A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 SLC16A2 Zornitza Stark reviewed gene: SLC16A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 SERAC1 Zornitza Stark reviewed gene: SERAC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 REEP2 Zornitza Stark reviewed gene: REEP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 NT5C2 Zornitza Stark reviewed gene: NT5C2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 NKX6-2 Zornitza Stark reviewed gene: NKX6-2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 L1CAM Zornitza Stark reviewed gene: L1CAM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 KIF1C Zornitza Stark reviewed gene: KIF1C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 KIDINS220 Zornitza Stark reviewed gene: KIDINS220: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 KDM5C Zornitza Stark reviewed gene: KDM5C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 HACE1 Zornitza Stark reviewed gene: HACE1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.24 RAD50 Arina Puzriakova Tag watchlist tag was added to gene: RAD50.
Severe microcephaly v2.24 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder, MIM# 613078 to Nijmegen breakage syndrome-like disorder, 613078
Severe microcephaly v2.23 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 19409520; 32212377
Severe microcephaly v2.22 RAD50 Arina Puzriakova Classified gene: RAD50 as Amber List (moderate evidence)
Severe microcephaly v2.22 RAD50 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype (two unrelated cases with severe congenital microcephaly) but additional cases required before inclusion of RAD50 on a diagnostic panel.

Rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Severe microcephaly v2.22 RAD50 Arina Puzriakova Gene: rad50 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype. ; to: Comment on list classification: Note uncertainty regarding ID in the first patient - PMID:1887849 states 'lack of mental retardation', while a later report PMID:19409520 describes 'mild to moderate retardation of psychomotor development'. ID was borderline in the second patient (at age 15 estimated IQ: 85).

Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the phenotype associated with RAD50 variants.
Intellectual disability v3.330 RAD50 Arina Puzriakova changed review comment from: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.; to: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to clarify the relevance of ID to the overall phenotype.
Intellectual disability v3.330 RAD50 Arina Puzriakova Phenotypes for gene: RAD50 were changed from Nijmegen breakage syndrome-like disorder,613078; NBSLD to Nijmegen breakage syndrome-like disorder, 613078
Intellectual disability v3.329 RAD50 Arina Puzriakova Publications for gene: RAD50 were set to 1887849; 19409520
Intellectual disability v3.328 RAD50 Arina Puzriakova Classified gene: RAD50 as Red List (low evidence)
Intellectual disability v3.328 RAD50 Arina Puzriakova Added comment: Comment on list classification: Borderline ID in second patient (at age 15 estimated IQ: 85). Therefore, keeping rating Red awaiting further cases to ascertain the contribution of RAD50 variants to an ID phenotype.
Intellectual disability v3.328 RAD50 Arina Puzriakova Gene: rad50 has been classified as Red List (Low Evidence).
Genetic epilepsy syndromes v2.154 DHX16 Sarah Leigh Tag watchlist tag was added to gene: DHX16.
Genetic epilepsy syndromes v2.154 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.154 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.153 DHX16 Sarah Leigh gene: DHX16 was added
gene: DHX16 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733
Review for gene: DHX16 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing and seizures were reported in 2 of these cases. No functional studies were reported.
Sources: Literature
Osteopetrosis v1.2 Sarah Leigh Panel version has been signed off
Intellectual disability v3.327 WASHC4 Arina Puzriakova Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Mental retardation, autosomal recessive 43, 615817
Intellectual disability v3.326 WASHC4 Arina Puzriakova Classified gene: WASHC4 as Amber List (moderate evidence)
Intellectual disability v3.326 WASHC4 Arina Puzriakova Added comment: Comment on list classification: Rating Amber in view of mild/borderline ID in 2/3 families. Additional cases with a more significant manifestation of ID required before inclusion of WASHC4 on a diagnostic panel.
Intellectual disability v3.326 WASHC4 Arina Puzriakova Gene: washc4 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.325 WASHC4 Arina Puzriakova reviewed gene: WASHC4: Rating: ; Mode of pathogenicity: None; Publications: 21498477, 31953988; Phenotypes: Mental retardation, autosomal recessive 43, 615817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteopetrosis v1.0 Sarah Leigh promoted panel to version 1.0
Intellectual disability v3.325 AFG3L2 Arina Puzriakova Phenotypes for gene: AFG3L2 were changed from SPINOCEREBELLAR ATAXIA 28 to Spastic ataxia 5, autosomal recessive, 614487
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Classified gene: AFG3L2 as Green List (high evidence)
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Added comment: Comment on list classification: This gene should be downgraded from Green to Red at the next major review, in accordance with the review by Zornitza Stark.
Intellectual disability v3.324 AFG3L2 Arina Puzriakova Gene: afg3l2 has been classified as Green List (High Evidence).
Intellectual disability v3.323 AFG3L2 Arina Puzriakova Publications for gene: AFG3L2 were set to 22022284
Intellectual disability v3.322 AFG3L2 Arina Puzriakova Tag for-review tag was added to gene: AFG3L2.
Intellectual disability v3.322 RASA1 Arina Puzriakova Classified gene: RASA1 as Red List (low evidence)
Intellectual disability v3.322 RASA1 Arina Puzriakova Gene: rasa1 has been classified as Red List (Low Evidence).
Structural eye disease v1.11 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: The eye disorders relevant to this panel are associated with Osteoporosis-pseudoglioma syndrome 259770, which is biallelic. Exudative vitreoretinopathy 4, 601813, which can be biallelic or monoallelic is relavant to the Retinal disorders panel, where both biallelic and monoallelic variants are considered (https://panelapp.genomicsengland.co.uk/panels/307/gene/LRP5/#!review).
Structural eye disease v1.11 LRP5 Sarah Leigh Mode of inheritance for gene: LRP5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v1.10 LRP5 Sarah Leigh Publications for gene: LRP5 were set to 29131652, 28111184, 20034086
Intellectual disability v3.321 LRP5 Sarah Leigh Added comment: Comment on mode of inheritance: Other phenotypes associated with LRP5 variants (https://www.omim.org/entry/603506?search=LRP5&highlight=lrp5#geneMap) have monoallelic inheritance, however, these phenotypes are not relevant for this panel as ID has not been reported.
Intellectual disability v3.321 LRP5 Sarah Leigh Mode of inheritance for gene: LRP5 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.320 WDFY3 Arina Puzriakova Classified gene: WDFY3 as Amber List (moderate evidence)
Intellectual disability v3.320 WDFY3 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of cases with moderate ID to meet the threshold for inclusion on a diagnostic ID panel. Furthermore, ID is currently the most applicable clinical indication for detecting these cases using PanelApp panels.

Therefore, recommending a rating upgrade from Amber to Green at the next major review.
Intellectual disability v3.320 WDFY3 Arina Puzriakova Gene: wdfy3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.319 WDFY3 Arina Puzriakova Tag for-review tag was added to gene: WDFY3.
Osteopetrosis v0.10 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: Comment on list classification: Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).
Intellectual disability v3.319 TRAK1 Arina Puzriakova Phenotypes for gene: TRAK1 were changed from to Epileptic encephalopathy, early infantile, 68, 618201
Intellectual disability v3.318 TRAK1 Arina Puzriakova Publications for gene: TRAK1 were set to
Intellectual disability v3.317 TRAK1 Arina Puzriakova Mode of inheritance for gene: TRAK1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.316 TRAK1 Arina Puzriakova changed review comment from: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).; to: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, TRAK1 currently does not meet the threshold to say that variants cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Classified gene: TRAK1 as Amber List (moderate evidence)
Intellectual disability v3.316 TRAK1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber - with ID seemingly following seizures, and being in association with a single recurrent variant, there is currently insufficient evidence to say that variants in this gene cause ID. This may, however, be reviewed if new evidence emerges.

All cases have presented with seizures which should be an adequate indication for diagnostic testing (this gene is rated Green on the Genetic epilepsy syndromes (v2.152) panel).
Intellectual disability v3.316 TRAK1 Arina Puzriakova Gene: trak1 has been classified as Amber List (Moderate Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Classified gene: DIS3L2 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence for this gene to be rated Green. It is also Green on Tumour predisposition - childhood onset (Version 2.13), Childhood solid tumours cancer susceptibility (Version 1.13), Skeletal dysplasia (Version 2.19), Fetal anomalies (Version 1.95), DDG2P (Version 2.9), Intellectual disability (Version 3.315) and Severe Paediatric Disorders (Version 1.11).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.99 DIS3L2 Ivone Leong Gene: dis3l2 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.98 DIS3L2 Ivone Leong Phenotypes for gene: DIS3L2 were changed from Perlman syndrome, MIM# 267000 to Perlman syndrome, 267000
Intellectual disability v3.315 TRAK1 Arina Puzriakova reviewed gene: TRAK1: Rating: ; Mode of pathogenicity: None; Publications: 28940097, 28364549, 29846532; Phenotypes: Epileptic encephalopathy, early infantile, 68, 618201; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.8 NSUN3 Zornitza Stark reviewed gene: NSUN3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27356879, 32488845; Phenotypes: Combined oxidative phosphorylation deficiency 48, MIM# 619012; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.315 SLC12A2 Konstantinos Varvagiannis reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28135719, 32658972, 27900370, 32294086, 29288388, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.93 FOXI1 Eleanor Williams Tag for-review tag was added to gene: FOXI1.
Hearing loss v2.93 FOXI1 Eleanor Williams Classified gene: FOXI1 as Amber List (moderate evidence)
Hearing loss v2.93 FOXI1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. There are 2 homozygous and several heterozygous cases reported and it could be promoted to green after GMS review. Although most cases are syndromic hearing loss is a major feature. There is some debate about the whether it is homozygous only or also heterozygously inherited, however the homozygous cases are more convincing.
Hearing loss v2.93 FOXI1 Eleanor Williams Gene: foxi1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.92 FOXI1 Eleanor Williams edited their review of gene: FOXI1: Changed rating: GREEN
Hearing loss v2.92 FOXI1 Eleanor Williams reviewed gene: FOXI1: Rating: ; Mode of pathogenicity: None; Publications: 17503324, 29242249, 12642503, 9843211; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.92 FOXF2 Eleanor Williams Classified gene: FOXF2 as Amber List (moderate evidence)
Hearing loss v2.92 FOXF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 1 case reported with segregation of the variants, plus some mouse model evidence.
Hearing loss v2.92 FOXF2 Eleanor Williams Gene: foxf2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.91 FOXF2 Eleanor Williams reviewed gene: FOXF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30561639, 22022403; Phenotypes: sensorineural hearing loss (SNHL); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.91 ESRP1 Eleanor Williams Classified gene: ESRP1 as Amber List (moderate evidence)
Hearing loss v2.91 ESRP1 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. 1 case with segregation data reported, plus mouse knockout model.
Hearing loss v2.91 ESRP1 Eleanor Williams Gene: esrp1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.90 ESRP1 Eleanor Williams Phenotypes for gene: ESRP1 were changed from Deafness, autosomal recessive 109, MIM# 618013 to Deafness, autosomal recessive 109, 618013
Hearing loss v2.89 ESRP1 Eleanor Williams reviewed gene: ESRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29107558; Phenotypes: ?Deafness, autosomal recessive 109, 618013; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - adult onset v1.7 GJA1 Zornitza Stark gene: GJA1 was added
gene: GJA1 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GJA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GJA1 were set to 31023660
Phenotypes for gene: GJA1 were set to Hereditary spastic paraplegia; Oculodentodigital dysplasia, MIM#164200
Review for gene: GJA1 was set to GREEN
gene: GJA1 was marked as current diagnostic
Added comment: 8 individuals from 5 families with oculodentodigital dysplasia presenting in adulthood with onset of spastic paraplegia and white matter changes on imaging.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 GBE1 Zornitza Stark gene: GBE1 was added
gene: GBE1 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GBE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBE1 were set to 23034915
Phenotypes for gene: GBE1 were set to Polyglucosan body disease, adult form MIM#263570
Review for gene: GBE1 was set to GREEN
gene: GBE1 was marked as current diagnostic
Added comment: Spastic paraplegia is a reported as a prominent feature of the condition in 45/50 cases diagnosed with adult polyglucosan body disease.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 GALC Zornitza Stark gene: GALC was added
gene: GALC was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: GALC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALC were set to 9272171; 11971051; 22959700; 26396125; 26915362; 28547031; 31185936; 32064984
Phenotypes for gene: GALC were set to Krabbe disease MIM#245200
Review for gene: GALC was set to GREEN
gene: GALC was marked as current diagnostic
Added comment: Adult onset spastic paraplegia is reported as a feature of the condition in greater than 3 cases.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 FBXO7 Zornitza Stark gene: FBXO7 was added
gene: FBXO7 was added to Hereditary spastic paraplegia - adult onset. Sources: Expert list
Mode of inheritance for gene: FBXO7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXO7 were set to 18513678; 19038853
Phenotypes for gene: FBXO7 were set to Parkinson disease 15, autosomal recessive MIM#260300
Review for gene: FBXO7 was set to GREEN
gene: FBXO7 was marked as current diagnostic
Added comment: Lower limb spasticity reported in at least three families.
Sources: Expert list
Hereditary spastic paraplegia - adult onset v1.7 FARS2 Zornitza Stark reviewed gene: FARS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 ERLIN1 Zornitza Stark reviewed gene: ERLIN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 ENTPD1 Zornitza Stark reviewed gene: ENTPD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 CPT1C Zornitza Stark Deleted their review
Hereditary spastic paraplegia - adult onset v1.7 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: GREEN; Mode of pathogenicity: None; Publications: 23973755; Phenotypes: Spastic paraplegia 73, autosomal dominant, 616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hearing loss v2.89 COL11A1 Eleanor Williams Tag for-review tag was added to gene: COL11A1.
Hearing loss v2.89 COL2A1 Eleanor Williams Classified gene: COL2A1 as Amber List (moderate evidence)
Hearing loss v2.89 COL2A1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to amber. Should be reviewed by the GMS as to whether it is appropriate to make green.
Hearing loss v2.89 COL2A1 Eleanor Williams Gene: col2a1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.88 COL2A1 Eleanor Williams Mode of inheritance for gene: COL2A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.87 COL2A1 Eleanor Williams Publications for gene: COL2A1 were set to
Hearing loss v2.86 COL2A1 Eleanor Williams Phenotypes for gene: COL2A1 were changed from Stickler syndrome, type I, 108300Kniest dysplasia, 156550Achondrogenesis, type II or hypochondrogenesis, 200610SED congenita, 183900SMED Strudwick type, 184250Epiphyseal dysplasia, multiple, with myopia and deafness, 132450Spondyloperipheral dysplasia, 271700SED, Namaqualand typeOsteoarthritis with mild chondrodysplasia, 604864Vitreoretinopathy with phalangeal epiphyseal dysplasiaPlatyspondylic skeletal dysplasia, Torrance type, 151210Otospondylomegaepiphyseal dysplasia, 215150Avascular necrosis of the femoral head, 608805Legg-Calve-Perthes disease, 150600Stickler sydrome, type I, nonsyndromic ocular, 609508Czech dysplasia, 609162; ticklersyndrome,typeI,108300Kniestdysplasia,156550Achondrogenesis,typeIIorhypochondrogenesis,200610SEDcongenita,183900 to Stickler syndrome, type I, 108300
Hearing loss v2.85 COL9A2 Eleanor Williams Tag for-review tag was added to gene: COL9A2.
Hereditary spastic paraplegia - adult onset v1.7 C12orf65 Zornitza Stark reviewed gene: C12orf65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 ARG1 Zornitza Stark reviewed gene: ARG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 AP4S1 Zornitza Stark reviewed gene: AP4S1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 AP4M1 Zornitza Stark reviewed gene: AP4M1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 AP4E1 Zornitza Stark reviewed gene: AP4E1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.85 COL9A3 Eleanor Williams Tag for-review tag was added to gene: COL9A3.
Hereditary spastic paraplegia - adult onset v1.7 AP4B1 Zornitza Stark reviewed gene: AP4B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.85 COL9A3 Eleanor Williams Classified gene: COL9A3 as Amber List (moderate evidence)
Hearing loss v2.85 COL9A3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber. 2 cases of a Stickler syndrome phenotype reported, which includes hearing loss.
Hearing loss v2.85 COL9A3 Eleanor Williams Gene: col9a3 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - adult onset v1.7 ALS2 Zornitza Stark reviewed gene: ALS2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.84 COL9A3 Eleanor Williams Phenotypes for gene: COL9A3 were changed from to Stickler syndrome
Hearing loss v2.83 COL9A3 Eleanor Williams Publications for gene: COL9A3 were set to
Hearing loss v2.82 COL9A3 Eleanor Williams Mode of inheritance for gene: COL9A3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.81 COL9A3 Eleanor Williams edited their review of gene: COL9A3: Changed rating: AMBER; Changed publications: 31090205, 24273071; Changed phenotypes: Stickler syndrome; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.81 COL9A3 Eleanor Williams commented on gene: COL9A3
Hereditary spastic paraplegia - adult onset v1.7 AIMP1 Zornitza Stark reviewed gene: AIMP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary spastic paraplegia - adult onset v1.7 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive 614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v2.15 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 8, autosomal dominant, 603563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hearing loss v2.81 COL9A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.; to: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 1 unknown ethnicity family with R507X variants and 2 distantly related Moroccan families with R295X COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.

PMID: 31090205 - Nixon et al 2019 - report 1 case of a 6 year old child with a homozygous nonsense variant in COL9A1 (c.1519C>T, p.(Arg507Ter)) and a diagnosis of Stickler syndrome. This variant has been described previously (Nikopoulos et al., 2011). The child had high‐frequency sensorineural hearing loss.
Hearing loss v2.81 COL9A2 Eleanor Williams Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2, 600204{Intervertebral disc disease, susceptibility to}, 603932Stickler syndrome, type V, 614284; Epiphysealdysplasia,multiple,2,600204{Intervertebraldiscdisease,susceptibilityto},603932Sticklersyndrome,typeV,614284 to ?Stickler syndrome, type V, 614284
Hearing loss v2.80 COL9A2 Eleanor Williams Publications for gene: COL9A2 were set to
Hearing loss v2.79 COL9A2 Eleanor Williams Added comment: Comment on mode of inheritance: 3 reported cases are all homozygous
Hearing loss v2.79 COL9A2 Eleanor Williams Mode of inheritance for gene: COL9A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.78 COL9A2 Eleanor Williams Classified gene: COL9A2 as Amber List (moderate evidence)
Hearing loss v2.78 COL9A2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber, but sufficient cases to rate green following GMS review of appropriateness of this gene for a non-syndromic hearing loss panel.
Hearing loss v2.78 COL9A2 Eleanor Williams Gene: col9a2 has been classified as Amber List (Moderate Evidence).
Hereditary spastic paraplegia - childhood onset v2.15 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hearing loss v2.77 COL9A2 Eleanor Williams reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 21671392, 31090205; Phenotypes: ?Stickler syndrome, type V, 614284; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.77 COL11A1 Eleanor Williams commented on gene: COL11A1: PMID: 23967202 - Miyagawa et al 2013 - report 3 missense variants in Japanese hearing loss patients through targeted exome sequencing. 1 familial case shown with two affected siblings. They suggest the inheritance is autosomal dominant.
Hearing loss v2.77 COL9A1 Eleanor Williams Tag for-review tag was added to gene: COL9A1.
Hearing loss v2.77 COL9A1 Eleanor Williams Classified gene: COL9A1 as Amber List (moderate evidence)
Hearing loss v2.77 COL9A1 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber, but maybe appropriate for green rating following GMS review.
Hearing loss v2.77 COL9A1 Eleanor Williams Gene: col9a1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.76 COL9A1 Eleanor Williams Phenotypes for gene: COL9A1 were changed from Epiphyseal dysplasia, multiple, 6, 614135Stickler syndrome, type IV, 614134; Epiphysealdysplasia,multiple,6,614135Sticklersyndrome,typeIV,614134 to Stickler syndrome, type IV, 614134; hearing loss
Hearing loss v2.75 COL9A1 Eleanor Williams Publications for gene: COL9A1 were set to
Hereditary spastic paraplegia - childhood onset v2.15 RNF170 Zornitza Stark gene: RNF170 was added
gene: RNF170 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: RNF170 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF170 were set to 31636353
Phenotypes for gene: RNF170 were set to Hereditary spastic paraplegia
Review for gene: RNF170 was set to GREEN
Added comment: Four families reported with a complicated HSP phenotype.
Sources: Expert list
Hearing loss v2.74 COL9A1 Eleanor Williams changed review comment from: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases on non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.; to: Associated with Stickler syndrome, type IV #614134 in OMIM. No inheritance given.

Summary: 1 Turkish and 2 distantly related Moroccan families with frameshift COL9A1 variants and Stickler syndrome. 2 cases of non-syndromic hearing loss (1 missense, 1 in-frame deletion of several exons).

PMID: 16909383 Van Camp et al 2006 - report a family of Moroccan origin with 4 children affected by Stickler syndrome and 6 unaffected children. The distantly related parents are unaffected. The 4 children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. Targeted analysis of COL9A1 resulted in the identification of a homozygous R295X variant in the four affected children. 4 unaffected children and the parents were heterozygous carriers. Two unaffected children did not carry the variant at all.

PMID: 21421862 - Nikopoulos et al 2011 - Report two consanguineous families with children with Stickler syndrome. One Turkish family has two affected sisters, the other Moroccan family has one affected boy. The Turkish girls were found to have a homozygous COL9A1 mutation (p.R507X) while the Moroccan boy had the same variant found in the Moroccan family published by Van Camp et al 2006 (p.R295X). Phenotypic features include myopia, cataracts, distinct vitreous changes, progressive chorioretinal degeneration, and exudative and rhegmatogenous retinal detachments. All three had sensorineural hearing loss and epiphyseal dysplasia. Haplotype analysis of the Moroccan family showed they shared the identical disease haplotype in the 2-cM area encompassing COL9A1 as the previously described Moroccan family, indicating a possible relationship.

PMID: 23967202 - Miyagawa et al 2013 - report one case of a missense variant (NM_001851.3, c.2395G>C, p.G799R)in COL9A1 in a patient with sporadic early onset hearing loss, identified by targeted exome sequencing. Detailed phenotype information not available.

PMID: 31315069 - Hofrichter et al 2019 - report 2 patients with non-syndromic HL from an Iranian family. Both siblings were homozygous for a 44.6 kb in-frame deletion spanning exons 6 to 33 of COL9A1. The parents were heterozygous for the deletion. The initially presented non-syndromic HL at the age of 28 years, but clinical follow up has not been undertaken.
Hearing loss v2.74 COL9A1 Eleanor Williams reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16909383, 21421862, 23967202, 31315069; Phenotypes: Stickler syndrome, type IV, 614134, hearing loss; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v2.15 RNASEH2B Zornitza Stark reviewed gene: RNASEH2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29691679, 30223285, 29239743, 28762473; Phenotypes: Aicardi-Goutieres syndrome 2, MIM# 610181; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia - childhood onset v2.15 RAB3GAP2 Zornitza Stark reviewed gene: RAB3GAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32376645; Phenotypes: Martsolf syndrome, MIM# 212720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia - childhood onset v2.15 MAPK8IP3 Zornitza Stark gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693; 30945334
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities, MIM# 618443
Review for gene: MAPK8IP3 was set to GREEN
gene: MAPK8IP3 was marked as current diagnostic
Added comment: PMID: 30612693 - 13 unrelated children patients with de novo variants, supported by functional studies. Patients have developmental delay (13/13), spasticity (4/13), ataxia (2/13), unstable gait (1/13), microcephaly (3/13), generalized seizures (3/13). No signs of regression, but cerebellar atrophy (3/12), thin corpus callosum (4/10), perisylvian polymicrogyria (2/12), white matter loss (4/12) was noted

PMID: 30945334 - 5 child patients (4 families) with spastic diplegia (4/5), ID (5/5), epilepsy (2/5) and cerebellar atrophy (5/5), corpus callosum hypoplasia (5/5).

Overall 8/18 individuals with spasticity.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia - childhood onset v2.15 KLC2 Zornitza Stark gene: KLC2 was added
gene: KLC2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy, MIM#609541
Review for gene: KLC2 was set to GREEN
gene: KLC2 was marked as current diagnostic
Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Gene is associated with disease, however deletion may not be tractable by all testing methods and/or this association may be better defined as a CNV.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFIH1 were set to 25243380; 31427910; 24686847; 24995871
Phenotypes for gene: IFIH1 were set to Aicardi-Goutieres syndrome 7 MIM#615846
Review for gene: IFIH1 was set to GREEN
Added comment: At least four cases reported with spastic paraparesis as a feature of the condition.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 IBA57 Zornitza Stark reviewed gene: IBA57: Rating: GREEN; Mode of pathogenicity: None; Publications: 25609768, 30258207; Phenotypes: Spastic paraplegia 74, autosomal recessive MIM#616451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia - childhood onset v2.15 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233, Spastic paraplegia 13, autosomal dominant, MIM# 605280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary spastic paraplegia - childhood onset v2.15 GPT2 Zornitza Stark gene: GPT2 was added
gene: GPT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 29882329; 31471722; 27601654
Phenotypes for gene: GPT2 were set to Mental retardation, autosomal recessive 49 MIM#616281
Review for gene: GPT2 was set to GREEN
gene: GPT2 was marked as current diagnostic
Added comment: Paediatric onset spastic paraglegia is a prominent feature of the condition, >3 unrelated families reported.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 GLRX5 Zornitza Stark gene: GLRX5 was added
gene: GLRX5 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia 616859
Review for gene: GLRX5 was set to GREEN
gene: GLRX5 was marked as current diagnostic
Added comment: Spasticity is a key presenting feature of this condition.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 EXOSC3 Zornitza Stark gene: EXOSC3 was added
gene: EXOSC3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: EXOSC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC3 were set to 25149867; 23975261
Phenotypes for gene: EXOSC3 were set to Complicated hereditary spastic paraplegia
Review for gene: EXOSC3 was set to AMBER
Added comment: Two families with a complicated HSP phenotype.
Sources: Expert list
Hereditary spastic paraplegia - childhood onset v2.15 ELOVL1 Zornitza Stark gene: ELOVL1 was added
gene: ELOVL1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 29496980; 32123819; 30487246
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527
Review for gene: ELOVL1 was set to GREEN
gene: ELOVL1 was marked as current diagnostic
Added comment: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity. Affected individuals have mild facial dysmorphism.

Same two individuals reported in two publications. Both had the same variant, p.S165F, which arose de novo, suggesting the residue is important in pathogenesis. Mouse model.
Sources: Expert list
Intellectual disability v3.315 ZMYM2 Konstantinos Varvagiannis gene: ZMYM2 was added
gene: ZMYM2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Abnormality of the urinary system; Global developmental delay; Intellectual disability; Microcephaly; Abnormality of the cardiovascular system; Autism; Seizures; Abnormality of the head or neck; Abnormality of the nail; Small hand; Short foot; Clinodactyly
Penetrance for gene: ZMYM2 were set to unknown
Review for gene: ZMYM2 was set to AMBER
Added comment: Heterozygous pathogenic (pLoF) ZMYM2 variants have been reported in individuals with syndromic presentation including CAKUT (in several cases) and variable neurological manifestations among extra-renal features. DD and ID were reported in some of the families described to date as summarized below. You might consider inclusion with green/amber rating in the ID panel and green in the panel for CAKUT.

--

Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. [Article not reviewed in detail].

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Literature
Disorders of sex development v2.7 DHX37 Arina Puzriakova Classified gene: DHX37 as Amber List (moderate evidence)
Disorders of sex development v2.7 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review.
Disorders of sex development v2.7 DHX37 Arina Puzriakova Gene: dhx37 has been classified as Amber List (Moderate Evidence).
Disorders of sex development v2.6 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 31287541, 31745530, 31337883; Phenotypes: 46, XY sex reversal 11, 273250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.315 DHX37 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene (albeit association with monoallelic variants in 2 cases warrants further investigation).
Intellectual disability v3.315 DHX37 Arina Puzriakova Classified gene: DHX37 as Amber List (moderate evidence)
Intellectual disability v3.315 DHX37 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 6 unrelated cases with ID associated with variants in this gene.
Intellectual disability v3.315 DHX37 Arina Puzriakova Gene: dhx37 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.314 DHX37 Arina Puzriakova Tag for-review tag was added to gene: DHX37.
Intellectual disability v3.314 DHX37 Arina Puzriakova reviewed gene: DHX37: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891, 31256877; Phenotypes: Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, 618731; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency v2.193 TLR7 Arina Puzriakova Classified gene: TLR7 as Amber List (moderate evidence)
Primary immunodeficiency v2.193 TLR7 Arina Puzriakova Added comment: Comment on list classification: Phenotype is more relevant to a severe COVID-19 clinical course - this gene is already Green on the COVID-19 research panel (Version 1.69).
Therefore, rating Amber, but this can be reviewed if new evidence emerges.
Primary immunodeficiency v2.193 TLR7 Arina Puzriakova Gene: tlr7 has been classified as Amber List (Moderate Evidence).
Cardiomyopathies - including childhood onset v1.9 FNIP1 Arina Puzriakova Tag for-review tag was added to gene: FNIP1.
Cardiomyopathies - including childhood onset v1.9 FNIP1 Arina Puzriakova Classified gene: FNIP1 as Amber List (moderate evidence)
Cardiomyopathies - including childhood onset v1.9 FNIP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 5 unrelated cases with hypertrophic cardiomyopathy associated with biallelic FNIP1 variants, as well as supportive functional data and animal model.
Cardiomyopathies - including childhood onset v1.9 FNIP1 Arina Puzriakova Gene: fnip1 has been classified as Amber List (Moderate Evidence).
Cardiomyopathies - including childhood onset v1.8 FNIP1 Arina Puzriakova gene: FNIP1 was added
gene: FNIP1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FNIP1 were set to 32181500; 32905580
Phenotypes for gene: FNIP1 were set to Hypertrophic Cardiomyopathy; Primary Immunodeficiency; Agammaglobulinemia; Neutropenia
Review for gene: FNIP1 was set to GREEN
Added comment: - PMID: 32181500 (2020) - Three patients from two independent consanguineous families with homozygous variants (c.3353G>A, p.Ser1118Asn and c.1289delA, p.His430Profs7*) in the FNIP1 gene. Both variants segregated with the disease phenotype in each family. Clinically, patients presented with combined immunodeficiency, cardiac findings (hypertrophic cardiomyopathy, Wolff‐Parkinson‐White syndrome), and myopathy of skeletal muscles with motor DD. Authors note phenotypic overlap with the murine model of FNIP1 deficiency, but no functional analyses of the variants or patient cells were performed.

- PMID: 32905580 (2020) - Three cases from unrelated families, all harbouring novel biallelic variants in FNIP1. Clinical manifestations in all patients include hypertrophic cardiomyopathy, severe and/or recurrent infections, absent circulating B-cells, and agammaglobulinemia; as well as either severe or intermittent neutropenia in two cases. Functional studies showed impairment of B-cell metabolism, including disruptions to mitochondrial numbers/activity and the PI3K/AKT pathway.
Sources: Literature
Primary immunodeficiency v2.192 FNIP1 Arina Puzriakova Publications for gene: FNIP1 were set to 32905580
Primary immunodeficiency v2.191 FNIP1 Arina Puzriakova Classified gene: FNIP1 as Amber List (moderate evidence)
Primary immunodeficiency v2.191 FNIP1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 5 unrelated cases with immunodeficiency associated with biallelic FNIP1 variants, as well as supportive functional data and animal model.
Primary immunodeficiency v2.191 FNIP1 Arina Puzriakova Gene: fnip1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.190 FNIP1 Arina Puzriakova Tag for-review tag was added to gene: FNIP1.
Primary immunodeficiency v2.190 FNIP1 Arina Puzriakova reviewed gene: FNIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32181500, 32905580; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency v2.190 TOM1 Arina Puzriakova Classified gene: TOM1 as Red List (low evidence)
Primary immunodeficiency v2.190 TOM1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single family reported. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency v2.190 TOM1 Arina Puzriakova Gene: tom1 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.189 TOM1 Arina Puzriakova reviewed gene: TOM1: Rating: ; Mode of pathogenicity: None; Publications: 31263572; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency v2.189 TNFSF13 Arina Puzriakova Classified gene: TNFSF13 as Red List (low evidence)
Primary immunodeficiency v2.189 TNFSF13 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but currently only a single case. Therefore, rating Red awaiting additional cases/clinical evidence to validate pathogenicity.
Primary immunodeficiency v2.189 TNFSF13 Arina Puzriakova Gene: tnfsf13 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.188 TNFSF13 Arina Puzriakova reviewed gene: TNFSF13: Rating: ; Mode of pathogenicity: None; Publications: 32298700; Phenotypes: Common variable immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v2.15 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: RED; Mode of pathogenicity: None; Publications: 25751282; Phenotypes: Spastic paraplegia 73, autosomal dominant, 616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic epilepsy syndromes v2.152 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to AMBER
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.314 LMNB1 Konstantinos Varvagiannis gene: LMNB1 was added
gene: LMNB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMNB1 were set to 32910914
Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis
Penetrance for gene: LMNB1 were set to unknown
Mode of pathogenicity for gene: LMNB1 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: LMNB1 was set to GREEN
Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants.

The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some.

Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies).

LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development.

Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development.

Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants.

Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells).

LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu).

Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency).

Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc.
Sources: Literature
Intellectual disability v3.314 SPTBN4 Konstantinos Varvagiannis edited their review of gene: SPTBN4: Added comment: ** Consider also the GeneReview on this disorder - PMID : 32672909; Changed publications: 28540413, 28940097, 29861105, 31230720, 31857255, 32672909
Primary immunodeficiency v2.188 TET2 Arina Puzriakova changed review comment from: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel.

Rating Amber in anticipation of further publications/clinical evidence.; to: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel. Rating Amber in anticipation of further publications/clinical evidence.
Primary immunodeficiency v2.188 TET2 Arina Puzriakova Classified gene: TET2 as Amber List (moderate evidence)
Primary immunodeficiency v2.188 TET2 Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion of this gene on a diagnostic panel.

Rating Amber in anticipation of further publications/clinical evidence.
Primary immunodeficiency v2.188 TET2 Arina Puzriakova Gene: tet2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.187 TET2 Arina Puzriakova changed review comment from: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T,
p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.; to: PMID: 32518946 (2020) - Three cases from two unrelated consanguineous families with immunodeficiency and lymphoproliferative disease, associated with homozygous variants (c.4145A>G, p.H1382R and c.4894C>T, p.Q1632*) in the TET2 gene. Molecular studies showed that the variants result in altered DNA methylation and B-cell maturation, as well as skewed T-cell differentiation and hematopoiesis.
Primary immunodeficiency v2.187 TET2 Arina Puzriakova reviewed gene: TET2: Rating: ; Mode of pathogenicity: None; Publications: 32518946; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency v2.187 MCM10 Arina Puzriakova Classified gene: MCM10 as Red List (low evidence)
Primary immunodeficiency v2.187 MCM10 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency v2.187 MCM10 Arina Puzriakova Gene: mcm10 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.186 MAPK8 Arina Puzriakova Classified gene: MAPK8 as Red List (low evidence)
Primary immunodeficiency v2.186 MAPK8 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency v2.186 MAPK8 Arina Puzriakova Gene: mapk8 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.185 MAPK8 Arina Puzriakova reviewed gene: MAPK8: Rating: ; Mode of pathogenicity: None; Publications: 31784499; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteopetrosis v0.10 Sarah Leigh removed gene:IKBKG from the panel
Osteopetrosis v0.9 IKBKG Sarah Leigh changed review comment from: GMS specialist disease group expert has requested that this gene should be deleted from this panel (email 16/09/2020). This is due to the issue of the presence of a pseudogene.; to: GMS specialist disease group experts has requested that this gene should be deleted from this panel (email 16/09/2020). This is due to the issue of the presence of a pseudogene.
Osteopetrosis v0.9 IKBKG Sarah Leigh commented on gene: IKBKG
Primary immunodeficiency v2.185 CTNNBL1 Arina Puzriakova Classified gene: CTNNBL1 as Red List (low evidence)
Primary immunodeficiency v2.185 CTNNBL1 Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel, but additional cases required to validate pathogenicity.
Primary immunodeficiency v2.185 CTNNBL1 Arina Puzriakova Gene: ctnnbl1 has been classified as Red List (Low Evidence).
Primary immunodeficiency v2.184 CTNNBL1 Arina Puzriakova reviewed gene: CTNNBL1: Rating: ; Mode of pathogenicity: None; Publications: 32484799; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Tag watchlist tag was added to gene: PLEKHM1.
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Tag watchlist tag was added to gene: PLEKHM1.
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Classified gene: PLEKHM1 as Amber List (moderate evidence)
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts. They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity was not reported (PMID 32415263).; to: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts (email 16/09/20200). They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Classified gene: PLEKHM1 as Amber List (moderate evidence)
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: This rating change from Green to Amber has been suggested by the GMS specialist disease group experts. They have not found PLEKHM1 variants in 257 diagnostic and familial cases listed in the OP database.
Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity was not reported (PMID 32415263).
Osteopetrosis v0.9 PLEKHM1 Sarah Leigh Gene: plekhm1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.18 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159; 28290981
Osteopetrosis v0.8 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to
Osteopetrosis v0.7 TCIRG1 Sarah Leigh Publications for gene: TCIRG1 were set to
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova changed review comment from: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red/Amber.; to: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red.
Skeletal dysplasia v2.17 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709; 21054159
Haematological malignancies cancer susceptibility v2.5 TSR2 Arina Puzriakova Phenotypes for gene: TSR2 were changed from Class: BM failure syndrome (typ AR); Diamond Blackfan Anemia; MDS, AML, Leukemia risk not well defined; Osteosarcoma, soft tissue sarcomas to Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, 300946
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Classified gene: TSR2 as Green List (high evidence)
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Added comment: Comment on list classification: Currently only one family reported (PMID:24942156) and leukemia risk not well defined - therefore recommending a rating downgrade from Green to Red/Amber.
Haematological malignancies cancer susceptibility v2.4 TSR2 Arina Puzriakova Gene: tsr2 has been classified as Green List (High Evidence).
Skeletal dysplasia v2.16 PLEKHM1 Sarah Leigh Publications for gene: PLEKHM1 were set to 17404618; 27291868; 17997709
Bleeding and platelet disorders v1.9 IKZF5 Arina Puzriakova Publications for gene: IKZF5 were set to 1217188
Bleeding and platelet disorders v1.8 IKZF5 Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 unrelated families with thrombocytopenia associated with different missense variants in the IKZF5 gene.
Bleeding and platelet disorders v1.8 COL3A1 Arina Puzriakova Phenotypes for gene: COL3A1 were changed from 130050 Ehlers-Danlos syndrome, vascular type to Ehlers-Danlos syndrome, vascular type, 130050
Bleeding and platelet disorders v1.7 COL3A1 Arina Puzriakova reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29050841, 27259332, 31391389, 25940258, 20720362; Phenotypes: Ehlers-Danlos syndrome, vascular type, 130050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v1.69 DOCK8 Sarah Leigh Phenotypes for gene: DOCK8 were changed from Combined immunodeficiency; Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper IgE syndrome (HIES); Immunodeficiencies affecting cellular and humoral immunity; Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections to Hyper-IgE recurrent infection syndrome, autosomal recessive 243700; Combined immunodeficiency; Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper IgE syndrome (HIES); Immunodeficiencies affecting cellular and humoral immunity; Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections
Bleeding and platelet disorders v1.7 CHST14 Arina Puzriakova Phenotypes for gene: CHST14 were changed from 601776 Ehlers-Danlos syndrome, musculocontractural type 1 to Ehlers-Danlos syndrome, musculocontractural type 1, 601776
Bleeding and platelet disorders v1.6 CHST14 Arina Puzriakova Tag for-review tag was added to gene: CHST14.
Bleeding and platelet disorders v1.6 CHST14 Arina Puzriakova reviewed gene: CHST14: Rating: GREEN; Mode of pathogenicity: None; Publications: 20004762, 26373698, 26646600; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v2.15 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 28158749, 27640307; Phenotypes: Harel-Yoon syndrome, MIM# 617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia - childhood onset v2.15 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26085577; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia - childhood onset v2.15 ALDH3A2 Zornitza Stark gene: ALDH3A2 was added
gene: ALDH3A2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH3A2 were set to 8528251; 29704247
Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome, MIM#270200
Review for gene: ALDH3A2 was set to GREEN
Added comment: Early-onset spastic paraparesis is a feature of the condition. >3 families reported with biallelic variants.
Sources: Expert list
Intellectual disability v3.314 CAMK2G Arina Puzriakova Publications for gene: CAMK2G were set to 26350204; 24896178; 23033978
Intellectual disability v3.313 CAMK2G Arina Puzriakova Phenotypes for gene: CAMK2G were changed from to Mental retardation, autosomal dominant 59, 618522
Intellectual disability v3.312 CAMK2G Arina Puzriakova Mode of pathogenicity for gene: CAMK2G was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v3.311 CAMK2G Arina Puzriakova Classified gene: CAMK2G as Amber List (moderate evidence)
Intellectual disability v3.311 CAMK2G Arina Puzriakova Added comment: Comment on list classification: Rating has been upgraded from Red to Amber based on the review by Konstantinos Varvagiannis - two unrelated individuals with severe ID, associated with de novo CAMK2G variants, with addition of functional data.
Intellectual disability v3.311 CAMK2G Arina Puzriakova Gene: camk2g has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.310 FIBP Arina Puzriakova Classified gene: FIBP as Amber List (moderate evidence)
Intellectual disability v3.310 FIBP Arina Puzriakova Added comment: Comment on list classification: Rating upgraded from Red to Amber based on review by Zornitza Stark.
Intellectual disability v3.310 FIBP Arina Puzriakova Gene: fibp has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.309 FIBP Arina Puzriakova Phenotypes for gene: FIBP were changed from Thauvin-Robinet-Faivre syndrome to Thauvin-Robinet-Faivre syndrome, 617107
Intellectual disability v3.308 FIBP Arina Puzriakova Added comment: Comment on publications: Two publications (PMID: 26660953; 27183861) describing four individuals from two unrelated families.
Intellectual disability v3.308 FIBP Arina Puzriakova Publications for gene: FIBP were set to 26660953
Intellectual disability v3.307 TANC2 Arina Puzriakova Tag watchlist tag was added to gene: TANC2.
Genetic epilepsy syndromes v2.152 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Intellectual disability v3.307 TANC2 Arina Puzriakova Phenotypes for gene: TANC2 were changed from NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay to Intellectual developmental disorder with autistic features and language delay, with or without seizures, 618906
Intellectual disability v3.306 VAMP1 Arina Puzriakova Tag watchlist tag was added to gene: VAMP1.
Intellectual disability v3.306 VAMP1 Arina Puzriakova Phenotypes for gene: VAMP1 were changed from congenital myasthenic syndrome (CMS) and delayed development to Myasthenic syndrome, congenital, 25, 618323
Intellectual disability v3.305 VAMP1 Arina Puzriakova Publications for gene: VAMP1 were set to 28253535
Intellectual disability v3.304 VAMP1 Arina Puzriakova Classified gene: VAMP1 as Green List (high evidence)
Intellectual disability v3.304 VAMP1 Arina Puzriakova Added comment: Comment on list classification: Literature search revealed that developmental delay primarily affects motor function, and it is unclear whether patients exhibit any cognitive deficit. Additional cases would help delineate the association with this phenotype.

Therefore, recommending a rating downgrade from Green to Amber/Red at the next major review, awaiting further publications/clinical evidence.
Intellectual disability v3.304 VAMP1 Arina Puzriakova Gene: vamp1 has been classified as Green List (High Evidence).
Intellectual disability v3.303 VAMP1 Arina Puzriakova Tag for-review tag was added to gene: VAMP1.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Tag for-review tag was added to gene: TRIM32.
Intellectual disability v3.303 TRIM32 Arina Puzriakova Phenotypes for gene: TRIM32 were changed from BARDET-BIEDL SYNDROME TYPE 11 (BBS11) to Bardet-Biedl syndrome 11, 615988
Intellectual disability v3.302 TRIM32 Arina Puzriakova Publications for gene: TRIM32 were set to 0
Intellectual disability v3.301 TRIM32 Arina Puzriakova Classified gene: TRIM32 as Green List (high evidence)
Intellectual disability v3.301 TRIM32 Arina Puzriakova Added comment: Comment on list classification: Recommended Green-to-Red rating downgrade on the next major review - only one family reported to date for association with BBS. Currently also Red on the Bardet-Biedl Syndrome (Version 1.5) gene panel.
Intellectual disability v3.301 TRIM32 Arina Puzriakova Gene: trim32 has been classified as Green List (High Evidence).
Intellectual disability v3.300 VARS2 Arina Puzriakova Classified gene: VARS2 as Amber List (moderate evidence)
Intellectual disability v3.300 VARS2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - >3 unrelated families with different variants. Severe psychomotor delay was an early and significant manifestation on clinical evaluation.
Intellectual disability v3.300 VARS2 Arina Puzriakova Gene: vars2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.299 VARS2 Arina Puzriakova Tag for-review tag was added to gene: VARS2.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Classified gene: SUCLA2 as Amber List (moderate evidence)
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Added comment: Comment on list classification: Although sufficient number of cases with relevant clinical presentation, psychomotor delay is a component of a broader phenotype. Patients are more likely to be recognised via other routes (Metabolic/White Matter Disorders/Mitochondrial) - SUCLA2 is already Green on these PanelApp panels.

Therefore, rating Amber on the ID panel.
Intellectual disability v3.299 SUCLA2 Arina Puzriakova Gene: sucla2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.13 LARS2 Sarah Leigh Tag for-review tag was added to gene: LARS2.
Ataxia and cerebellar anomalies - narrow panel v2.13 LARS2 Sarah Leigh edited their review of gene: LARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
White matter disorders - adult onset v1.6 LARS2 Sarah Leigh Publications for gene: LARS2 were set to 32442335; 30737337
Ataxia and cerebellar anomalies - narrow panel v2.13 LARS2 Sarah Leigh Classified gene: LARS2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.13 LARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Perrault syndrome. At least 6 variants reported as compound heterozygotes in three unrelated cases whose varied phenotypes included ataxia (PMID 30737337).
Ataxia and cerebellar anomalies - narrow panel v2.13 LARS2 Sarah Leigh Gene: lars2 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v1.4 CSNK1D Sarah Leigh reviewed gene: CSNK1D: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Paroxysmal central nervous system disorders v1.4 CSNK1D Sarah Leigh Tag for-review tag was added to gene: CSNK1D.
White matter disorders and cerebral calcification - narrow panel v1.14 VPS11 Zornitza Stark reviewed gene: VPS11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27120463, 26307567, 27473128; Phenotypes: Leukodystrophy, hypomyelinating, 12, MIM# 616683; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 WARS2 Zornitza Stark gene: WARS2 was added
gene: WARS2 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WARS2 were set to 31282308; 28650581; 30920170
Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, MIM# 617710
Review for gene: WARS2 was set to GREEN
gene: WARS2 was marked as current diagnostic
Added comment: At least three affected individuals where white matter changes were a prominent feature of the phenotype.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 GNB1 Shekeeb Mohammad reviewed gene: GNB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31034681, 27668284; Phenotypes: Myoclonus, Dystonia, Childhood onset dystonia, Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v1.14 ZFYVE26 Zornitza Stark reviewed gene: ZFYVE26: Rating: GREEN; Mode of pathogenicity: None; Publications: 19084844; Phenotypes: Spastic paraplegia 15, autosomal recessive, MIM# 270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 UFM1 Zornitza Stark gene: UFM1 was added
gene: UFM1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: UFM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFM1 were set to 28931644; 29868776
Phenotypes for gene: UFM1 were set to Leukodystrophy, hypomyelinating, 14, MIM# 617899
Review for gene: UFM1 was set to GREEN
gene: UFM1 was marked as current diagnostic
Added comment: 16 children from Roma descent reported initially, all had homozygous 3bp deletion in the promoter of UFM1 (founder). Another 4 individuals from 2 Sudanese families reported subsequently, with missense variant in gene.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 TUFM Zornitza Stark reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: 28132884, 26741492, 17160893; Phenotypes: Combined oxidative phosphorylation deficiency 4, MIM# 610678, Mitochondrial Leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - narrow panel v1.14 TMEM63A Zornitza Stark gene: TMEM63A was added
gene: TMEM63A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: TMEM63A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM63A were set to 31587869
Phenotypes for gene: TMEM63A were set to Leukodystrophy, hypomyelinating, 19, transient infantile, MIM# 618688
Review for gene: TMEM63A was set to GREEN
Added comment: 4 unrelated patients with infantile-onset leukodystrophy with heterozygous variants, three of which were de novo.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 TMEM106B Zornitza Stark edited their review of gene: TMEM106B: Changed mode of pathogenicity: Other
White matter disorders and cerebral calcification - narrow panel v1.14 TMEM106B Zornitza Stark reviewed gene: TMEM106B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29186371, 29444210, 28728022, 30643851; Phenotypes: Leukodystrophy, hypomyelinating, 16 617964; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v1.14 SPG11 Zornitza Stark reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 18067136; Phenotypes: Spastic paraplegia 11, autosomal recessive, MIM# 604360; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 SPART Zornitza Stark reviewed gene: SPART: Rating: GREEN; Mode of pathogenicity: None; Publications: 28875386, 15372254; Phenotypes: Troyer syndrome 275900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 SNORD118 Zornitza Stark reviewed gene: SNORD118: Rating: GREEN; Mode of pathogenicity: None; Publications: 27571260; Phenotypes: Leukoencephalopathy, brain calcifications, and cysts 614561; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 SDHA Zornitza Stark reviewed gene: SDHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22972948; Phenotypes: Mitochondrial respiratory chain complex II deficiency, MIM#252011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 RPIA Zornitza Stark gene: RPIA was added
gene: RPIA was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: RPIA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPIA were set to 31247379; 14988808; 31056085
Phenotypes for gene: RPIA were set to Ribose 5-phosphate isomerase deficiency, MIM# 608611
Review for gene: RPIA was set to GREEN
Added comment: Four unrelated individuals described to date, variable onset of leukodystrophy in childhood/adolescence, though other symptoms generally precede.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 RAB11B Zornitza Stark reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter 617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
White matter disorders and cerebral calcification - narrow panel v1.14 PTEN Zornitza Stark gene: PTEN was added
gene: PTEN was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTEN were set to 29720545; 29152901; 30664625
Phenotypes for gene: PTEN were set to Cowden syndrome 1, MIM# 158350
Review for gene: PTEN was set to GREEN
gene: PTEN was marked as current diagnostic
Added comment: White matter changes described in many individuals.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 POLH Zornitza Stark reviewed gene: POLH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, variant type 278750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 NFU1 Zornitza Stark gene: NFU1 was added
gene: NFU1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 21944046; 22077971; 32747156; 29441221
Phenotypes for gene: NFU1 were set to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711
Review for gene: NFU1 was set to GREEN
gene: NFU1 was marked as current diagnostic
Added comment: Bi-allelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death. Cavitating leukodystrophy and other white matter changes described in multiple affected individuals.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 NAXE Zornitza Stark reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27122014, 27616477, 31758406; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 NAXD Zornitza Stark gene: NAXD was added
gene: NAXD was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Review for gene: NAXD was set to GREEN
gene: NAXD was marked as current diagnostic
Added comment: Six unrelated families reported.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 MPLKIP Zornitza Stark reviewed gene: MPLKIP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 4, nonphotosensitive 234050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 KIF5A Zornitza Stark gene: KIF5A was added
gene: KIF5A was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5A were set to 27463701; 27414745
Phenotypes for gene: KIF5A were set to Myoclonus, intractable, neonatal, MIM# 617235
Review for gene: KIF5A was set to GREEN
gene: KIF5A was marked as current diagnostic
Added comment: Variants in KIF5A cause a range of phenotypes with variable range of onset including spastic paraplegia and neuropathy. Three unrelated families reported with de novo frame-shifts in the C-terminal domain of KIF5A and neonatal intractable myoclonus, a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants had intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging showed a progressive leukoencephalopathy.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 ISCA2 Zornitza Stark reviewed gene: ISCA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25539947, 29297947, 29122497, 29359243; Phenotypes: Multiple mitochondrial dysfunctions syndrome 4, MIM# 616370; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ISCA1 Zornitza Stark gene: ISCA1 was added
gene: ISCA1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122
Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613
Review for gene: ISCA1 was set to GREEN
gene: ISCA1 was marked as current diagnostic
Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families.
Sources: Expert list
Hearing loss v2.74 COL2A1 Eleanor Williams edited their review of gene: COL2A1: Changed rating: AMBER; Changed publications: 23110709, 27408751, 20179744; Changed phenotypes: Stickler syndrome, type I, 108300; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.74 COL2A1 Eleanor Williams commented on gene: COL2A1
Primary immunodeficiency v2.184 CTNNBL1 Boaz Palterer edited their review of gene: CTNNBL1: Changed rating: RED
White matter disorders - adult onset v1.5 LARS2 Sarah Leigh edited their review of gene: LARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
White matter disorders - adult onset v1.5 LARS2 Sarah Leigh Tag for-review tag was added to gene: LARS2.
White matter disorders - adult onset v1.5 LARS2 Sarah Leigh Classified gene: LARS2 as Amber List (moderate evidence)
White matter disorders - adult onset v1.5 LARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Perrault syndrome. At least 10 variants reported as compound heterozygotes in five unrelated cases whose varied phenotypes included leukodystrophy (PMIDs 32442335;30737337).
White matter disorders - adult onset v1.5 LARS2 Sarah Leigh Gene: lars2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.7 SVIL Sarah Leigh Tag watchlist tag was added to gene: SVIL.
Congenital myopathy v2.7 SVIL Sarah Leigh Classified gene: SVIL as Amber List (moderate evidence)
Congenital myopathy v2.7 SVIL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two terminating variants reported in two unrelated, consanguineous families with a childhood/adolescence onset myopathy (PMID 32779703).
Congenital myopathy v2.7 SVIL Sarah Leigh Gene: svil has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.6 DHX16 Sarah Leigh Classified gene: DHX16 as Amber List (moderate evidence)
Congenital myopathy v2.6 DHX16 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing. No functional studies were reported.
Congenital myopathy v2.6 DHX16 Sarah Leigh Gene: dhx16 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.14 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18571143, 27405012, 32532876, 28377887, 27405012; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - narrow panel v1.14 HIKESHI Zornitza Stark gene: HIKESHI was added
gene: HIKESHI was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, MIM# 616881
Review for gene: HIKESHI was set to GREEN
gene: HIKESHI was marked as current diagnostic
Added comment: Six children from three unrelated Ashkenazi Jewish families reported, segregating same homozygous variant. Neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. Other features: visual impairment; cardiac failure during acute illness.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 GTF2H5 Zornitza Stark reviewed gene: GTF2H5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 3, photosensitive 616395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 GLRX5 Zornitza Stark gene: GLRX5 was added
gene: GLRX5 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia, MIM# 616859
Review for gene: GLRX5 was set to GREEN
gene: GLRX5 was marked as current diagnostic
Added comment: PMID: 24334290 - 3 patients (3 families) with non-ketotic hyperglycinemia, supported by functional studies. Patients had normal development with childhood-onset spastic paraplegia (3/3), spinal lesion (1/3), optic atrophy (1/3) and brain signal abnormalities involving the frontal and parietal white matter (2/3)

PMID: 30770271 - 1 patient with childhood onset cavitating leukoencephalopathy.

p.Lys51del is a recurring variant.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 GLB1 Zornitza Stark gene: GLB1 was added
gene: GLB1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: GLB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLB1 were set to 25691190
Phenotypes for gene: GLB1 were set to GM1-gangliosidosis, type I, MIM# 230500; GM1-gangliosidosis, type II, MIM# 230600
Review for gene: GLB1 was set to GREEN
gene: GLB1 was marked as current diagnostic
Added comment: Well established gene-disease association, white matter changes are a feature.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 30740813; 29688489
Phenotypes for gene: FIG4 were set to Charcot-Marie-Tooth disease, type 4J 611228; Yunis-Varon syndrome 216340; leukoencephalopathy
Review for gene: FIG4 was set to GREEN
gene: FIG4 was marked as current diagnostic
Added comment: Four unrelated families reported with bi-allelic variants in this gene and a leukoencephalopathy phenotype. Mouse model recapitulates the phenotype. Please note gene is associated with multiple other phenotypes including Yunis-Varon syndrome, CMT, ALS
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 FA2H Zornitza Stark reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: None; Publications: 31837835, 30446360, 22965561, 21592092; Phenotypes: Spastic paraplegia 35, autosomal recessive, MIM# 612319; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrooculofacioskeletal syndrome 3 616570, Xeroderma pigmentosum, group G 278780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ERCC4 Zornitza Stark reviewed gene: ERCC4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Xeroderma pigmentosum, group F, MIM# 278760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ERCC3 Zornitza Stark reviewed gene: ERCC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Trichothiodystrophy 2, photosensitive 616390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ERCC2 Zornitza Stark reviewed gene: ERCC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 29451896; Phenotypes: Trichothiodystrophy 1, photosensitive 601675; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 ERCC1 Zornitza Stark reviewed gene: ERCC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrooculofacioskeletal syndrome 4 610758; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 EPRS Zornitza Stark gene: EPRS was added
gene: EPRS was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: EPRS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPRS were set to 29576217
Phenotypes for gene: EPRS were set to Leukodystrophy, hypomyelinating, 15, MIM# 617951
Review for gene: EPRS was set to GREEN
gene: EPRS was marked as current diagnostic
Added comment: Four unrelated families reported with this neurodegenerative disorder. Onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, dysphagia, severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 DEGS1 Zornitza Stark gene: DEGS1 was added
gene: DEGS1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620338; 30620337
Phenotypes for gene: DEGS1 were set to Leukodystrophy, hypomyelinating, 18, MIM#618404
Review for gene: DEGS1 was set to GREEN
gene: DEGS1 was marked as current diagnostic
Added comment: 20 individuals from 14 unrelated families. Hypomyelinating leukodystorphy is the prominent feature of this condition.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 DCAF17 Zornitza Stark gene: DCAF17 was added
gene: DCAF17 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: DCAF17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCAF17 were set to 19026396; 20507343
Phenotypes for gene: DCAF17 were set to Woodhouse-Sakati syndrome, MIM# 241080
Review for gene: DCAF17 was set to GREEN
gene: DCAF17 was marked as current diagnostic
Added comment: White matter changes are part of the phenotype.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 CYP7B1 Zornitza Stark reviewed gene: CYP7B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24117163, 19439420, 19187859; Phenotypes: Spastic paraplegia 5A, autosomal recessive, MIM# 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - narrow panel v1.14 COA7 Zornitza Stark gene: COA7 was added
gene: COA7 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: COA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COA7 were set to 27683825; 29718187
Phenotypes for gene: COA7 were set to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MIM#618387
Review for gene: COA7 was set to GREEN
gene: COA7 was marked as current diagnostic
Added comment: At least 3 unrelated cases reported with leukoencephalopathy as a feature of the condition. Paediatric age of onset.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 CNTNAP1 Zornitza Stark reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28374019, 29882456; Phenotypes: Hypomyelinating neuropathy, congenital, 3, MIM# 618186, Lethal congenital contracture syndrome 7, MIM# 616286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.14 CLPP Zornitza Stark gene: CLPP was added
gene: CLPP was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 27899912
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
gene: CLPP was marked as current diagnostic
Added comment: Prominent white matter changes identified in at least three unrelated individuals.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 BOLA3 Zornitza Stark reviewed gene: BOLA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30302924, 29654549, 30302924; Phenotypes: Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, MIM# 614299; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
White matter disorders and cerebral calcification - narrow panel v1.14 APOPT1 Zornitza Stark gene: APOPT1 was added
gene: APOPT1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347
Phenotypes for gene: APOPT1 were set to Mitochondrial complex IV deficiency, MIM# 220110
Review for gene: APOPT1 was set to GREEN
gene: APOPT1 was marked as current diagnostic
Added comment: Cavitating leukodystrophy reported as part of this mitochondrial disorder, onset described as late infancy/early childhood.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 29193663
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive MIM#614066
Review for gene: AP4B1 was set to GREEN
gene: AP4B1 was marked as current diagnostic
Added comment: White matter changes have been reported as a feature of the condition in at least ten unrelated cases with biallelic variants. The onset of the condition is in childhood.
Sources: Expert list
Intellectual disability v3.298 FRY Arina Puzriakova Publications for gene: FRY were set to 21937992
Intellectual disability v3.297 FRY Arina Puzriakova Classified gene: FRY as Amber List (moderate evidence)
Intellectual disability v3.297 FRY Arina Puzriakova Gene: fry has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.296 ELN Arina Puzriakova Classified gene: ELN as Red List (low evidence)
Intellectual disability v3.296 ELN Arina Puzriakova Gene: eln has been classified as Red List (Low Evidence).
Intellectual disability v3.295 ELN Arina Puzriakova changed review comment from: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark; to: Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark and Konstantinos Varvagiannis.
White matter disorders and cerebral calcification - narrow panel v1.14 AIFM1 Zornitza Stark gene: AIFM1 was added
gene: AIFM1 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AIFM1 were set to 28842795; 27102849
Phenotypes for gene: AIFM1 were set to Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, MIM# 300232
Review for gene: AIFM1 was set to GREEN
Added comment: Seven unrelated families reported with X-linked spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy (SEMDHL), an X-linked recessive developmental disorder characterised by slowly progressive skeletal and neurologic abnormalities, including short stature, large and deformed joints, significant motor impairment, visual defects, and sometimes cognitive deficits. Affected individuals typically have normal early development in the first year or so of life, followed by development regression and the development of symptoms. Brain imaging shows white matter abnormalities consistent with hypomyelinating leukodystrophy.
Sources: Expert list
White matter disorders and cerebral calcification - narrow panel v1.14 AARS Zornitza Stark gene: AARS was added
gene: AARS was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 28493438; 25817015
Phenotypes for gene: AARS were set to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Review for gene: AARS was set to GREEN
gene: AARS was marked as current diagnostic
Added comment: Bi-allelic variants associated with a severe phenotype comprising leukodystrophy, epilepsy, microcephaly and neurodevelopmental delay reported in three families.
Sources: Expert list
Haematological malignancies cancer susceptibility v2.3 TSR2 Zornitza Stark reviewed gene: TSR2: Rating: RED; Mode of pathogenicity: None; Publications: 24942156; Phenotypes: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis, MIM# 300946; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Cytopenia - NOT Fanconi anaemia v1.6 SRP54 Zornitza Stark gene: SRP54 was added
gene: SRP54 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: SRP54 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRP54 were set to 28972538
Phenotypes for gene: SRP54 were set to Syndromic neutropenia with Shwachman-Diamond-like features
Review for gene: SRP54 was set to GREEN
gene: SRP54 was marked as current diagnostic
Added comment: 3 unrelated families presented with neutropaenia associated with other symptoms, including exocrine pancreatic deficiency and/or autistic behavior, phenotypic overlap with Swachman-Diamond syndrome.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C, functional impact of this variant is likely deleterious but not proven. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark edited their review of gene: RPL9: Changed rating: RED
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. ; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad. PMID 23718193, cannot find RPL9 variant in main results table.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark changed review comment from: PMID: 29114930, de novo splice site variant, c.-2+1G>C.; to: PMID: 29114930, de novo splice site variant, c.-2+1G>C. Inherited missense variant reported in PMID 20116044, p.Arg125Ser is present in 31 hets in gnomad.
Cytopenia - NOT Fanconi anaemia v1.6 RPL9 Zornitza Stark reviewed gene: RPL9: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diamond Blackfan anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 RPL31 Zornitza Stark reviewed gene: RPL31: Rating: AMBER; Mode of pathogenicity: None; Publications: 25042156, 25424902; Phenotypes: Diamond Blackfan anaemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 RPL26 Zornitza Stark reviewed gene: RPL26: Rating: RED; Mode of pathogenicity: None; Publications: 22431104; Phenotypes: Diamond-Blackfan anemia 11, MIM# 614900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cytopenia - NOT Fanconi anaemia v1.6 NPM1 Zornitza Stark gene: NPM1 was added
gene: NPM1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: NPM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPM1 were set to 31570891
Phenotypes for gene: NPM1 were set to radial ray defects; short stature; nail dsytrophy; bone marrow failure
Review for gene: NPM1 was set to GREEN
gene: NPM1 was marked as current diagnostic
Added comment: Two unrelated individuals with a dyskeratosis congenita phenotype and extensive functional data to support gene-disease relationship.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 NOP10 Zornitza Stark reviewed gene: NOP10: Rating: RED; Mode of pathogenicity: None; Publications: 17507419; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cytopenia - NOT Fanconi anaemia v1.6 NHP2 Zornitza Stark reviewed gene: NHP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18523010, 31985013; Phenotypes: Dyskeratosis congenita, autosomal recessive 2, MIM# 613987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 MYSM1 Zornitza Stark reviewed gene: MYSM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24288411, 28115216, 26220525, 32640305; Phenotypes: Bone marrow failure syndrome 4, MIM#618116; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 KIF23 Zornitza Stark reviewed gene: KIF23: Rating: RED; Mode of pathogenicity: None; Publications: 23570799; Phenotypes: Congenital dyserythropoietic anemia type III; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.6 HOXA11 Zornitza Stark reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832; Phenotypes: Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, MIM# 605432; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia - adult onset v2.9 ERCC4 Zornitza Stark gene: ERCC4 was added
gene: ERCC4 was added to Hereditary ataxia - adult onset. Sources: Expert list
Mode of inheritance for gene: ERCC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC4 were set to 29403087; 28431612; 29892709
Phenotypes for gene: ERCC4 were set to Cerebellar ataxia; Xeroderma pigmentosum, group F, MIM# 278760
Review for gene: ERCC4 was set to GREEN
gene: ERCC4 was marked as current diagnostic
Added comment: Bi-allelic variants in ERCC4 cause a range of phenotypes, including xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anaemia. Seven unrelated individuals reported with slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with onset in adolescence/adulthood. Brain MRIs demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild in 5/7: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn.
Sources: Expert list
Cytopenia - NOT Fanconi anaemia v1.6 DDX41 Zornitza Stark reviewed gene: DDX41: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698430, 31484648; Phenotypes: {Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to} MIM# 616871; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Cytopenia - NOT Fanconi anaemia v1.6 AK2 Zornitza Stark gene: AK2 was added
gene: AK2 was added to Cytopenia - NOT Fanconi anaemia. Sources: Expert list
Mode of inheritance for gene: AK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AK2 were set to 19043416
Phenotypes for gene: AK2 were set to Reticular dysgenesis, MIM# 267500
Review for gene: AK2 was set to GREEN
gene: AK2 was marked as current diagnostic
Added comment: Well established gene-disease association.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 AP1S2 Zornitza Stark reviewed gene: AP1S2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mental retardation, X-linked syndromic 5, Pettigrew syndrome, 304340; Mode of inheritance: None
Hereditary ataxia - adult onset v2.9 AMPD2 Zornitza Stark reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hyoplasia 9, 615809; Mode of inheritance: None
Hereditary ataxia - adult onset v2.9 ADGRG1 Zornitza Stark reviewed gene: ADGRG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia - adult onset v2.9 ABCB7 Zornitza Stark reviewed gene: ABCB7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Anemia, sideroblastic, with ataxia 301310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v2.12 XRCC1 Zornitza Stark reviewed gene: XRCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28002403, 29472272; Phenotypes: Spinocerebellar ataxia, autosomal recessive 26 MIM#617633; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia - adult onset v2.9 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: RED; Mode of pathogenicity: None; Publications: 28007905, 23359680, 11555633; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM#615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 UCHL1 Zornitza Stark reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28007905, 23359680, 11555633; Phenotypes: Spastic paraplegia 79, autosomal recessive, MIM#615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v2.12 UBTF Zornitza Stark gene: UBTF was added
gene: UBTF was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: UBTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBTF were set to 29300972
Phenotypes for gene: UBTF were set to Neurodegeneration, childhood-onset, with brain atrophy MIM#617672
Review for gene: UBTF was set to GREEN
gene: UBTF was marked as current diagnostic
Added comment: Paediatric ataxia reported as a feature of the condition in 4 unrelated cases with de novo missense variants.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 TMEM106B Zornitza Stark gene: TMEM106B was added
gene: TMEM106B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TMEM106B were set to 29186371; 29444210
Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16, MIM# 617964
Review for gene: TMEM106B was set to GREEN
gene: TMEM106B was marked as current diagnostic
Added comment: Cerebellar signs including ataxia prominent.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 TGM6 Zornitza Stark reviewed gene: TGM6: Rating: RED; Mode of pathogenicity: None; Publications: 32426513, 30670339; Phenotypes: Spinocerebellar ataxia 35, MIM# 613908; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v2.12 TDP2 Zornitza Stark gene: TDP2 was added
gene: TDP2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TDP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: At least 6 individuals from 4 unrelated families reported.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 TBC1D23 Zornitza Stark reviewed gene: TBC1D23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pontocerebellar hypoplasia, type 11, MIM# 617695; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 TBC1D23 Zornitza Stark gene: TBC1D23 was added
gene: TBC1D23 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: TBC1D23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D23 were set to 28823707; 28823706
Phenotypes for gene: TBC1D23 were set to Pontocerebellar hypoplasia, type 11, MIM# 617695
Review for gene: TBC1D23 was set to GREEN
gene: TBC1D23 was marked as current diagnostic
Added comment: Seven unrelated families reported, ataxia is part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SVBP Zornitza Stark gene: SVBP was added
gene: SVBP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SVBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVBP were set to 31363758; 30607023
Phenotypes for gene: SVBP were set to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569
Review for gene: SVBP was set to GREEN
gene: SVBP was marked as current diagnostic
Added comment: 5 families with homozygous mutations in SVBP; syndromic cause of paediatric ataxia. Some shared same founder variant, p.Q28*. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SQSTM1 Zornitza Stark gene: SQSTM1 was added
gene: SQSTM1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SQSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQSTM1 were set to 27545679
Phenotypes for gene: SQSTM1 were set to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145
Review for gene: SQSTM1 was set to GREEN
gene: SQSTM1 was marked as current diagnostic
Added comment: Four unrelated families, presenting feature of this progressive neurological disorder was ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SPR Zornitza Stark gene: SPR was added
gene: SPR was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SPR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SPR were set to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716
Review for gene: SPR was set to GREEN
gene: SPR was marked as current diagnostic
Added comment: Complex movement disorder, dystonia predominant, but ataxia described in some individuals. Most individuals have had bi-allelic variants identified, uncertain whether there is an association with mono-allelic variants.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SPG7 Zornitza Stark reviewed gene: SPG7: Rating: AMBER; Mode of pathogenicity: None; Publications: 32893728; Phenotypes: Spastic paraplegia 7, autosomal recessive, MIM# 607259; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 SNAP25 Zornitza Stark gene: SNAP25 was added
gene: SNAP25 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNAP25 were set to 29491473; 25381298; 17283335
Phenotypes for gene: SNAP25 were set to Myasthenic syndrome, congenital, 18, 616330; cerebellar ataxia and seizures
Review for gene: SNAP25 was set to GREEN
gene: SNAP25 was marked as current diagnostic
Added comment: Phenotype in 3 reported cases and mouse model includes ataxia as a feature.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 SLC9A1 Zornitza Stark reviewed gene: SLC9A1: Rating: RED; Mode of pathogenicity: None; Publications: 25205112, 30018422, 25760855; Phenotypes: Lichtenstein-Knorr syndrome, MIM# 616291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 SLC9A1 Zornitza Stark gene: SLC9A1 was added
gene: SLC9A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC9A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC9A1 were set to 25205112; 30018422; 25760855
Phenotypes for gene: SLC9A1 were set to Lichtenstein-Knorr syndrome, MIM# 616291
Review for gene: SLC9A1 was set to AMBER
Added comment: Two families with bi-allelic variants in this gene reported and combination of deafness and ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SLC52A2 Zornitza Stark gene: SLC52A2 was added
gene: SLC52A2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC52A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC52A2 were set to 30377535
Phenotypes for gene: SLC52A2 were set to Brown-Vialetto-Van Laere syndrome 2, MIM# 614707
Review for gene: SLC52A2 was set to GREEN
gene: SLC52A2 was marked as current diagnostic
Added comment: Generally presents with a range of neuropathies but ataxia described. Treatable condition.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SLC25A46 Zornitza Stark gene: SLC25A46 was added
gene: SLC25A46 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC25A46 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A46 were set to 30178502; 26168012; 27543974; 27430653; 27390132; 28934388; 28558379
Phenotypes for gene: SLC25A46 were set to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505
Review for gene: SLC25A46 was set to GREEN
gene: SLC25A46 was marked as current diagnostic
Added comment: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus.

At least 10 unrelated families reported, supportive functional data.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SLC17A5 Zornitza Stark gene: SLC17A5 was added
gene: SLC17A5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SLC17A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC17A5 were set to 26171070
Phenotypes for gene: SLC17A5 were set to Sialic acid storage disorder, infantile, MIM# 269920
Review for gene: SLC17A5 was set to GREEN
gene: SLC17A5 was marked as current diagnostic
Added comment: Ataxia is prominent in childhood.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 SCYL1 Zornitza Stark reviewed gene: SCYL1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 SCYL1 Zornitza Stark gene: SCYL1 was added
gene: SCYL1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCYL1 were set to 29419818; 17571074; 26581903; 30531813
Phenotypes for gene: SCYL1 were set to Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719
Review for gene: SCYL1 was set to GREEN
gene: SCYL1 was marked as current diagnostic
Added comment: Early-onset ataxia (<1 year) with recurrent episodes of liver failure, sensory-motor axonal neuropathy, cerebellar atrophy. At least 7 unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SCN8A Zornitza Stark reviewed gene: SCN8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31904124, 31887642, 31675620; Phenotypes: Cognitive impairment with or without cerebellar ataxia, MIM# 614306, Epileptic encephalopathy, early infantile, 13, MIM# 614558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v2.12 SCN2A Zornitza Stark gene: SCN2A was added
gene: SCN2A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN2A were set to 31924505; 32893078; 31904126
Phenotypes for gene: SCN2A were set to Epileptic encephalopathy, early infantile, 11, MIM# 613721
Review for gene: SCN2A was set to GREEN
gene: SCN2A was marked as current diagnostic
Added comment: Classically presents with seizures and DD/ID although a range of other manifestations reported, including movement abnormalities, including ataxia, especially episodic ataxia.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SCN1A Zornitza Stark gene: SCN1A was added
gene: SCN1A was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: SCN1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN1A were set to 27264139; 27817982; 28732259
Phenotypes for gene: SCN1A were set to Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208
Review for gene: SCN1A was set to GREEN
gene: SCN1A was marked as current diagnostic
Added comment: Ataxia is part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 SAR1B Zornitza Stark reviewed gene: SAR1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chylomicron retention disease, 246700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 RUBCN Zornitza Stark reviewed gene: RUBCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20826435, 30237576, 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, MIM#615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary ataxia - adult onset v2.9 RORA Zornitza Stark reviewed gene: RORA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v2.12 RORA Zornitza Stark gene: RORA was added
gene: RORA was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: RORA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RORA were set to 29656859
Phenotypes for gene: RORA were set to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060
Review for gene: RORA was set to GREEN
gene: RORA was marked as current diagnostic
Added comment: 11 unrelated individuals with syndromic intellectual disability and de novo variants in this gene. Severity varied from mild borderline intellectual disability with mild speech delay or normal speech, through to severe cognitive impairment with poor or absent speech. Most had ataxia, hypotonia, poor coordination, and/or mild tremor, suggesting cerebellar dysfunction. Three individuals had documented cerebellar hypoplasia or pontocerebellar atrophy on brain imaging. Seven had seizures of variable types, including neonatal myoclonic, tonic-clonic, multifocal, generalized, and absence. Five were diagnosed with autism spectrum disorder. More variable features included strabismus, esotropia, nystagmus, and oculomotor apraxia. Postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 PRICKLE1 Zornitza Stark reviewed gene: PRICKLE1: Rating: RED; Mode of pathogenicity: None; Publications: 20301774; Phenotypes: Epilepsy, progressive myoclonic 1B, MIM# 612437; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.12 POLR3B Zornitza Stark gene: POLR3B was added
gene: POLR3B was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: POLR3B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3B were set to 22036171; 22036172
Phenotypes for gene: POLR3B were set to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381
Review for gene: POLR3B was set to GREEN
gene: POLR3B was marked as current diagnostic
Added comment: Ataxia is a presenting feature.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 PMPCB Zornitza Stark gene: PMPCB was added
gene: PMPCB was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMPCB were set to 29576218
Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954
Review for gene: PMPCB was set to GREEN
gene: PMPCB was marked as current diagnostic
Added comment: Progressive disorder, includes ataxia. Four unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 PITRM1 Zornitza Stark gene: PITRM1 was added
gene: PITRM1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: PITRM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PITRM1 were set to 26697887; 29764912; 29383861
Phenotypes for gene: PITRM1 were set to Ataxia; Intellectual disability
Review for gene: PITRM1 was set to GREEN
gene: PITRM1 was marked as current diagnostic
Added comment: Three families with two unique variants and in vitro functional assays. Cases and mouse model have spinocerebellar ataxia as a prominent feature of the phenotype. No OMIM phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 OPA1 Zornitza Stark edited their review of gene: OPA1: Set current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v2.12 OPA1 Zornitza Stark gene: OPA1 was added
gene: OPA1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: OPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OPA1 were set to 28494813
Phenotypes for gene: OPA1 were set to Optic atrophy plus syndrome, MIM# 125250
Review for gene: OPA1 was set to GREEN
Added comment: Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. See PMID 28494813 for three unrelated children where ataxia was a prominent part of the phenotype.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 NKX2-1 Zornitza Stark gene: NKX2-1 was added
gene: NKX2-1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: NKX2-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NKX2-1 were set to 10931427; 27066577; 26839702; 26103969
Phenotypes for gene: NKX2-1 were set to Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700
Review for gene: NKX2-1 was set to GREEN
gene: NKX2-1 was marked as current diagnostic
Added comment: Paediatric onset ataxia reported in greater than 3 families with the condition.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 MVK Zornitza Stark reviewed gene: MVK: Rating: GREEN; Mode of pathogenicity: None; Publications: 12563048, 10401001, 28095071; Phenotypes: Mevalonic aciduria MIM#610377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 MTFMT Zornitza Stark gene: MTFMT was added
gene: MTFMT was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: MTFMT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTFMT were set to 26060307; 24461907
Phenotypes for gene: MTFMT were set to Combined oxidative phosphorylation deficiency 15 MIM#614947; Mitochondrial complex I deficiency, nuclear type 27 MIM#618248
Review for gene: MTFMT was set to GREEN
gene: MTFMT was marked as current diagnostic
Added comment: Five unrelated cases reported with paediatric onset ataxia as a prominent feature of the condition.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 MSTO1 Zornitza Stark gene: MSTO1 was added
gene: MSTO1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: MSTO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MSTO1 were set to 28554942; 28544275; 31604776; 31463572; 31130378; 30684668; 29339779
Phenotypes for gene: MSTO1 were set to Myopathy, mitochondrial, and ataxia, MIM# 617675
Review for gene: MSTO1 was set to GREEN
gene: MSTO1 was marked as current diagnostic
Added comment: Impaired mitochondrial fusion disorder. Multiple families reported with bi-allelic variants and childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy and ataxia. One family reported with heterozygous variant in this gene, gene-disease association for mono allelic variants not well established.
Sources: Expert list
White matter disorders - adult onset v1.4 LARS2 Zornitza Stark gene: LARS2 was added
gene: LARS2 was added to White matter disorders - adult onset. Sources: Expert list
Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS2 were set to 32442335; 30737337
Phenotypes for gene: LARS2 were set to Leukodystrophy
Review for gene: LARS2 was set to GREEN
gene: LARS2 was marked as current diagnostic
Added comment: Five individuals reported where leukodystrophy was part of LARS2-associated Perrault syndrome. Neurological decline and MRI abnormalities were primarily in adulthood.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 LARS2 Zornitza Stark gene: LARS2 was added
gene: LARS2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: LARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS2 were set to 29205794; 32423379; 30737337
Phenotypes for gene: LARS2 were set to Perrault syndrome 4, MIM# 615300; Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Leukodystrophy
Review for gene: LARS2 was set to GREEN
gene: LARS2 was marked as current diagnostic
Added comment: Bi-allelic variants in LARS2 cause a range of phenotypes, with some individuals displaying neurological features, including at least three individuals reported with ataxia (reviewed in PMID 32423379)
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 LAMA1 Zornitza Stark gene: LAMA1 was added
gene: LAMA1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: LAMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA1 were set to 25105227
Phenotypes for gene: LAMA1 were set to Cerebellar ataxia, intellectual disability, oculomotor apraxia, cerebellar cysts; Poretti Boltshauser syndrome MIM#615960
Review for gene: LAMA1 was set to GREEN
gene: LAMA1 was marked as current diagnostic
Added comment: Five unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 KCNA2 Zornitza Stark gene: KCNA2 was added
gene: KCNA2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: KCNA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA2 were set to 29050392
Phenotypes for gene: KCNA2 were set to Early infantile encephalopathy 32, MIM#616366
Review for gene: KCNA2 was set to GREEN
gene: KCNA2 was marked as current diagnostic
Added comment: Ataxia is part of the phenotype.

Review of 23 affected individuals in PMID 29050392: some variants are LoF and others GoF, and some genotype-phenotype correlations made. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalised and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 IRF2BPL Zornitza Stark gene: IRF2BPL was added
gene: IRF2BPL was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF2BPL were set to 30057031
Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088
Review for gene: IRF2BPL was set to GREEN
gene: IRF2BPL was marked as current diagnostic
Added comment: Progressive ataxia is a feature reported in the original cohort of 7 unrelated patients.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 FBXL4 Zornitza Stark gene: FBXL4 was added
gene: FBXL4 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL4 were set to 28383868
Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), MIM# 615471
Review for gene: FBXL4 was set to GREEN
Added comment: Ataxia is a reported feature of this mitochondrial disorder.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 FA2H Zornitza Stark gene: FA2H was added
gene: FA2H was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to 31135052
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive MIM#612319
Review for gene: FA2H was set to GREEN
Added comment: Limb ataxia is reported as a feature of the condition in at least 13 cases with mainly paediatric onset.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 EBF3 Zornitza Stark reviewed gene: EBF3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypotonia, ataxia, and delayed development syndrome, MIM# 617330; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v2.12 EBF3 Zornitza Stark gene: EBF3 was added
gene: EBF3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: EBF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EBF3 were set to 28017373; 28017372; 28017370; 32366537
Phenotypes for gene: EBF3 were set to Hypotonia, ataxia, and delayed development syndrome, MIM# 617330
Review for gene: EBF3 was set to GREEN
gene: EBF3 was marked as current diagnostic
Added comment: Twenty unrelated families reported with mono-allelic variants in this gene and HADDS, a neurodevelopmental syndrome characterised by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 DOCK3 Zornitza Stark gene: DOCK3 was added
gene: DOCK3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: DOCK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK3 were set to 28195318; 29130632; 30976111
Phenotypes for gene: DOCK3 were set to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, MIM#618292
Review for gene: DOCK3 was set to GREEN
gene: DOCK3 was marked as current diagnostic
Added comment: Five unrelated families reported.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: RED; Mode of pathogenicity: None; Publications: 10921354; Phenotypes: Dyskeratosis congenita, X-linked, MIM# 305000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Ataxia and cerebellar anomalies - narrow panel v2.12 CYP2U1 Zornitza Stark reviewed gene: CYP2U1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 CSTB Zornitza Stark reviewed gene: CSTB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), MIM# 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 COA7 Zornitza Stark gene: COA7 was added
gene: COA7 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: COA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COA7 were set to 29718187; 27683825
Phenotypes for gene: COA7 were set to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3, MIM#618387
Review for gene: COA7 was set to GREEN
gene: COA7 was marked as current diagnostic
Added comment: Five unrelated individuals reported with bi-allelic variants in this gene. Slowly progressive condition with variable onset, but at least three individuals presented at <5 years of age.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 CLPP Zornitza Stark gene: CLPP was added
gene: CLPP was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 25254289
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to GREEN
gene: CLPP was marked as current diagnostic
Added comment: Neurological abnormalities including cerebellar ataxia are present in some individuals with this condition.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 CLN5 Zornitza Stark edited their review of gene: CLN5: Set current diagnostic: yes
Ataxia and cerebellar anomalies - narrow panel v2.12 CLN5 Zornitza Stark gene: CLN5 was added
gene: CLN5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: CLN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN5 were set to 25359263
Phenotypes for gene: CLN5 were set to Ceroid lipofuscinosis, neuronal, 5, MIM# 256731
Review for gene: CLN5 was set to GREEN
Added comment: Ataxia is part of the phenotype of this disorder, which is typically of paediatric onset. Please also note report of adult-onset ataxia in PMID 25359263.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 BBS1 Zornitza Stark gene: BBS1 was added
gene: BBS1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: BBS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBS1 were set to 15637713
Phenotypes for gene: BBS1 were set to Bardet-Biedl syndrome 1, MIM#209900
Review for gene: BBS1 was set to GREEN
gene: BBS1 was marked as current diagnostic
Added comment: Ataxia is a common feature of the phenotype.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 ATP8A2 Zornitza Stark reviewed gene: ATP8A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar ataxia, mental retardation and dysequilibirum syndrome 4; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.12 ATP8A2 Zornitza Stark reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 31612321; Phenotypes: Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4, MIM#615268; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 ATCAY Zornitza Stark reviewed gene: ATCAY: Rating: AMBER; Mode of pathogenicity: None; Publications: 14556008; Phenotypes: Ataxia, cerebellar, Cayman type, MIM# 601238; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.12 ALDH5A1 Zornitza Stark gene: ALDH5A1 was added
gene: ALDH5A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ALDH5A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH5A1 were set to 14635103
Phenotypes for gene: ALDH5A1 were set to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Review for gene: ALDH5A1 was set to GREEN
gene: ALDH5A1 was marked as current diagnostic
Added comment: Over 50 unrelated families reported. Ataxia is part of the phenotype, which also includes developmental delay, hypotonia, intellectual disability, seizures, hyperkinetic behaviour, aggression, and sleep disturbances.
Sources: Expert list
Hereditary ataxia - adult onset v2.9 ADPRHL2 Zornitza Stark reviewed gene: ADPRHL2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.12 ADPRHL2 Zornitza Stark gene: ADPRHL2 was added
gene: ADPRHL2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ADPRHL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADPRHL2 were set to 30100084; 30401461
Phenotypes for gene: ADPRHL2 were set to Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, MIM#618170
Review for gene: ADPRHL2 was set to GREEN
gene: ADPRHL2 was marked as current diagnostic
Added comment: Fourteen unrelated families reported with stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS), an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. The disorder is characterised by cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some individuals develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy.
Sources: Expert list
Ataxia and cerebellar anomalies - narrow panel v2.12 ACO2 Zornitza Stark gene: ACO2 was added
gene: ACO2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list
Mode of inheritance for gene: ACO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACO2 were set to 32519519
Phenotypes for gene: ACO2 were set to Infantile cerebellar-retinal degeneration, MIM#614559
Review for gene: ACO2 was set to GREEN
gene: ACO2 was marked as current diagnostic
Added comment: Ataxia is part of the phenotype, particularly in more mildly affected individuals, where it can be the presenting feature.
Sources: Expert list
Hearing loss v2.74 COL11A1 Eleanor Williams Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II, 604841Marshall syndrome, 154780{Lumbar disc herniation, susceptibility to}, 603932Fibrochondrogenesis, 228520; Sticklersyndrome,typeII,604841 to Stickler syndrome, type II, MIM#604841; Deafness, autosomal dominant 37, MIM#618533
Hearing loss v2.73 COL11A1 Eleanor Williams Publications for gene: COL11A1 were set to
Hearing loss v2.72 COL11A1 Eleanor Williams Mode of inheritance for gene: COL11A1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.71 COL11A1 Eleanor Williams Classified gene: COL11A1 as Amber List (moderate evidence)
Hearing loss v2.71 COL11A1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 1 case of non-syndromic hearing loss in a large pedigree. Other reports are from patients with Stickler/Marshal syndrome.
Hearing loss v2.71 COL11A1 Eleanor Williams Gene: col11a1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.70 COL11A1 Eleanor Williams reviewed gene: COL11A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30245514, 17236192; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.70 ATP6V1B2 Eleanor Williams Phenotypes for gene: ATP6V1B2 were changed from to Deafness, congenital, with onychodystrophy, autosomal dominant, 124480; Zimmermann-Laband syndrome 2, 616455
Hearing loss v2.69 ATP6V1B2 Eleanor Williams Publications for gene: ATP6V1B2 were set to
Hearing loss v2.68 ATP6V1B2 Eleanor Williams Tag for-review tag was added to gene: ATP6V1B2.
Hearing loss v2.68 ATP6V1B2 Eleanor Williams changed review comment from: Comment on list classification: The rating of this gene should be reviewed after consultation with the Genomics England clinical team and at the next GMS review.; to: Comment on list classification: Sufficient cases with Deafness, congenital, with onychodystrophy to rate green. This gene should be reviewed at the next GMS update.
Hearing loss v2.68 ATP6V1B2 Eleanor Williams changed review comment from: Adding gene at request of Alistair Pagnamenta (University of Oxford).

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.
Sources: Expert Review, Literature; to: Adding gene at request of Alistair Pagnamenta (University of Oxford).

Associated with Deafness, congenital, with onychodystrophy, autosomal dominant #124480 (AD) and Zimmermann-Laband syndrome 2 #616455 (AD) in OMIM.

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.

PMID: 28396750 Menendez et al 2017 - report a Guatemalan famliy with one child with deafness–onychodystrophy. The proband was found to be heterozygous for c.1516C>T [p.(Arg506*)] in ATP6V1B2. Neither parents or sisters had this variant.

PMID: 24913193 Yuan et al 2014 - report 3 Chinese families with severe congenital sensorineural hearing loss, absence of nails and aplasia of the middle phalanx in the fifth fingers, but no inner ear malformation or intellectual disability. Using exome sequencing an identical heterozygous de novo c.1516 C>T (p.Arg506X) mutation in ATP6V1B2 was verified in two probands. In the third family the same variant was found by Sanger sequencing. A cochlea-specific Atp6v1b2-knockdown mouse model demonstrates that Atp6v1b2 deficiency leads to severe sensorineural hearing loss.
Primary immunodeficiency v2.184 FNIP1 Boaz Palterer gene: FNIP1 was added
gene: FNIP1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FNIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FNIP1 were set to 32905580
Phenotypes for gene: FNIP1 were set to Primary Immunodeficiency; Agammaglobulinemia; Hypertrophic Cardiomyopathy; Neutropenia
Penetrance for gene: FNIP1 were set to unknown
Review for gene: FNIP1 was set to AMBER
Added comment: Sources: Literature
Hearing loss v2.68 ATP6V1B2 Eleanor Williams Classified gene: ATP6V1B2 as Amber List (moderate evidence)
Hearing loss v2.68 ATP6V1B2 Eleanor Williams Gene: atp6v1b2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.67 ATP6V1B2 Eleanor Williams Classified gene: ATP6V1B2 as Red List (low evidence)
Hearing loss v2.67 ATP6V1B2 Eleanor Williams Added comment: Comment on list classification: The rating of this gene should be reviewed after consultation with the Genomics England clinical team and at the next GMS review.
Hearing loss v2.67 ATP6V1B2 Eleanor Williams Gene: atp6v1b2 has been classified as Red List (Low Evidence).
Hearing loss v2.66 ATP6V1B2 Eleanor Williams edited their review of gene: ATP6V1B2: Changed rating: GREEN
Hearing loss v2.66 ATP6V1B2 Eleanor Williams gene: ATP6V1B2 was added
gene: ATP6V1B2 was added to Hearing loss. Sources: Expert Review,Literature
Mode of inheritance for gene: ATP6V1B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added comment: Adding gene at request of Alistair Pagnamenta (University of Oxford).

PMID: 32873933 Beauregard-Lacroix et al 2020 - identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. All individuals presented with deafness as well as as onychodystrophy and abnormal fingers and/or toes. In addition, all families but one had developmental delay or intellectual disability and five individuals had epilepsy. Two additional familes with dominant deafness onychodystrophy (DDOD) syndrome also had the same variant in ATP6V1B2. Abstract only accessed.
Sources: Expert Review, Literature
Hearing loss v2.65 SOX2 Eleanor Williams Tag for-review tag was added to gene: SOX2.
Hearing loss v2.65 SOX2 Eleanor Williams Classified gene: SOX2 as Green List (high evidence)
Hearing loss v2.65 SOX2 Eleanor Williams Added comment: Comment on list classification: Limited evidence for green rating. Should be reviewed at the next major review of this panel.
Hearing loss v2.65 SOX2 Eleanor Williams Gene: sox2 has been classified as Green List (High Evidence).
Hearing loss v2.64 SOX2 Eleanor Williams Publications for gene: SOX2 were set to PMID:10564870; 11135495; 12002146; 12036291; 12461687; 12612584; 14517545; 15240551; 15346919; 15389708; 15812812; 15846349; 16145681; 16283891; 16470798; 16543359; 16651659; 16712695; 16892407; 16904174; 16932809; 17015430; 17219395; 17515932; 17522155; 17554336; 17554338; 18029452; 18157115; 18285410; 18385377; 18806776; 18818365; 18831064; 18845712; 19254784; 19403656; 19801978; 19898493; 19921648; 20803647; 21326281; 21331042; 21532573; 21919124; 24048479; 24909994; 7849401; 8741917
Hearing loss v2.63 SOX2 Eleanor Williams edited their review of gene: SOX2: Changed rating: AMBER
Hearing loss v2.63 SOX2 Eleanor Williams commented on gene: SOX2
Paroxysmal central nervous system disorders v1.4 CSNK1D Zornitza Stark reviewed gene: CSNK1D: Rating: AMBER; Mode of pathogenicity: None; Publications: 15800623, 23636092; Phenotypes: Advanced sleep-phase syndrome, familial, 2 615224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.51 XK Zornitza Stark gene: XK was added
gene: XK was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: XK was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: XK were set to 11761473
Phenotypes for gene: XK were set to McLeod syndrome with or without chronic granulomatous disease MIM#300842
Review for gene: XK was set to GREEN
gene: XK was marked as current diagnostic
Added comment: 5 out of 13 cases had dystonia as a feature of the condition.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 UBTF Zornitza Stark gene: UBTF was added
gene: UBTF was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: UBTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBTF were set to 28777933; 29300972
Phenotypes for gene: UBTF were set to Neurodegeneration, childhood-onset, with brain atrophy MIM#617672
Mode of pathogenicity for gene: UBTF 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: UBTF was set to GREEN
gene: UBTF was marked as current diagnostic
Added comment: 7 out of 11 unrelated cases with a recurrent de novo gain of function missense variant (p.Glu210Lys) have dystonia as a feature of the condition.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 TBC1D24 Zornitza Stark gene: TBC1D24 was added
gene: TBC1D24 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: TBC1D24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D24 were set to 31257402
Phenotypes for gene: TBC1D24 were set to Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp, MIM# 608105
Review for gene: TBC1D24 was set to GREEN
Added comment: Three unrelated families reported with rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC), an autosomal recessive neurologic disorder characterised by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist. Three unrelated families reported with this specific phenotype, though variants in this gene are associated with a range of other neurological disorders and may represent a spectrum of severity.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 SYT1 Zornitza Stark gene: SYT1 was added
gene: SYT1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SYT1 were set to 30107533
Phenotypes for gene: SYT1 were set to Baker-Gordon syndrome MIM#618218
Review for gene: SYT1 was set to GREEN
gene: SYT1 was marked as current diagnostic
Added comment: 4 out of 11 individuals with a de novo variant had dystonia as a feature of the phenotype.
Sources: Expert list
Fetal anomalies v1.95 ASXL3 Rhiannon Mellis reviewed gene: ASXL3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29316359; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Laterality disorders and isomerism v1.19 FOXJ1 Zornitza Stark changed review comment from: PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy of demonstrated cilia were unable to general fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function is less likely the mechanism of pathogenicity
Sources: Expert list; to: PMID 31630787 - Six unrelated individuals with de novo variants in this gene. Patients have hydrocephaly, bronchiectasis and respiratory disease. Situs inversus was shown in 3/6 patients.
Electron microscopy demonstrated cilia were unable to generate fluid flow and were less frequent on cells. All reported variants were truncating mutations affecting the last exon in the protein, therefore loss of function is less likely the mechanism of pathogenicity
Sources: Expert list
Hearing loss v2.63 TOP2B Zornitza Stark edited their review of gene: TOP2B: Changed rating: AMBER
Hearing loss v2.63 SPATC1L Zornitza Stark edited their review of gene: SPATC1L: Changed rating: AMBER
Childhood onset dystonia or chorea or related movement disorder v1.51 SQSTM1 Zornitza Stark changed review comment from: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia. None noted to have myopathy.
Sources: Expert list; to: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 SQSTM1 Zornitza Stark edited their review of gene: SQSTM1: Changed phenotypes: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145
Childhood onset dystonia or chorea or related movement disorder v1.51 SQSTM1 Zornitza Stark gene: SQSTM1 was added
gene: SQSTM1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SQSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SQSTM1 were set to 27545679
Phenotypes for gene: SQSTM1 were set to Myopathy, distal, with rimmed vacuoles , MIM#617158
Review for gene: SQSTM1 was set to GREEN
Added comment: PMID: 27545679 - 9 patients (4 families) with childhood/adolescent onset neurodegeneration syndrome. 7/9 patients presented with dystonia. None noted to have myopathy.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 SNORD118 Zornitza Stark gene: SNORD118 was added
gene: SNORD118 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SNORD118 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNORD118 were set to 27571260
Phenotypes for gene: SNORD118 were set to Leukoencephalopathy, brain calcifications, and cysts MIM#614561
Review for gene: SNORD118 was set to GREEN
Added comment: At least 6 cases/families reported with dystonia as a feature of the condition.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 SLC16A2 Zornitza Stark gene: SLC16A2 was added
gene: SLC16A2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SLC16A2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SLC16A2 were set to 31410843
Phenotypes for gene: SLC16A2 were set to Allan-Herndon-Dudley syndrome, MIM# 300523
Review for gene: SLC16A2 was set to GREEN
gene: SLC16A2 was marked as current diagnostic
Added comment: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In a recent review of 24 affected individuals (PMID 31410843), 16 presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.51 PRNP Zornitza Stark reviewed gene: PRNP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Huntington disease-like 1, MIM# 603218; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.95 B9D2 Rhiannon Mellis gene: B9D2 was added
gene: B9D2 was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: B9D2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B9D2 were set to PMID: 21763481; 26092869
Phenotypes for gene: B9D2 were set to Joubert syndrome; Meckel syndrome
Review for gene: B9D2 was set to GREEN
gene: B9D2 was marked as current diagnostic
Added comment: 2 fetuses with MKS in one consanguineous family with homozygous B9D2 pathogenic variants. Functional studies of the variant confirmed loss of function. (PMID: 21763481)
2 unrelated patients with Joubert syndrome with different compound het B9D2 variants. (PMID: 26092869)

NB: Currently Green in ciliopathies panels. We report variants in this gene on our postnatal ciliopathies panel at GOSH/NTGLH.
Sources: Literature, NHS GMS
Fetal anomalies v1.95 B9D1 Rhiannon Mellis reviewed gene: B9D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32622957, 24886560; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.95 TMEM107 Rhiannon Mellis gene: TMEM107 was added
gene: TMEM107 was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: TMEM107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM107 were set to PMID: 26123494; 26518474; 26595381
Phenotypes for gene: TMEM107 were set to ?Joubert syndrome 29; Meckel syndrome 13; Orofaciodigital syndrome XVI
Review for gene: TMEM107 was set to GREEN
gene: TMEM107 was marked as current diagnostic
Added comment: 2 unrelated infants, born of consanguineous Saudi parents, with Meckel syndrome-13 (PMID: 26123494)
1 patient with oro-facio-digital syndrome, and a mouse model with ciliopathy phenotype (PMID: 26518474)
1 man with Jouberts syndrome and female twins (from an unrelated family) with orofaciodigital syndrome. Additional functional studies. (PMID: 26595381)

NB: Currently Green on rare multisystem/renal/neurological ciliopathies panels. We report variants in this gene on our postnatal ciliopathies panel at GOSH/NTGLH
Sources: Literature, NHS GMS
Fetal anomalies v1.95 TMEM216 Rhiannon Mellis reviewed gene: TMEM216: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20036350, 20512146; Phenotypes: Joubert syndrome, Meckel syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.95 KIF14 Rhiannon Mellis gene: KIF14 was added
gene: KIF14 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to PMID: 24128419; 30388224; 28892560; 29343805
Phenotypes for gene: KIF14 were set to ?Meckel syndrome 12; Microcephaly 20, primary
Review for gene: KIF14 was set to GREEN
gene: KIF14 was marked as current diagnostic
Added comment: Two fetuses in one family with complex multiple congenital anomalies consistent with ciliopathy phenotype. (PMID: 24128419)
Four more families with fetuses with similar phenotype (microcephaly, brain malformations and renal agenesis or hypodysplasia). Also functional (zebrafish) studies. Authors conclude that LOF variants cause the above syndromic phenotype while hypomorphic variants cause microcephaly without kidney defects. (PMID: 30388224)

Four unrelated families with AR primary microcephaly and biallelic KIF14 pathogenic variants (PMID: 28892560)
Four more unrelated families with AR primary microcephaly and biallelic KIF14 pathogenic variants. Two sibs from one of the families were fetuses with severe microcephaly detected prenatally and leading to termination of pregnancy. (PMID: 29343805)
Sources: Literature
Hearing loss v2.63 SPATC1L Eleanor Williams Classified gene: SPATC1L as Amber List (moderate evidence)
Hearing loss v2.63 SPATC1L Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 3 cases reported but only one with segregation data.
Hearing loss v2.63 SPATC1L Eleanor Williams Gene: spatc1l has been classified as Amber List (Moderate Evidence).
Hearing loss v2.62 SPATC1L Eleanor Williams Added comment: Comment on mode of inheritance: I am not sure from the publication about the mode of inheritance. I read it that each family had one variant (no compound hets) and therefore the mode of inheritance would be mono-allelic. However, leaving as both monallelic and biallelic for now due to expert review.
Hearing loss v2.62 SPATC1L Eleanor Williams Mode of inheritance for gene: SPATC1L was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.61 SPATC1L Eleanor Williams reviewed gene: SPATC1L: Rating: AMBER; Mode of pathogenicity: None; Publications: 30177775; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.61 SPNS2 Eleanor Williams Classified gene: SPNS2 as Amber List (moderate evidence)
Hearing loss v2.61 SPNS2 Eleanor Williams Added comment: Comment on list classification: Updating the rating from grey to amber. 1 reported case plus mouse model.
Hearing loss v2.61 SPNS2 Eleanor Williams Gene: spns2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.60 SPNS2 Eleanor Williams reviewed gene: SPNS2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30973865, 25356849; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.51 SLC18A2 Zornitza Stark reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23363473, 31240161, 26497564; Phenotypes: Parkinsonism-dystonia, infantile, 2, MIM# 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.95 SLC20A1 Zornitza Stark gene: SLC20A1 was added
gene: SLC20A1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SLC20A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A1 were set to 32850778; 27013921
Phenotypes for gene: SLC20A1 were set to Bladder-Exstrophy-Epispadias Complex (BEEC)
Review for gene: SLC20A1 was set to GREEN
gene: SLC20A1 was marked as current diagnostic
Added comment: Three individuals and animal model supporting role of this gene in urinary tract and urorectal development. We have included on our CAKUT panel.
Sources: Literature
Intellectual disability v3.295 ATP1A3 Zornitza Stark edited their review of gene: ATP1A3: Added comment: Four additional individuals with dystonia, dysmorphism, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia, and neonatal onset. All had de novo missense variants. All are described to have global developmental delay, hence supporting upgrade in rating on this panel.; Changed rating: GREEN; Changed publications: https://doi.org/10.1212/NXG.0000000000000466; Changed phenotypes: Alternating hemiplegia of childhood 2, MIM#614820, Neurodevelopmental disorder; Set current diagnostic: yes
Intellectual disability v3.295 WASHC4 Zornitza Stark gene: WASHC4 was added
gene: WASHC4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WASHC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC4 were set to 31953988; 21498477
Phenotypes for gene: WASHC4 were set to Mental retardation, autosomal recessive 43, MIM #615817
Review for gene: WASHC4 was set to GREEN
gene: WASHC4 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Intellectual disability v3.295 RAD50 Zornitza Stark reviewed gene: RAD50: Rating: AMBER; Mode of pathogenicity: None; Publications: 32212377; Phenotypes: Nijmegen breakage syndrome-like disorder, MIM# 613078; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.21 RAD50 Zornitza Stark gene: RAD50 was added
gene: RAD50 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD50 were set to 19409520; 32212377
Phenotypes for gene: RAD50 were set to Nijmegen breakage syndrome-like disorder, MIM# 613078
Review for gene: RAD50 was set to GREEN
gene: RAD50 was marked as current diagnostic
Added comment: Two individuals reported with bi-allelic variants in this gene showing dysmorphic facial features similar to NBS, short stature, microcephaly, and mild/moderate intellectual disability. Fibroblasts established from one of the individuals showed chromosomal instability and abnormal radioresistant DNA synthesis. The MRE11/RAD50/NBN (MRN) complex is involved in signaling processes inducing the repair of DNA double-strand breaks. Variants in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)‐like disorder, respectively, so this gene is a strong biological candidate for this phenotype.
Sources: Literature
Congenital myopathy v2.5 SVIL Zornitza Stark gene: SVIL was added
gene: SVIL was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: SVIL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVIL were set to 32779703
Phenotypes for gene: SVIL were set to Myopathy
Review for gene: SVIL was set to AMBER
Added comment: Four individuals from two unrelated consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. Functional studies on muscle biopsies showed complete loss protein in muscle fibres by western blot.
Sources: Literature
Hearing loss v2.60 TMTC2 Eleanor Williams Classified gene: TMTC2 as Amber List (moderate evidence)
Hearing loss v2.60 TMTC2 Eleanor Williams Added comment: Comment on list classification: Changing rating from grey to amber. Two families reported. Same variant in each. Both northern european decent.
Hearing loss v2.60 TMTC2 Eleanor Williams Gene: tmtc2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.59 TMTC2 Eleanor Williams Phenotypes for gene: TMTC2 were changed from Deafness to Deafness; Sensorineural hearing loss
Hearing loss v2.58 TMTC2 Eleanor Williams Added comment: Comment on mode of inheritance: Changing to imprinted status unknown. In one family the trait had been passed through the maternal side for two generations, but more evidence needed before saying paternally imprinted.
Hearing loss v2.58 TMTC2 Eleanor Williams Mode of inheritance for gene: TMTC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.57 TMTC2 Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM.

PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project.


PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).; to: Not associated with a phenotype in OMIM.

PMID: 29671961- Guillen‐Ahlers et al 2018 - report a mother and son with of Northern European descent (mother and son) with Sensorineural hearing loss were found by exome sequencing to share a variant (rs35725509, missense variant) in the TMTC2 gene. This variant showed a minor allele frequency below 1% in 2,203 individuals of European American (EA) ancestry (NHLBI GO Exome Sequencing Project. In two generations, the trait has been passed through the maternal side


PMID: 27311106 - Runge et al 2016 - report a large multigenerational Northern European family in which 9 family members had bilateral, symmetric, progressive Sensorineural hearing loss that reached severe to profound loss in childhood. Using exome sequencing and linkage and association analyses they identified a fully penetrant sequence variant (rs35725509) in the TMTC2 gene region. The variant segregates with SNHL in the family. However, the mutation is found in a relatively high percentage of individuals of Northern European descent in the 1000 Genomes and Exome Sequencing (http://evs.gs.washington.edu/EVS/) European call sets (1% and 0.8%, respectively).
Hearing loss v2.57 TMTC2 Eleanor Williams edited their review of gene: TMTC2: Changed rating: AMBER; Changed publications: 29671961, 27311106; Changed phenotypes: Sensorineural hearing loss; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.57 TMTC2 Eleanor Williams commented on gene: TMTC2
Neurodegenerative disorders - adult onset v2.16 DNAJC7 Zornitza Stark gene: DNAJC7 was added
gene: DNAJC7 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: DNAJC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNAJC7 were set to https://doi.org/10.1212/NXG.0000000000000503
Phenotypes for gene: DNAJC7 were set to amyotrophic lateral sclerosis
Review for gene: DNAJC7 was set to AMBER
Added comment: Two cohort studies in ALS patients identified 11 and 1 patient, respectively, with variants in DNAJC7. Seven of these are putative PTVs. No segregation or functional data. A small number of individuals with LOF variants are present in gnomad albeit less than expected. Given these are cohort studies, and an adult-onset condition, potentially of variable penetrance, we have taken a cautious approach and rated Amber for now but would be interested in other expert opinions. No PMID yet.
Sources: Literature
Primary immunodeficiency v2.184 TET2 Zornitza Stark reviewed gene: TET2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32518946; Phenotypes: Immune dysregulation, Lymphoma; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital myopathy v2.5 DHX16 Zornitza Stark gene: DHX16 was added
gene: DHX16 was added to Congenital myopathy. Sources: Literature
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Neuromuscular disease and ocular or auditory anomalies with or without seizures, MIM# 618733
Review for gene: DHX16 was set to AMBER
gene: DHX16 was marked as current diagnostic
Added comment: This gene is somewhat difficult to place on the right panels.

Overall, there are four unrelated individuals reported with de novo missense variants. Three of the individuals died in infancy, so phenotypic information is limited, though hypotonia was prominent. Two had seizures. Individual with long-term survival had a progressive course, evidence of neuropathy, myopathy, loss of hearing and vision, and normal IQ.
Sources: Literature
Hearing loss v2.57 TOP2B Eleanor Williams Phenotypes for gene: TOP2B were changed from Deafness, autosomal dominant to Deafness, autosomal dominant; nonsyndromic hearing loss
Hearing loss v2.56 TOP2B Eleanor Williams Classified gene: TOP2B as Amber List (moderate evidence)
Hearing loss v2.56 TOP2B Eleanor Williams Added comment: Comment on list classification: Changing the rating from grey to amber. 1 familial case plus 3 sporadic cases reported. Supportive animal model. All reported in one publication so will wait until there is an additional supporting familial case before rating green.
Hearing loss v2.56 TOP2B Eleanor Williams Gene: top2b has been classified as Amber List (Moderate Evidence).
Hearing loss v2.55 TOP2B Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM.

PMID: 31198993 - Xia et al 2019 - Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. A variant in TOP2B (c.G4837C:p.D1613H) segregated with hearing loss in this family. Two variants other of TOP2B were detected in 66 sporadic patients with hearing loss. In zebrafish, top2b knockdown led to defects in the inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling.; to: Not associated with a phenotype in OMIM.

PMID: 31198993 - Xia et al 2019 - Whole-exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal-dominant nonsyndromic hearing loss. A variant in TOP2B (c.G4837C:p.D1613H) segregated with hearing loss in this family. Two other variants of TOP2B were detected in 66 sporadic patients with hearing loss (p.L721F and p. K1435del, plus another case with p.D1613H). In zebrafish, top2b knockdown led to defects in the inner ears and caused downregulation of akt which resulted in inactivation of PI3K-Akt signalling.
Hearing loss v2.55 TOP2B Eleanor Williams reviewed gene: TOP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: 31198993; Phenotypes: nonsyndromic hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.55 WBP2 Eleanor Williams Phenotypes for gene: WBP2 were changed from Deafness, autosomal recessive 107, MIM#617639 to Deafness, autosomal recessive 107, 617639
Hearing loss v2.54 WBP2 Eleanor Williams Classified gene: WBP2 as Amber List (moderate evidence)
Hearing loss v2.54 WBP2 Eleanor Williams Added comment: Comment on list classification: Changing the rating from grey to Amber. 2 cases plus mouse model but all from one paper. No further evidence since 2016.
Hearing loss v2.54 WBP2 Eleanor Williams Gene: wbp2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.53 WBP2 Eleanor Williams edited their review of gene: WBP2: Changed rating: AMBER; Changed publications: 26881968; Changed phenotypes: Deafness, autosomal recessive 107 617639; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.53 WBP2 Eleanor Williams commented on gene: WBP2
Hearing loss v2.53 FDXR Eleanor Williams edited their review of gene: FDXR: Changed rating: GREEN
Hearing loss v2.53 FDXR Eleanor Williams Tag for-review tag was added to gene: FDXR.
Hearing loss v2.53 FDXR Eleanor Williams changed review comment from: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype.; to: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype. Rating amber for now until this gene can be reviewed by the GMS.
Hearing loss v2.53 FDXR Eleanor Williams Classified gene: FDXR as Amber List (moderate evidence)
Hearing loss v2.53 FDXR Eleanor Williams Added comment: Comment on list classification: There are 3 cases where hearing loss is reported as the first symptom, although there are other cases in which variants in this gene do not result in hearing loss, or hearing loss after an optic phenotype.
Hearing loss v2.53 FDXR Eleanor Williams Gene: fdxr has been classified as Amber List (Moderate Evidence).
Hearing loss v2.52 FDXR Eleanor Williams changed review comment from: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018) ; to: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals from 3 families hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018)
Hearing loss v2.52 FDXR Eleanor Williams changed review comment from: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.; to: Associated with Auditory neuropathy and optic atrophy #617717 (AR) in OMIM.

PMID: 28965846 - Paul et al 2017 - report 8 individuals from 4 families from Tunisia, Algeria, France and Russia/Azerbaijan. All were affected by auditory neuropathy and optic atrophy with first onset before age 20. In 4/8 individuals hearing loss was the first symptom. In all cases biallelic (homozygous or compound het) variants in FDXR were found (exome sequencing in family 1, direct sequencing in the other 3 families). The variants segregated with the phenotype in family 1 (homozygous variant). Parental DNA was not available for other families. No FDXR variants were found in 86 other patients with different types of hearing loss. FDXR encodes a mitochondrial NADPH. FDXR levels were decreased in fibroblasts derived from patients in two of the families. Functional studies suggest a defect in iron homeostasis. Yeast studies showed that some of the FDXR variants failed to rescue growth defects in FDXR ortholog arh1 knockouts, but wildtype FDXR was able to rescue the defect.

PMID: 29040572 (Peng et al 2017) - report 17 individuals from 13 unrelated families with recessive mutations in FDXR. The core clinical features were optic atrophy, ataxia, and hypotonia but hearing loss was also noted as a less common phenotype.

Note, other cases reported with variants FDXR but no hearing loss phenotype e.g. PMID: 30250212 (Slone et al, 2018)
Intellectual disability v3.295 ATP1A2 Sarah Leigh commented on gene: ATP1A2: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.295 ATP1A2 Sarah Leigh Tag for-review tag was added to gene: ATP1A2.
Intellectual disability v3.295 ATP1A2 Sarah Leigh edited their review of gene: ATP1A2: Added comment: Associated with phenotype in OMIM and in G2P for MIGRAINE, FAMILIAL HEMIPLEGIC, ATP1A2-related. Three variants associated with congnitive impairment in 2/7 and 1/5 members of two families with Migraine, familial hemiplegic, 2 602481. At least 12 variants have been reported in Migraine, familial hemiplegic, 2 602481 families (PMID 15159495). An additional variant was reported in a case of Alternating hemiplegia of childhood 1, 104290 with impared cognitive function (PMID 29610157).; Changed rating: GREEN
Intellectual disability v3.295 ANKH Sarah Leigh commented on gene: ANKH: There is no evidence for this gene to be rated GREEN, it should be rated RED at the next major review.
Intellectual disability v3.295 ANKH Sarah Leigh reviewed gene: ANKH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.295 ANKH Sarah Leigh Publications for gene: ANKH were set to
Intellectual disability v3.294 ANKH Sarah Leigh Tag for-review tag was added to gene: ANKH.
Intellectual disability v3.294 TNR Arina Puzriakova Classified gene: TNR as Amber List (moderate evidence)
Intellectual disability v3.294 TNR Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.
Intellectual disability v3.294 TNR Arina Puzriakova Gene: tnr has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.293 TNR Arina Puzriakova reviewed gene: TNR: Rating: GREEN; Mode of pathogenicity: None; Publications: 22730557, 32099069; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.52 FDXR Eleanor Williams reviewed gene: FDXR: Rating: ; Mode of pathogenicity: None; Publications: 28965846; Phenotypes: Auditory neuropathy and optic atrophy 617717; Mode of inheritance: None
Hearing loss v2.52 CISD2 Eleanor Williams Tag for-review tag was added to gene: CISD2.
Hearing loss v2.52 CISD2 Eleanor Williams Classified gene: CISD2 as Amber List (moderate evidence)
Hearing loss v2.52 CISD2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber as several cases reported with hearing loss as a feature, but not as the first presenting feature.
Hearing loss v2.52 CISD2 Eleanor Williams Gene: cisd2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.51 CISD2 Eleanor Williams Phenotypes for gene: CISD2 were changed from hearing loss to hearing loss; Wolfram syndrome 2 604928
Hearing loss v2.50 CISD2 Eleanor Williams Publications for gene: CISD2 were set to
Hearing loss v2.49 CISD2 Eleanor Williams edited their review of gene: CISD2: Changed rating: AMBER; Changed publications: 10739754, 17846994, 25056293, 25371195; Changed phenotypes: Wolfram syndrome 2 #604928; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hearing loss v2.49 CISD2 Eleanor Williams commented on gene: CISD2
Intellectual disability v3.293 EARS2 Sarah Leigh Tag for-review tag was added to gene: EARS2.
Intellectual disability v3.293 EARS2 Sarah Leigh edited their review of gene: EARS2: Added comment: There is enough evidence for this gene to be rated GREEN at the next major review.; Changed rating: GREEN
Intellectual disability v3.293 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.293 EARS2 Sarah Leigh Publications for gene: EARS2 were set to 22492562
Intellectual disability v3.292 EARS2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.; to: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 15 variants reported in at least 12 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Classified gene: EARS2 as Amber List (moderate evidence)
Intellectual disability v3.292 EARS2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 14 variants reported in at least 11 unrelated cases, with variable degrees of psycomotor motor delay or regression and little or no language.
Intellectual disability v3.292 EARS2 Sarah Leigh Gene: ears2 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy - teen and adult v2.9 ALPK3 Ivone Leong Phenotypes for gene: ALPK3 were changed from Hypertrophic cardiomyopathy to Cardiomyopathy, familial hypertrophic 27, 618052
Cardiomyopathies - including childhood onset v1.7 MRAS Ivone Leong Classified gene: MRAS as Amber List (moderate evidence)
Cardiomyopathies - including childhood onset v1.7 MRAS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is also Green on the RASopathies panel (v 1.61).

Review copied from RASopathies panel:
"Associated with Noonan syndrome in OMIM and G2P (confirmed). PMID: 28289718 (2017) - In two unrelated patients with Noonan syndrome and cardiac hypertrophy, trio WES/targeted sequencing revealed de novo missense variants (c.68G>T, p.G23V and c.203C>T, p.T68I) in the MRAS gene. Functional studies of the p.Gly23Val variant showed the change yields a constitutively active form of MRAS.

PMID: 31173466 (2019) - One patient with a severe a Noonan syndrome phenotype, associated with a de novo MRAS variant (c.212A>G, p.Q71R). Functional studies were not performed.

PMID: 31108500 (2020) - Two unrelated patients with Noonan syndrome, including hypertrophic cardiomyopathy and dysmorphic features. Targeted sequencing revealed de novo activating MRAS variants (c.203C>T, p.T68I and c.67G>C, p.G23R). Functional studies demonstrated that the variants yields a constitutively active form of MRAS.
Arina Puzriakova (Genomics England Curator), 4 Aug 2020"

Therefore, this gene will be promoted to Green status at the next major review.
Cardiomyopathies - including childhood onset v1.7 MRAS Ivone Leong Gene: mras has been classified as Amber List (Moderate Evidence).
Cardiomyopathies - including childhood onset v1.6 MRAS Ivone Leong Tag for-review tag was added to gene: MRAS.
Hearing loss v2.49 SLC12A2 Arina Puzriakova Phenotypes for gene: SLC12A2 were changed from to Bilateral sensorineural hearing loss; Intellectual disability; Secretory defects
Hearing loss v2.48 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to
Hearing loss v2.47 SLC12A2 Arina Puzriakova Mode of inheritance for gene: SLC12A2 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.46 SLC12A2 Arina Puzriakova Classified gene: SLC12A2 as Amber List (moderate evidence)
Hearing loss v2.46 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 10 unrelated cases (and animal models) presenting significant sensorineural hearing loss, associated with variants in SLC12A2.
Hearing loss v2.46 SLC12A2 Arina Puzriakova Gene: slc12a2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.45 SLC12A2 Arina Puzriakova Tag for-review tag was added to gene: SLC12A2.
Hearing loss v2.45 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30740830, 32294086, 32754646, 32658972; Phenotypes: Bilateral sensorineural hearing loss, Intellectual disability, Secretory defects; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cardiomyopathies - including childhood onset v1.6 MRAS Ivone Leong Phenotypes for gene: MRAS were changed from Noonan syndrome, MIM#618499 to Noonan syndrome, 618499
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Tag watchlist tag was added to gene: DNAH6.
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Classified gene: DNAH6 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Based on the evidence there is not enough evidence to support a gene-disease association. This gene has been given an Amber gene rating until further evidence is available.
Laterality disorders and isomerism v1.19 DNAH6 Ivone Leong Gene: dnah6 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Classified gene: FOXJ1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There are enough cases to support a gene-disease association. There are also several animal models (PMID: 9739041, 15504371) that show that this gene has a role in L-R body assymmetry determination during early embryogenesis. This gene will be upgraded to Green status at the next major update.
Laterality disorders and isomerism v1.18 FOXJ1 Ivone Leong Gene: foxj1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.17 FOXJ1 Ivone Leong Tag for-review tag was added to gene: FOXJ1.
Intellectual disability v3.291 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 28940097; 30740830; 32754646
Intellectual disability v3.290 SLC12A2 Arina Puzriakova Mode of inheritance for gene: SLC12A2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Laterality disorders and isomerism v1.17 FOXJ1 Ivone Leong Publications for gene: FOXJ1 were set to 31630787
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.; to: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least nine unrelated cases presenting a relevant phenotype in association with variants in SLC12A2.
Intellectual disability v3.289 SLC12A2 Arina Puzriakova edited their review of gene: SLC12A2: Changed publications: 28940097, 30740830, 32754646, 32658972; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.289 SLC12A2 Arina Puzriakova changed review comment from: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.; to: - PMID: 28940097 (2017) - SLC12A2 first identified as a novel candidate gene in a 3.3-year-old male with GDD, failure to thrive, hypotonia, microcephaly, neonatal respiratory distress, recurrent aspiration pneumonia, and osteopenia. Sequencing revealed a homozygous variant (c.2617-2A>G) that segregated within the family.

- PMID: 30740830 (2019) - Homozygous 22kb deletion identified in a 5-year-old male with GDD, sensorineural hearing loss, gastrointestinal abnormalities, early postnatal respiratory distress, generalised hypotonia, and absent salivation. Neuropsychological testing demonstrated profound delays in all developmental areas, with skills ranging from 1 to 6 months. The deletion was the result of uniparental paternal isodisomy.

Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein levels compared to control. Knockout mouse model recapitulated phenotypic features such as deafness, abnormal neuronal growth and migration, gastrointestinal abnormalities, and absent salivation.

- PMID: 32754646 (2020) - Compound heterozygous variants (c.1431delT and c.2006-1G>A) were identified in two sibs. The proband, an 8-year-old girl, presented a severe neurodevelopmental disorder (including severe ID), hearing impairment, gastrointestinal problems, hypotonia, and absent tear fluid, saliva, and sweat. Phenotypic overlap was noted in an affected older sister, who died at 22 days of age.

- PMID: 32658972 (2020) - Six unrelated children, all with mild-severe ID/DD, associated with de novo variants in SLC12A2. Additional clinical features included bilateral sensorineural hearing loss (2/6), abnormalities on brain MRI (2/4), and cerebral palsy (2/6). Some functional data in Xenopus laevis oocytes, indicating a role of SLC12A2 in neurogenesis.
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong reviewed gene: PKD1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong Tag for-review tag was added to gene: PKD1L1.
Laterality disorders and isomerism v1.16 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to 31026592; 27616478
Laterality disorders and isomerism v1.15 PKD1L1 Ivone Leong Mode of inheritance for gene: PKD1L1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Severe Paediatric Disorders v1.11 HNRNPH1 Arina Puzriakova Phenotypes for gene: HNRNPH1 were changed from Mental retardation, X-linked, syndromic, Bain type, 300986 to HNRNPH1-related neurodevelopmental disorder
Laterality disorders and isomerism v1.14 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to 31026592
Laterality disorders and isomerism v1.13 PKD1L1 Ivone Leong Publications for gene: PKD1L1 were set to
Laterality disorders and isomerism v1.12 PKD1L1 Ivone Leong Phenotypes for gene: PKD1L1 were changed from to Heterotaxy, visceral, 8, autosomal, 617205
Intellectual disability v3.289 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DHX37 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 26539891; 31256877
Phenotypes for gene: DHX37 were set to Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, MIM#618731
Review for gene: DHX37 was set to GREEN
gene: DHX37 was marked as current diagnostic
Added comment: Overall, 5 unrelated families with bi-allelic variants, all with ID as part of the phenotype. Green for bi-allelic disease

Much less clear association between mono-allelic variants and ID, two missense variants reported. Note one was mosaic, and for the other, paternal sample was not available, so not confirmed to be de novo. No mechanism for mono-allelic vs bi-allelic disease proposed. Overall, Red for mono-allelic variants causing a neurodevelopmental phenotype at this stage. Note there is a separate association between mono allelic variants and DSD.
Sources: Literature
Fetal anomalies v1.95 TRPM7 Zornitza Stark gene: TRPM7 was added
gene: TRPM7 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRPM7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM7 were set to 32503408; 31423533
Phenotypes for gene: TRPM7 were set to Cardiac arrhythmia, stillbirth
Review for gene: TRPM7 was set to AMBER
Added comment: I am not sure if genes linked to stillbirth belong on this panel. This gene encodes an ion channel expressed in the nervous and cardiac systems. It has previously been associated with ALS/dementia in the Guam population, but the variant in question, p.Thr1482Ile is present in >23,000 hets in gnomad, which is out of keeping for a rare Mendelian disorder. Note recent publication associating missense variants with cardiac arrhythmia and stillbirth, with some functional data provided to substantiate effect of variant on protein function but not necessarily establish gene-disease association.
Sources: Literature
Proteinuric renal disease v2.26 YRDC Zornitza Stark gene: YRDC was added
gene: YRDC was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: YRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YRDC were set to 31481669
Phenotypes for gene: YRDC were set to Galloway-Mowat syndrome
Review for gene: YRDC was set to GREEN
gene: YRDC was marked as current diagnostic
Added comment: Three individuals from two unrelated families with typical features of Galloway-Mowat syndrome including proteinuria, microcephaly, developmental delay and brain malformations. Supportive functional data.
Sources: Literature
Proteinuric renal disease v2.26 GON7 Zornitza Stark gene: GON7 was added
gene: GON7 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: GON7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON7 were set to 31481669
Phenotypes for gene: GON7 were set to Galloway-Mowat syndrome
Review for gene: GON7 was set to GREEN
gene: GON7 was marked as current diagnostic
Added comment: 11 individuals from 5 families. Four of the families had the same homozygous variant, shared haplotype suggestive of founder effect. Clinical features included proteinuria, microcephaly, brain malformations and developmental delay. Supportive functional data.
Sources: Literature
Primary immunodeficiency v2.184 TLR7 Zornitza Stark gene: TLR7 was added
gene: TLR7 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TLR7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TLR7 were set to 32706371
Phenotypes for gene: TLR7 were set to Immunodeficiency 74, COVID19-related, X-linked, MIM# 301051
Review for gene: TLR7 was set to GREEN
Added comment: Four affected individuals from two unrelated families and some functional data.
Sources: Literature
Mitochondrial disorders v2.8 NDUFA13 Zornitza Stark reviewed gene: NDUFA13: Rating: AMBER; Mode of pathogenicity: None; Publications: 25901006, 32722639; Phenotypes: Mitochondrial complex I deficiency, nuclear type 28, MIM# 618249; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal central nervous system disorders v1.4 PDE2A Zornitza Stark reviewed gene: PDE2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32467598, 32196122, 29392776; Phenotypes: Paroxysmal dyskinesia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital myopathy v2.5 MYOD1 Zornitza Stark gene: MYOD1 was added
gene: MYOD1 was added to Congenital myopathy. Sources: Literature
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, MIM# 618975
Review for gene: MYOD1 was set to GREEN
gene: MYOD1 was marked as current diagnostic
Added comment: Three unrelated families reported.
Sources: Literature
Cataracts v2.13 PSMC3 Zornitza Stark gene: PSMC3 was added
gene: PSMC3 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to Deafness; cataract
Review for gene: PSMC3 was set to AMBER
Added comment: Three affected individuals from a single consanguineous family reported with homozygous intronic variant. Gene-disease association is supported by an animal model.
Sources: Literature
Intellectual disability v3.289 SLC12A2 Arina Puzriakova Publications for gene: SLC12A2 were set to 30740830
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Classified gene: SLC12A2 as Amber List (moderate evidence)
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least three unrelated cases presenting a relevant phenotype in association with biallelic variants in SLC12A2.
Intellectual disability v3.288 SLC12A2 Arina Puzriakova Gene: slc12a2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.287 SLC12A2 Arina Puzriakova Tag for-review tag was added to gene: SLC12A2.
Intellectual disability v3.287 SLC12A2 Arina Puzriakova reviewed gene: SLC12A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28940097, 30740830, 32754646; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Segmental overgrowth disorders v2.7 SUZ12 Sarah Leigh Classified gene: SUZ12 as Amber List (moderate evidence)
Segmental overgrowth disorders v2.7 SUZ12 Sarah Leigh Gene: suz12 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders v2.6 SUZ12 Sarah Leigh gene: SUZ12 was added
gene: SUZ12 was added to Segmental overgrowth disorders. Sources: Literature
for-review tags were added to gene: SUZ12.
Mode of inheritance for gene: SUZ12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SUZ12 were set to 28229514; 30019515; 31736240; 15385962; 19535498; 31724824
Phenotypes for gene: SUZ12 were set to Imagawa-Matsumoto syndrome 618786
Review for gene: SUZ12 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Classified gene: SUZ12 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in at least 13 affected individuals from 12 families.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.97 SUZ12 Sarah Leigh Gene: suz12 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.96 SUZ12 Sarah Leigh Phenotypes for gene: SUZ12 were changed from Imagawa-Matsumoto syndrome, MIM# 618786 to Imagawa-Matsumoto syndrome 618786
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.95 SUZ12 Sarah Leigh Publications for gene: SUZ12 were set to 31736240; 28229514
Genetic epilepsy syndromes v2.150 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.150 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Three patients from two unrelated families with myoclonic seizures, and additional focal epilepsy with versive head movement in one patient (onset at birth/6 months, respectively).

Additional unrelated cases required before inclusion on a diagnostic panel; and therefore, rating Amber in anticipation of further publications (added to watchlist).
Genetic epilepsy syndromes v2.150 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.149 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Genetic epilepsy syndromes v2.149 EXOC7 Arina Puzriakova gene: EXOC7 was added
gene: EXOC7 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to Brain atrophy; Seizures; Developmental delay; Microcephaly
Added comment: PMID: 32103185 (2020) - 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Literature
Intellectual disability v3.287 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Intellectual disability v3.287 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild-severe DD is reported in all surviving patients to date (4 individuals from 2 families), additional unrelated cases required before inclusion on a diagnostic panel.

Therefore, rating Amber in anticipation of further publications (added to watchlist).
Intellectual disability v3.287 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Classified gene: EXOC7 as Amber List (moderate evidence)
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Added comment: Comment on list classification: Though mild microcephaly reported in 5/8 cases (-0.5 to -2.6 SD), rating Amber as severity of presentation is not within the scope of this panel.
Severe microcephaly v2.21 EXOC7 Arina Puzriakova Gene: exoc7 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.286 EXOC7 Arina Puzriakova Tag watchlist tag was added to gene: EXOC7.
Childhood onset dystonia or chorea or related movement disorder v1.51 HNRNPH1 Arina Puzriakova Tag for-review tag was added to gene: HNRNPH1.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Tag for-review tag was added to gene: HNRNPH1.
Childhood onset dystonia or chorea or related movement disorder v1.51 HNRNPH1 Arina Puzriakova Classified gene: HNRNPH1 as Amber List (moderate evidence)
Childhood onset dystonia or chorea or related movement disorder v1.51 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 6 unrelated cases with a movement phenotype.
Childhood onset dystonia or chorea or related movement disorder v1.51 HNRNPH1 Arina Puzriakova Gene: hnrnph1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia or chorea or related movement disorder v1.50 HNRNPH1 Arina Puzriakova gene: HNRNPH1 was added
gene: HNRNPH1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPH1 were set to 29938792; 32335897
Phenotypes for gene: HNRNPH1 were set to HNRNPH1-related neurodevelopmental disorder
Review for gene: HNRNPH1 was set to GREEN
Added comment: Probable gene for HNRNPH1-related neurodevelopmental disorder in G2P, but currently not associated with any phenotype in OMIM (last edited on 21/07/2017).

Two studies report de novo variants in 8 unrelated cases with a syndromic intellectual disability disorder. Clinical features included moderate-severe GDD/ID (7/7), abnormalities on brain MRI (8/8), ophthalmological abnormalities (7/8), short stature (6/8), and microcephaly (6/8). Movement manifestations were also observed - 3 individuals were non-ambulatory, while another 3 presented dystonia, one of whom also had ataxia, tremor, and wide‐based gait.
Sources: Literature
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova changed review comment from: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.; to: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Classified gene: HNRNPH1 as Amber List (moderate evidence)
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: Two studies report de novo variants in at least 7 unrelated cases with moderate-severe GDD/ID.
Intellectual disability v3.286 HNRNPH1 Arina Puzriakova Gene: hnrnph1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.12 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Ataxia and cerebellar anomalies - narrow panel v2.12 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Ataxia and cerebellar anomalies - narrow panel v2.12 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.12 HARS Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel but additional cases required. Therefore, rating Amber in anticipation of further publications.
Ataxia and cerebellar anomalies - narrow panel v2.12 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.11 HARS Arina Puzriakova gene: HARS was added
gene: HARS was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: HARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HARS were set to 32333447
Phenotypes for gene: HARS were set to Multisystem ataxic syndrome; Intellectual disability
Review for gene: HARS was set to AMBER
Added comment: PMID: 32333447 (2020) - Three individuals from two unrelated families harbouring biallelic HARS variants. Manifestations included microcephaly, mild‐to severe ID, skeletal deformities, and ataxic broad base gait with clinical features affecting the cerebellar and pyramidal tract system. Some supportive functional analysis of the variants in skin fibroblasts and yeast.
Sources: Literature
Intellectual disability v3.285 HARS Arina Puzriakova commented on gene: HARS: Added new-gene-name tag, new approved HGNC gene symbol for HARS is HARS1
Intellectual disability v3.285 HARS Arina Puzriakova Tag new-gene-name tag was added to gene: HARS.
Intellectual disability v3.285 HARS Arina Puzriakova Classified gene: HARS as Amber List (moderate evidence)
Intellectual disability v3.285 HARS Arina Puzriakova Added comment: Comment on list classification: Relevant phenotype for this panel but additional cases required. Therefore, rating Amber in anticipation of further publications.
Intellectual disability v3.285 HARS Arina Puzriakova Gene: hars has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.95 GDF2 Zornitza Stark gene: GDF2 was added
gene: GDF2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GDF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDF2 were set to 32618121
Phenotypes for gene: GDF2 were set to Lymphatic dysplasia; hydrothorax; hydrops
Review for gene: GDF2 was set to RED
Added comment: Single family reported, two affected individuals. New MOI.

Monoallelic variants in this gene are associated with HHT/PAH.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.10 EXOSC5 Arina Puzriakova changed review comment from: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature; to: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.10 EXOSC5 Arina Puzriakova Classified gene: EXOSC5 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.10 EXOSC5 Arina Puzriakova Added comment: Comment on list classification: Three unrelated families presenting ataxia in association with cerebellar hypoplasia/atrophy. However, all harbour the same p.Thr114Ile variant, and thus it is unclear whether other EXOSC5 variants result in cerebellar ataxia.

Therefore, rating Amber in anticipation of additional publications/clinical evidence.
Ataxia and cerebellar anomalies - narrow panel v2.10 EXOSC5 Arina Puzriakova Gene: exosc5 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.9 EXOSC5 Arina Puzriakova Publications for gene: EXOSC5 were set to 32504085
Ataxia and cerebellar anomalies - narrow panel v2.8 EXOSC5 Arina Puzriakova edited their review of gene: EXOSC5: Changed publications: 32504085, 29302074
Ataxia and cerebellar anomalies - narrow panel v2.8 EXOSC5 Arina Puzriakova gene: EXOSC5 was added
gene: EXOSC5 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EXOSC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC5 were set to 32504085
Phenotypes for gene: EXOSC5 were set to Short stature; Motor developmental delays; Cerebellar hypoplasia; Ataxia
Added comment: - PMID: 32504085 (2020) - Five patients from four families with biallelic variants in EXCOSC5. Clinical features included short stature (3/5), developmental delays that affect motor skills (3/5), hypotonia (4/5), ataxia (3/4), cerebellar hypoplasia/atrophy (4/5). Cognitive function was generally preserved, but included mild speech delays in one patient.
Cerebellar ataxia was described in two sibs and one singleton - all of whom were compound heterozygous for the p.Thr114Ile variant, inherited in trans with a frameshift variant (p.His30Thrfs*35) or deletion involving exons 5–6 of EXOSC5, respectively.

A LoF zebrafish model resulted in a variety of morphological defects including shortened and curved tails/bodies, reduced eye/head size and oedema. Functional studies of the variants in budding yeast and cultured cells showed some defects in RNA exosome function and interactions, that could not be explained by decrease in the steady-state level of EXOSC5.

- PMID: 29302074 (2019) - Three sibs with a homozygous EXCOSC5 variant (p.Thr114Ile), associated with mild motor delays, cerebellar ataxia, nystagmus, dysarthria, and moderate ID. The family is also described in PMID: 30950035. No functional studies of the variant were undertaken.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.49 PDGFB Zornitza Stark reviewed gene: PDGFB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 4 615007; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.49 OCLN Zornitza Stark reviewed gene: OCLN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudo-TORCH syndrome 1, MIM# 251290; Mode of inheritance: None
Childhood onset dystonia or chorea or related movement disorder v1.49 L2HGDH Zornitza Stark reviewed gene: L2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753671, 18780161, 15824270, 10399870; Phenotypes: L-2-hydroxyglutaric aciduria MIM#236792; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset dystonia or chorea or related movement disorder v1.49 KCNQ2 Zornitza Stark reviewed gene: KCNQ2: Rating: RED; Mode of pathogenicity: None; Publications: 12742592; Phenotypes: Epileptic encephalopathy, early infantile, 7 MIM#613720; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.49 IRF2BPL Zornitza Stark gene: IRF2BPL was added
gene: IRF2BPL was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF2BPL were set to 30057031; 30166628
Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088
Review for gene: IRF2BPL was set to GREEN
gene: IRF2BPL was marked as current diagnostic
Added comment: PMID: 30057031 - 7 individuals with neurodevelopmental regression (5/7), progressive ataxia (5/7), seizures (7/7), spasticity (2/7), dystonia (3/7) and global devel delay (7/7). PTCs produced a more severe phenotype than missense. Onset was in childhood. Cerebellar changes also less frequently reported.

PMID: 30166628 - 11 individuals with de novo PTCs with childhood neurological regression, epilepsy (7/11), hypotonia (5/11), dystonia (3/11), cerebellar atrophy (5/10). MRI showed CNS defects in 6/10 patients.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.49 HPRT1 Zornitza Stark reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301328; Phenotypes: Lesch-Nyhan syndrome, MIM# 300322; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset dystonia or chorea or related movement disorder v1.49 GRIN1 Zornitza Stark gene: GRIN1 was added
gene: GRIN1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: GRIN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072
Phenotypes for gene: GRIN1 were set to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820
Review for gene: GRIN1 was set to GREEN
gene: GRIN1 was marked as current diagnostic
Added comment: Over 20 individuals reported with de novo missense variants in GRIN1 and severe neurodevelopmental phenotype, comprising ID, seizures, and a movement disorder, in particular dystonia. Two families reported with bi-allelic variants: different mechanism postulated (LOF vs affecting channel functioning or hypomorphic alleles), parents were carriers and unaffected. Movement disorder, in particular dystonia also reported in bi-allelic cases.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.49 GNB1 Zornitza Stark gene: GNB1 was added
gene: GNB1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: GNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNB1 were set to 27108799; 30194818; 27668284; 31034681
Phenotypes for gene: GNB1 were set to Mental retardation, autosomal dominant 42, MIM# 616973
Review for gene: GNB1 was set to GREEN
gene: GNB1 was marked as current diagnostic
Added comment: Multiple reports of dystonia in this disorder. In a recent series of 18 individuals with de novo mutations, the most observed substitution affected the p.Ile80 residue in exon 6, with 28% of individuals carrying a variant at this residue. Dystonia and growth delay were observed more frequently in individuals carrying variants in this residue, suggesting a potential genotype-phenotype correlation.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.49 GLRB Zornitza Stark reviewed gene: GLRB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperekplexia 2, MIM# 614619; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.49 FXN Zornitza Stark reviewed gene: FXN: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Friedreich ataxia, MIM# 229300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.49 FUCA1 Zornitza Stark reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31064022; Phenotypes: Fucosidosis, MIM#230000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.49 FOXG1 Zornitza Stark reviewed gene: FOXG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27029630; Phenotypes: Rett syndrome, congenital variant, MIM# 613454; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Childhood onset dystonia or chorea or related movement disorder v1.49 FITM2 Zornitza Stark gene: FITM2 was added
gene: FITM2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: FITM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FITM2 were set to 28067622; 30214770; 30288795
Phenotypes for gene: FITM2 were set to Siddiqi syndrome MIM#618635; dystonia; deafness
Review for gene: FITM2 was set to GREEN
gene: FITM2 was marked as current diagnostic
Added comment: 7 cases from 3 unrelated families (2 consanguineous) with a dystonia-deafness syndrome and a supporting Drosophila model.
Sources: Expert list
Childhood onset dystonia or chorea or related movement disorder v1.49 CSTB Zornitza Stark reviewed gene: CSTB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) 254800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.49 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: RED; Mode of pathogenicity: None; Publications: 10762541, 9628818, 27003325; Phenotypes: Episodic ataxia, type 5, MIM#613855; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.49 C9orf72 Zornitza Stark changed review comment from: Dystonia is well described but this appears to be an adult-onset disorder.; to: Dystonia is well described but this appears to be an adult-onset disorder. Also note condition is caused by heterozygous hexanucleotide repeat expansion (GGGGCC) in a noncoding region of the C9ORF72 gene.
Childhood onset dystonia or chorea or related movement disorder v1.49 C9orf72 Zornitza Stark reviewed gene: C9orf72: Rating: RED; Mode of pathogenicity: None; Publications: 26166205, 24363131, 26187722; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, MIM# 105550; Mode of inheritance: None
Childhood onset dystonia or chorea or related movement disorder v1.49 BCS1L Zornitza Stark reviewed gene: BCS1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia or chorea or related movement disorder v1.49 ALDH18A1 Zornitza Stark reviewed gene: ALDH18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 9B, autosomal recessive, MIM# 616586, Spastic paraplegia 9A, autosomal dominant, MIM# 601162; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia or chorea or related movement disorder v1.49 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: 22964162, 16541453; Phenotypes: Spastic ataxia 5, autosomal recessive MIM#614487; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 YIF1B Zornitza Stark gene: YIF1B was added
gene: YIF1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098; 26077767
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Review for gene: YIF1B was set to GREEN
gene: YIF1B was marked as current diagnostic
Added comment: 6 individuals (from 5 families) with biallelic YIF1B truncating variants reported. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.
Sources: Expert list
Severe microcephaly v2.20 UNC80 Zornitza Stark gene: UNC80 was added
gene: UNC80 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UNC80 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC80 were set to 26708751; 26708753; 26545877; 29572195
Phenotypes for gene: UNC80 were set to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801
Review for gene: UNC80 was set to GREEN
gene: UNC80 was marked as current diagnostic
Added comment: Summary: Many patients reported as microcephalic. Not all have head circumference < -3SD but there are at least 3 unrelated individuals reported with head circumference smaller than this.

PMID 26708751: 4 individuals from 3 families reported. At 4 years one had OFC -4SD (the others 2nd centile at 4yo, 3rd centile at 15yo, and 10th centile at 9yo).

PMID 26708753: Two 'not directly related' families F1 and F2 identified with the same variant. A third and fourth family had different variants. All affected individuals described were microcephalic (F1: -3.2SD at 4yo; F2: -4SD at 2yo and -2.9SD at 13mo; F3: -2.4SD at 7yo; F4: 9th centile at 4yo and 5th centile at 8yo).

PMID 26545877: 7 affected individuals from 2 distantly related families with the same nonsense variant were all microcephalic (<2nd centile).

PMID 29572195: 2 unrelated individuals reported. Head circumference of patient 1 was -0.5SD at 9yo; Patient 2 -3.7SD at 3yo.
Sources: Expert list
Severe microcephaly v2.20 UGP2 Zornitza Stark gene: UGP2 was added
gene: UGP2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGP2 were set to 31820119
Phenotypes for gene: UGP2 were set to Epileptic encephalopathy; intellectual disability; microcephaly
Review for gene: UGP2 was set to GREEN
gene: UGP2 was marked as current diagnostic
Added comment: 22 individuals from 15 families reported with the same homozygous missense variant in this gene, chr2:64083454A > G, which causes a disruption of the start codon in the shorter isoform, which is expressed in brain.
Sources: Expert list
Severe microcephaly v2.20 UBE3A Zornitza Stark gene: UBE3A was added
gene: UBE3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: UBE3A was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Phenotypes for gene: UBE3A were set to Angelman syndrome MIM#105830
Review for gene: UBE3A was set to GREEN
gene: UBE3A was marked as current diagnostic
Added comment: Microcephaly is a key feature.
Sources: Expert list
Severe microcephaly v2.20 TSEN54 Zornitza Stark gene: TSEN54 was added
gene: TSEN54 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN54 were set to 20952379; 20301773
Phenotypes for gene: TSEN54 were set to Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753)
Review for gene: TSEN54 was set to GREEN
gene: TSEN54 was marked as current diagnostic
Added comment: Microcephaly is a common feature of TSEN54 pontocerebellar hypoplasia (progressive in type 2, present at birth in type 4).
Sources: Expert list
Severe microcephaly v2.20 TSEN15 Zornitza Stark gene: TSEN15 was added
gene: TSEN15 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TSEN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN15 were set to 27392077
Phenotypes for gene: TSEN15 were set to Pontocerebellar hypoplasia, type 2F MIM#617026
Review for gene: TSEN15 was set to GREEN
gene: TSEN15 was marked as current diagnostic
Added comment: PMID 27392077 Reports four individuals from three families with PCH type 2 and different homozygous missense variants, all had progressive microcephaly (between -3SD and -9.7SD). Functional studies indicated that all variants resulted in almost complete lack of in vitro tRNA cleavage activity.
Sources: Expert list
Severe microcephaly v2.20 TRIO Zornitza Stark gene: TRIO was added
gene: TRIO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRIO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIO were set to 26721934; 32109419
Phenotypes for gene: TRIO were set to Mental retardation, autosomal dominant 44, MIM# 617061
Review for gene: TRIO was set to GREEN
gene: TRIO was marked as current diagnostic
Added comment: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly.
Sources: Expert list
Severe microcephaly v2.20 DYNC1I2 Zornitza Stark gene: DYNC1I2 was added
gene: DYNC1I2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492
Review for gene: DYNC1I2 was set to GREEN
gene: DYNC1I2 was marked as current diagnostic
Added comment: Five individuals from three unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 DPM1 Zornitza Stark gene: DPM1 was added
gene: DPM1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DPM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPM1 were set to 16641202; 10642602; 10642597
Phenotypes for gene: DPM1 were set to Congenital disorder of glycosylation, type Ie 608799
Review for gene: DPM1 was set to GREEN
gene: DPM1 was marked as current diagnostic
Added comment: PMID: 16641202 - 2 siblings of consanguineous parents. One patient showed retarded motor skills at 1, 2 and 4 years old, with distal myopathy present at 3 years of age. The younger sister presented at 7 weeks of age with generalized hypotonia. Both had normal CK levels. Both siblings were progressively microcephalic.

PMID: 10642602 - 2 chet siblings with hypotonia within the first year of life. Both had elevated CK. Both siblings were progressively microcephalic

PMID: 10642597 - 2 unrelated patients. One had profound hypotonia at 3 years of age. The other patient was markedly hypotonic in infancy. Both were microcephalic and hd elevated CK levels.
Sources: Expert list
Severe microcephaly v2.20 DNMT3A Zornitza Stark gene: DNMT3A was added
gene: DNMT3A was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: DNMT3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DNMT3A were set to 30478443
Phenotypes for gene: DNMT3A were set to intellectual disability; microcephaly; short stature
Review for gene: DNMT3A was set to GREEN
gene: DNMT3A was marked as current diagnostic
Added comment: Three individuals reported, two with the same de novo missense variant. Postulated to be GOF as opposed to LOF variants in this gene which cause an overgrowth syndrome. Animal model supports pathogenicity.
Sources: Expert list
Severe microcephaly v2.20 DNA2 Zornitza Stark reviewed gene: DNA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, MIM#615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.20 CTU2 Zornitza Stark gene: CTU2 was added
gene: CTU2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142)
Review for gene: CTU2 was set to GREEN
gene: CTU2 was marked as current diagnostic
Added comment: Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL) as proposed by authors.

PMID: 26633546
- 3 consanguineous families all with the same splice variant (NM_001012762.1:c.873G>A). Assumed to be founder variant
- all had microcephaly but measurements were not provided

PMID: 27480277
- 2 additional patients from an extended consanguineous family with the same variant as above
- Patient 1: head circumference of -3.5SD at birth, not growing
- Patient 2: head circumference of -4.3 SD

PMID: 31301155
- 5 new patients with microcephaly (no measurements provided)
- 3x PTVs and 1x missense
Sources: Expert list
Severe microcephaly v2.20 CTSF Zornitza Stark gene: CTSF was added
gene: CTSF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CTSF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTSF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTSF were set to Mental retardation, autosomal dominant 21 (MIM#615502)
Review for gene: CTSF was set to GREEN
gene: CTSF was marked as current diagnostic
Added comment: PMID: 23746550
- 4 probands, 2x PTV, 1x missense, 1x 280kb deletion (all de novo)
- OFCs ranges from -0.8 SD (the proband with the deletion) to -3.51 SD

PMID: 30893510
- 3 probands, de novo 2x PTV and 1x missense
- OFCs ranges from < -2 to < -3 SD

PMID: 28619046
- 1x proband with de novo fs
- head circumference was under 10th centle
Sources: Expert list
Severe microcephaly v2.20 CSNK2A1 Zornitza Stark gene: CSNK2A1 was added
gene: CSNK2A1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CSNK2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CSNK2A1 were set to 29240241
Phenotypes for gene: CSNK2A1 were set to Okur-Chung neurodevelopmental syndrome MIM#617062
Review for gene: CSNK2A1 was set to GREEN
gene: CSNK2A1 was marked as current diagnostic
Added comment: Microcephaly is a feature of the condition in 8/14 cases with de novo variants.
Sources: Expert list
Severe microcephaly v2.20 CHAMP1 Zornitza Stark gene: CHAMP1 was added
gene: CHAMP1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: CHAMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHAMP1 were set to 27148580; 26340335
Phenotypes for gene: CHAMP1 were set to Mental retardation, autosomal dominant 40 (MIM#616579)
Review for gene: CHAMP1 was set to GREEN
gene: CHAMP1 was marked as current diagnostic
Added comment: PMID: 27148580;
- 10 patients including 5 from Hempel et al (PMID: 26340335)
- 7 with microcephaly defined as <3rd centile
- all PTVs and de novo

PMID: 26340335;
- 5 unrelated patients OFC at birth ranges from -0.4 to -3.1 SD
Sources: Expert list
Severe microcephaly v2.20 CEP63 Zornitza Stark reviewed gene: CEP63: Rating: AMBER; Mode of pathogenicity: None; Publications: 21983783, 26158450; Phenotypes: Seckel syndrome 6, MIM#614728; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 BUB1B Zornitza Stark gene: BUB1B was added
gene: BUB1B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BUB1B were set to 18548531
Phenotypes for gene: BUB1B were set to Mosaic variegated aneuploidy syndrome 1 (MIM#257300)
Review for gene: BUB1B was set to GREEN
gene: BUB1B was marked as current diagnostic
Added comment: Severe microcephaly is a feature of MVAS. PMID: 18548531: review of 13 families with 12 presenting with microcephaly
Sources: Expert list
Severe microcephaly v2.20 BPTF Zornitza Stark gene: BPTF was added
gene: BPTF was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BPTF were set to 28942966
Phenotypes for gene: BPTF were set to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755
Review for gene: BPTF was set to GREEN
gene: BPTF was marked as current diagnostic
Added comment: Microcephaly observed in 7/9 individuals reported.
Sources: Expert list
Severe microcephaly v2.20 AARS Zornitza Stark gene: AARS was added
gene: AARS was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AARS were set to 28493438; 25817015
Phenotypes for gene: AARS were set to Epileptic encephalopathy, early infantile, 29, MIM# 616339
Review for gene: AARS was set to GREEN
gene: AARS was marked as current diagnostic
Added comment: Bi-allelic variants associated with a severe phenotype comprising leukodystrophy, epilepsy, microcephaly and neurodevelopmental delay reported in three families.
Sources: Expert list
Severe microcephaly v2.20 FOXG1 Zornitza Stark gene: FOXG1 was added
gene: FOXG1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: FOXG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Phenotypes for gene: FOXG1 were set to Rett syndrome, congenital variant, MIM# 613454
Review for gene: FOXG1 was set to GREEN
gene: FOXG1 was marked as current diagnostic
Added comment: More than 20 individuals reported with de novo variants in this gene. Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Expert list
Severe microcephaly v2.20 EIF2S3 Zornitza Stark gene: EIF2S3 was added
gene: EIF2S3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EIF2S3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: EIF2S3 were set to 23063529; 27333055; 28055140; 32799315
Phenotypes for gene: EIF2S3 were set to MEHMO syndrome, MIM# 300148
Review for gene: EIF2S3 was set to GREEN
Added comment: 9 families reported (3 had the same variant) with MEHMO syndrome (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity).
Sources: Expert list
Genetic epilepsy syndromes v2.148 TRIP13 Zornitza Stark changed review comment from: Phenotype is highly variable but seizures reported in 2/6 cases.; to: Phenotype is highly variable but seizures reported in 2/6 cases. Note 5/6 families had the same homozygous variant, p.Arg354X, suggestive of founder effect.
Genetic epilepsy syndromes v2.148 TRIP13 Zornitza Stark edited their review of gene: TRIP13: Changed rating: AMBER
Severe microcephaly v2.20 TRAPPC9 Zornitza Stark gene: TRAPPC9 was added
gene: TRAPPC9 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Phenotypes for gene: TRAPPC9 were set to Mental retardation, autosomal recessive 13, MIM# 613192
Review for gene: TRAPPC9 was set to GREEN
gene: TRAPPC9 was marked as current diagnostic
Added comment: Microcephaly is part of the phenotype.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC6B Zornitza Stark gene: TRAPPC6B was added
gene: TRAPPC6B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Review for gene: TRAPPC6B was set to GREEN
gene: TRAPPC6B was marked as current diagnostic
Added comment: Five unrelated families reported with autosomal recessive neurodegenerative disorder characterised by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC12 Zornitza Stark gene: TRAPPC12 was added
gene: TRAPPC12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC12 were set to 32369837; 28777934
Phenotypes for gene: TRAPPC12 were set to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Review for gene: TRAPPC12 was set to GREEN
gene: TRAPPC12 was marked as current diagnostic
Added comment: Four families reported with a severe progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss.
Sources: Expert list
Severe microcephaly v2.20 TPRKB Zornitza Stark gene: TPRKB was added
gene: TPRKB was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TPRKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPRKB were set to 28805828; 30053862
Phenotypes for gene: TPRKB were set to Galloway-Mowat syndrome 5, MIM# 617731
Review for gene: TPRKB was set to GREEN
gene: TPRKB was marked as current diagnostic
Added comment: Three unrelated families reported with renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly.
Sources: Expert list
Severe microcephaly v2.20 TP53RK Zornitza Stark gene: TP53RK was added
gene: TP53RK was added to Severe microcephaly. Sources: Expert Review
Mode of inheritance for gene: TP53RK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TP53RK were set to 28805828; 30053862
Phenotypes for gene: TP53RK were set to Galloway-Mowat syndrome 4, MIM# 617730
Review for gene: TP53RK was set to GREEN
gene: TP53RK was marked as current diagnostic
Added comment: At least 4 unrelated families reported with renal-neurologic disease characterised by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable.
Sources: Expert Review
Severe microcephaly v2.20 TCF4 Zornitza Stark gene: TCF4 was added
gene: TCF4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TCF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCF4 were set to 18728071; 22934316
Phenotypes for gene: TCF4 were set to Pitt-Hopkins syndrome, MIM# 610954
Review for gene: TCF4 was set to GREEN
gene: TCF4 was marked as current diagnostic
Added comment: Well established gene-disease association. Microcephaly reported in around 60%.
Sources: Expert list
Intellectual disability v3.284 CCDC88A Arina Puzriakova Classified gene: CCDC88A as Amber List (moderate evidence)
Intellectual disability v3.284 CCDC88A Arina Puzriakova Added comment: Comment on list classification: This gene has been upgraded from Red to Amber based on the external reviews by Konstantinos Varvagiannis and Zornitza Stark.
Intellectual disability v3.284 CCDC88A Arina Puzriakova Gene: ccdc88a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.283 CCDC174 Arina Puzriakova Classified gene: CCDC174 as Red List (low evidence)
Intellectual disability v3.283 CCDC174 Arina Puzriakova Added comment: Comment on list classification: Rating Red as only one founder variant reported to-date in a single publication - currently no evidence that other variants in this gene are disease-causing.

Added 'founder-effect' tag
Intellectual disability v3.283 CCDC174 Arina Puzriakova Gene: ccdc174 has been classified as Red List (Low Evidence).
Intellectual disability v3.282 CCDC174 Arina Puzriakova Tag founder-effect tag was added to gene: CCDC174.
Intellectual disability v3.282 TAF1C Arina Puzriakova Classified gene: TAF1C as Amber List (moderate evidence)
Intellectual disability v3.282 TAF1C Arina Puzriakova Gene: taf1c has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency v2.184 TET2 Boaz Palterer gene: TET2 was added
gene: TET2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TET2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TET2 were set to 32518946
Phenotypes for gene: TET2 were set to Primary Immunodeficiency; Lymphoma; Hepatosplenomegaly; Autoimmunity; Developmental delay
Penetrance for gene: TET2 were set to unknown
Review for gene: TET2 was set to AMBER
Added comment: Sources: Literature
Congenital myopathy v2.5 CFL2 Arina Puzriakova reviewed gene: CFL2: Rating: ; Mode of pathogenicity: None; Publications: 32160286; Phenotypes: Nemaline myopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.13 TDRD7 Arina Puzriakova reviewed gene: TDRD7: Rating: ; Mode of pathogenicity: None; Publications: 32420594; Phenotypes: Congenital cataracts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.281 PAK3 Arina Puzriakova reviewed gene: PAK3: Rating: ; Mode of pathogenicity: None; Publications: 31943058; Phenotypes: Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Severe microcephaly v2.20 SVBP Zornitza Stark gene: SVBP was added
gene: SVBP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SVBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SVBP were set to 31363758; 30607023
Phenotypes for gene: SVBP were set to Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, OMIM #618569
Review for gene: SVBP was set to GREEN
Added comment: 5 unrelated families with homozygous mutations in SVBP, microcephaly is part of the phenotype. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls.
Sources: Expert list
Severe microcephaly v2.20 SMO Zornitza Stark gene: SMO was added
gene: SMO was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMO were set to 32413283
Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis
Review for gene: SMO was set to GREEN
gene: SMO was marked as current diagnostic
Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Sources: Expert list
Severe microcephaly v2.20 SLC1A4 Zornitza Stark gene: SLC1A4 was added
gene: SLC1A4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A4 were set to 25930971; 26138499; 26041762; 27193218; 29989513
Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657
Review for gene: SLC1A4 was set to GREEN
Added comment: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly is an autosomal recessive neurodevelopmental disorder characterized by onset of those features and severely impaired global development in early infancy. Most patients are unable to achieve independent walking or speech; some patients have seizures. Multiple affected families reported. Note founder variant p.Glu256Lys is a common founder variant in the Ashkenazi Jewish population.
Sources: Expert list
Severe microcephaly v2.20 SASS6 Zornitza Stark reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 RUSC2 Zornitza Stark gene: RUSC2 was added
gene: RUSC2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: RUSC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RUSC2 were set to 27612186
Phenotypes for gene: RUSC2 were set to Mental retardation, autosomal recessive 61, MIM# 617773
Review for gene: RUSC2 was set to AMBER
Added comment: Two unrelated families reported.
Sources: Expert list
Severe microcephaly v2.20 PUS7 Zornitza Stark gene: PUS7 was added
gene: PUS7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PUS7 were set to 30526862; 30778726; 31583274
Phenotypes for gene: PUS7 were set to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342
Review for gene: PUS7 was set to GREEN
gene: PUS7 was marked as current diagnostic
Added comment: 11 patients from 6 families with ID, speech delay, short stature, microcephaly, and aggressive behavior, with homozygous PUS7 mutations, which segregated with disease.
Sources: Expert list
Severe microcephaly v2.20 PUF60 Zornitza Stark gene: PUF60 was added
gene: PUF60 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUF60 were set to 28327570
Phenotypes for gene: PUF60 were set to Verheij syndrome, MIM# 615583
Review for gene: PUF60 was set to GREEN
gene: PUF60 was marked as current diagnostic
Added comment: Over 15 affected individuals reported. Short stature and dev delay are consistent features. 5/12 in the largest case series had microcephaly in relation to stature (Z-scores −2.48, −4.22, −2.09, −2.99, −2.53 respectively).
Sources: Expert list
Severe microcephaly v2.20 PTPN23 Zornitza Stark gene: PTPN23 was added
gene: PTPN23 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065
Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890
Review for gene: PTPN23 was set to GREEN
Added comment: Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum.
Sources: Expert list
Severe microcephaly v2.20 PPP1R15B Zornitza Stark reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, MIM# 616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 POGZ Zornitza Stark gene: POGZ was added
gene: POGZ was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: POGZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POGZ were set to 26942287
Phenotypes for gene: POGZ were set to White-Sutton syndrome, MIM# 616364
Review for gene: POGZ was set to GREEN
gene: POGZ was marked as current diagnostic
Added comment: Microcephaly is reported in around half of affected individuals.
Sources: Expert list
Severe microcephaly v2.20 PDCD6IP Zornitza Stark gene: PDCD6IP was added
gene: PDCD6IP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDCD6IP were set to 32286682
Phenotypes for gene: PDCD6IP were set to Primary microcephaly
Review for gene: PDCD6IP was set to AMBER
Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. Borderline Red/Amber rating in view of the supportive animal model data.
Sources: Expert list
Severe microcephaly v2.20 DPP6 Zornitza Stark reviewed gene: DPP6: Rating: AMBER; Mode of pathogenicity: None; Publications: 23832105; Phenotypes: Mental retardation, autosomal dominant 33 (MIM#616311); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency v2.184 MCM10 Boaz Palterer edited their review of gene: MCM10: Changed phenotypes: NK Cell deficiency, primary Immunodeficiency
Primary immunodeficiency v2.184 TNFSF13 Boaz Palterer gene: TNFSF13 was added
gene: TNFSF13 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TNFSF13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF13 were set to 32298700
Phenotypes for gene: TNFSF13 were set to APRIL deficiency; Common variable immunodeficiency
Penetrance for gene: TNFSF13 were set to unknown
Primary immunodeficiency v2.184 TOM1 Boaz Palterer gene: TOM1 was added
gene: TOM1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TOM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TOM1 were set to 31263572
Phenotypes for gene: TOM1 were set to early-onset autoimmunity; antibody deficiency; combined immunodeficiency; primary immunodeficiency
Penetrance for gene: TOM1 were set to unknown
Review for gene: TOM1 was set to RED
Added comment: Sources: Literature
Primary immunodeficiency v2.184 MAPK8 Boaz Palterer gene: MAPK8 was added
gene: MAPK8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAPK8 were set to 31901076
Phenotypes for gene: MAPK8 were set to chronic mucocutaneous candidiasis; connective tissue disorders
Penetrance for gene: MAPK8 were set to unknown
Review for gene: MAPK8 was set to AMBER
Added comment: Sources: Literature
Primary immunodeficiency v2.184 CTNNBL1 Boaz Palterer gene: CTNNBL1 was added
gene: CTNNBL1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CTNNBL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNBL1 were set to 32484799
Phenotypes for gene: CTNNBL1 were set to Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency
Penetrance for gene: CTNNBL1 were set to unknown
Review for gene: CTNNBL1 was set to AMBER
Added comment: Sources: Literature
Primary immunodeficiency v2.184 MCM10 Boaz Palterer gene: MCM10 was added
gene: MCM10 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM10 were set to 32865517
Penetrance for gene: MCM10 were set to unknown
Review for gene: MCM10 was set to AMBER
Added comment: Compound heterozygous variants in minichromosomal maintenance complex member 10 (MCM10) were reported as a cause of NK-cell deficiency in a child with fatal susceptibility to CMV.
Sources: Literature
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Classified gene: TRAPPC2L as Amber List (moderate evidence)
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Added comment: Comment on list classification: Rating Amber as additional cases required to delineate the genotype-phenotype relationship. Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications.
Intellectual disability v3.281 TRAPPC2L Arina Puzriakova Gene: trappc2l has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.280 TRAPPC2L Arina Puzriakova gene: TRAPPC2L was added
gene: TRAPPC2L was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC2L were set to 30120216; 32843486
Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331
Review for gene: TRAPPC2L was set to AMBER
Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature
Childhood onset dystonia or chorea or related movement disorder v1.49 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Adult onset movement disorder v1.5 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Possible mitochondrial disorder - nuclear genes v1.16 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hearing loss v2.45 TIMM8A Arina Puzriakova reviewed gene: TIMM8A: Rating: ; Mode of pathogenicity: None; Publications: 32820032; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Intellectual disability v3.279 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.278 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Genetic epilepsy syndromes v2.148 LMBRD2 Arina Puzriakova Classified gene: LMBRD2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.148 LMBRD2 Arina Puzriakova Added comment: Comment on list classification: There is a sufficient number of unrelated cases to rate this gene GREEN at the next major review.
Genetic epilepsy syndromes v2.148 LMBRD2 Arina Puzriakova Gene: lmbrd2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.147 LMBRD2 Arina Puzriakova Tag for-review tag was added to gene: LMBRD2.
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Classified gene: TOGARAM1 as Red List (low evidence)
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Added comment: Comment on list classification: Single family. Additional cases required to corroborate pathogenicity.
Fetal anomalies v1.95 TOGARAM1 Arina Puzriakova Gene: togaram1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.94 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Severe microcephaly v2.20 PCDH12 Zornitza Stark gene: PCDH12 was added
gene: PCDH12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 27164683; 22822038; 30178464
Phenotypes for gene: PCDH12 were set to Diencephalic-mesencephalic junction dysplasia syndrome 1, MIM# 251280
Review for gene: PCDH12 was set to GREEN
Added comment: Diencephalic-mesencephalic junction dysplasia syndrome-1 (DMJDS1) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, severely delayed or even absent psychomotor development with profound intellectual disability, and spasticity or dystonia. Some patients may have seizures and/or visual impairment. Brain imaging shows a characteristic developmental malformation of the midbrain; subtle intracranial calcifications may also be present. At least 12 families reported.
Sources: Expert list
Cerebral vascular malformations v2.5 CCM2 Arina Puzriakova Publications for gene: CCM2 were set to 20301470; 14624391
Intellectual disability v3.278 SUPT16H Arina Puzriakova Publications for gene: SUPT16H were set to http://dx.doi.org/10.1136/jmedgenet-2019-106193
Intellectual disability v3.277 SUPT16H Arina Puzriakova Classified gene: SUPT16H as Amber List (moderate evidence)
Intellectual disability v3.277 SUPT16H Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for this gene to be rated GREEN at the next major review - at least four unrelated individuals with GDD/ID (plus another additional patient with a deletion, albeit encompassing other potentially clinically relevant genes).
Intellectual disability v3.277 SUPT16H Arina Puzriakova Gene: supt16h has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.276 SUPT16H Arina Puzriakova Tag for-review tag was added to gene: SUPT16H.
Severe microcephaly v2.20 ERCC5 Zornitza Stark edited their review of gene: ERCC5: Changed publications: 32052936, 24700531
Severe microcephaly v2.20 ERCC5 Zornitza Stark reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 32052936; Phenotypes: Cerebrooculofacioskeletal syndrome 3 MIM#616570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.20 COASY Sebastian Lunke reviewed gene: COASY: Rating: GREEN; Mode of pathogenicity: None; Publications: 30089828, 28489334; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting v2.3 CTNND1 Eleanor Williams changed review comment from: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).; to: PMID: 32196547 - Alharatani et al 2020 - report an expanded phenotype for CTNND1 patients. They report 13 individuals from nine families with novel protein-truncating variants in CTNND1 identified by WES. The mutations were not previously described in blepharocheilodontic (BCD), orofacial cleft cases nor in gnomAD. 8 patients had de novo variants, 2 inherited from affected parents, 2 participants inherited a variant from a parent with a mild phenotype. 8/13 patients showed cleft palate. Additional phenotypic features seen include mild limb phenotypes (9/13), cardiovascular anomalies (6/13) and Developmental delay and other neurodevelopmental problems (8/13).
Clefting v2.3 CTNND1 Eleanor Williams reviewed gene: CTNND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32196547; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia - adult onset v2.9 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to
Hereditary ataxia - adult onset v2.8 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.45 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to PMID:10325416; 10433969; 10449766; 10545955; 10615135; 10721735; 10753866; 10801130; 10888872; 10888886; 11005794; 11074872; 11290321; 11728338; 11884600; 11932749; 11940649; 12145218; 12473678; 12496760; 12702876; 12915469; 14615517; 14684836; 14749379; 14978102; 15215866; 15311210; 1559980; 15657147; 15684088; 15870198; 1594447; 1606615; 16357870; 16998846; 17312023; 17322882; 17359920; 17470536; 17673620; 17960246; 17994007; 18194272; 19098913; 19246518; 19433415; 1968655; 20081831; 2014266; 21163962; 21532572; 22323818; 22328086; 23365052; 24013172; 24107992; 3210246; 7898717; 8747854; 8917520; 8940105; 9302295; 9333948; 9449671
Hearing loss v2.44 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hereditary neuropathy v1.376 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 21532572
Hereditary neuropathy v1.375 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Paroxysmal central nervous system disorders v1.4 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 23904686; 22328086; 24709307
Paroxysmal central nervous system disorders v1.3 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.205 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.7 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to
Ataxia and cerebellar anomalies - narrow panel v2.6 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.48 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Kleine-Levin syndrome v1.5 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 22328086; 24709307; 23904686
Kleine-Levin syndrome v1.4 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders - adult onset v2.16 DNMT1 Eleanor Williams Publications for gene: DNMT1 were set to 23365052; 8747854; 22328086
Neurodegenerative disorders - adult onset v2.15 DNMT1 Eleanor Williams reviewed gene: DNMT1: Rating: ; Mode of pathogenicity: None; Publications: 31984424; Phenotypes: ; Mode of inheritance: None
Hearing loss v2.44 RIPOR2 Arina Puzriakova Added comment: Comment on mode of inheritance: Only two publications, describing different patterns of inheritance (AR or AD).
Hearing loss v2.44 RIPOR2 Arina Puzriakova Mode of inheritance for gene: RIPOR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hearing loss v2.43 RIPOR2 Arina Puzriakova Classified gene: RIPOR2 as Amber List (moderate evidence)
Hearing loss v2.43 RIPOR2 Arina Puzriakova Added comment: Comment on list classification: Recent publication described several families, but with a founder variant. Therefore currently still insufficient cases for a rating upgrade.
Hearing loss v2.43 RIPOR2 Arina Puzriakova Gene: ripor2 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.42 RIPOR2 Arina Puzriakova reviewed gene: RIPOR2: Rating: ; Mode of pathogenicity: None; Publications: 32631815; Phenotypes: Sensorineural hearing loss; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurodegenerative disorders - adult onset v2.15 NOTCH3 Eleanor Williams Publications for gene: NOTCH3 were set to
Neurodegenerative disorders - adult onset v2.14 NOTCH3 Eleanor Williams reviewed gene: NOTCH3: Rating: ; Mode of pathogenicity: None; Publications: 31960911; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders - adult onset v2.14 TET2 Eleanor Williams gene: TET2 was added
gene: TET2 was added to Neurodegenerative disorders - adult onset. Sources: Literature
Mode of inheritance for gene: TET2 was set to Unknown
Publications for gene: TET2 were set to 31943063
Added comment: PMID: 31943063 - Li et al 2020 - functional studies in mice show that Tet2 depletion in the hippocampus exacerbates Alzheimer disease pathology and cognitive dysfunction at early disease stages
Sources: Literature
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Tag for-review tag was added to gene: ZFYVE19.
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Classified gene: ZFYVE19 as Amber List (moderate evidence)
Cholestasis v1.24 ZFYVE19 Arina Puzriakova Gene: zfyve19 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.23 ZFYVE19 Arina Puzriakova gene: ZFYVE19 was added
gene: ZFYVE19 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: ZFYVE19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE19 were set to 32737136
Phenotypes for gene: ZFYVE19 were set to Cholestasis
Review for gene: ZFYVE19 was set to GREEN
Added comment: PMID: 32737136 (2020) - Nine Han Chinese children from seven families with biallelic, predicted complete LoF variants in ZFYVE19. All patients had high-GGT intrahepatic cholestasis, portal hypertension, and histopathological features of the ductal plate malformation/congenital hepatic fibrosis.

ZFYVE19 depletion in cultured cells from one patient yielded centriolar and axonemal abnormalities, and immunostaining for two ciliary proteins DCDC2 and ACALT showed abnormal localisation in patient cholangiocytes, indicating this as a novel ciliopathy disorder.
Sources: Literature
Hereditary neuropathy v1.375 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25428574
Hereditary neuropathy v1.374 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Paediatric motor neuronopathies v1.33 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25428574
Paediatric motor neuronopathies v1.32 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Possible mitochondrial disorder - nuclear genes v1.16 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Possible mitochondrial disorder - nuclear genes v1.15 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.419 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Neurodegenerative disorders - adult onset v2.13 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to 25113787; 30014597; 27810918; 25576308; 24934289
Inborn errors of metabolism v2.18 CHCHD10 Eleanor Williams Publications for gene: CHCHD10 were set to
Inborn errors of metabolism v2.17 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.418 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Neurodegenerative disorders - adult onset v2.12 CHCHD10 Eleanor Williams reviewed gene: CHCHD10: Rating: ; Mode of pathogenicity: None; Publications: 31261376; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.20 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Genetic epilepsy syndromes v2.147 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.276 ADARB1 Arina Puzriakova Publications for gene: ADARB1 were set to 32220291
Intellectual disability v3.275 ADARB1 Arina Puzriakova Phenotypes for gene: ADARB1 were changed from Intellectual disability; microcephaly; seizures to Neurodevelopmental disorder with hypotonia, microcephaly, and seizures, 618862
Severe microcephaly v2.19 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Genetic epilepsy syndromes v2.146 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
Intellectual disability v3.274 ADARB1 Arina Puzriakova edited their review of gene: ADARB1: Added comment: PMID: 32719099 (2020) - Three additional patients from two consanguineous families with novel biallelic variants in the ADARB1 gene. All affected individuals presented global DD, severe-profound ID, intractable early infantile-onset seizures, severe microcephaly, axial hypotonia and progressive appendicular spasticity. In vitro RNA editing assays showed that both variants resulted in severe impairment or loss of ADAR2 enzymatic activity.; Changed publications: 32220291, 32719099
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Classified gene: KIAA1217 as Amber List (moderate evidence)
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team rating this gene amber. Although there are 10 cases reported, the mode of inheritance and level of penterance is not clear, and it would be useful to have more information prior to diagnostic use
VACTERL-like phenotypes v1.27 KIAA1217 Eleanor Williams Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
VACTERL-like phenotypes v1.26 KIAA1217 Eleanor Williams gene: KIAA1217 was added
gene: KIAA1217 was added to VACTERL-like phenotypes. Sources: Literature
Mode of inheritance for gene: KIAA1217 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KIAA1217 were set to 32369272
Phenotypes for gene: KIAA1217 were set to vertebral malformations
Review for gene: KIAA1217 was set to AMBER
Added comment: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations. 1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency. In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Not associated with any phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams changed review comment from: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available.
Sources: Literature; to: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Not associated with any phenotype in OMIM or Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Classified gene: KIAA1217 as Amber List (moderate evidence)
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team rating this gene amber. Although there are 10 cases reported, the mode of inheritance and level of penterance is not clear, and it would be useful to have more information prior to diagnostic use
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Gene: kiaa1217 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.14 KIAA1217 Eleanor Williams Tag for-review tag was added to gene: KIAA1217.
Skeletal dysplasia v2.14 KIAA1217 Eleanor Williams gene: KIAA1217 was added
gene: KIAA1217 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: KIAA1217 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: KIAA1217 were set to 32369272
Phenotypes for gene: KIAA1217 were set to vertebral malformations
Review for gene: KIAA1217 was set to AMBER
Added comment: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations.  1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency.  In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available.
Sources: Literature
Severe microcephaly v2.19 HIST1H4C Zornitza Stark gene: HIST1H4C was added
gene: HIST1H4C was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: HIST1H4C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HIST1H4C were set to 28920961
Phenotypes for gene: HIST1H4C were set to Growth delay, microcephaly and intellectual disability
Review for gene: HIST1H4C was set to GREEN
gene: HIST1H4C was marked as current diagnostic
Added comment: Two families and a zebrafish model reported initially, another case identified through clinical testing internally.
Sources: Expert list
Severe microcephaly v2.19 KIF14 Zornitza Stark gene: KIF14 was added
gene: KIF14 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: KIF14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF14 were set to 28892560; 29343805
Phenotypes for gene: KIF14 were set to Microcephaly 20, primary, autosomal recessive, MIM# 617914
Review for gene: KIF14 was set to GREEN
gene: KIF14 was marked as current diagnostic
Added comment: At least 8 families reported. Microcephaly ranged from -3.6 to -11 SD.
Sources: Expert list
Severe microcephaly v2.19 LAGE3 Zornitza Stark edited their review of gene: LAGE3: Set current diagnostic: yes
Severe microcephaly v2.19 LAGE3 Zornitza Stark gene: LAGE3 was added
gene: LAGE3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: LAGE3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: LAGE3 were set to 28805828
Phenotypes for gene: LAGE3 were set to Galloway-Mowat syndrome 2, X-linked, MIM# 301006
Review for gene: LAGE3 was set to GREEN
Added comment: Renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. At least three unrelated families and a mouse model.
Sources: Expert list
Severe microcephaly v2.19 OSGEP Zornitza Stark gene: OSGEP was added
gene: OSGEP was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: OSGEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSGEP were set to 28805828; 28272532
Phenotypes for gene: OSGEP were set to Galloway-Mowat syndrome 3, MIM# 617729
Review for gene: OSGEP was set to GREEN
gene: OSGEP was marked as current diagnostic
Added comment: Early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most individuals have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Over 25 families reported.
Sources: Expert list
Severe microcephaly v2.19 NUP188 Zornitza Stark gene: NUP188 was added
gene: NUP188 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to 32021605; 28726809; 32275884
Phenotypes for gene: NUP188 were set to microcephaly; ID; cataract; structural brain abnormalities; hypoventilation
Review for gene: NUP188 was set to GREEN
gene: NUP188 was marked as current diagnostic
Added comment: Eight unrelated individuals reported.
Sources: Expert list
Severe microcephaly v2.19 NUP107 Zornitza Stark gene: NUP107 was added
gene: NUP107 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NUP107 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP107 were set to 28280135; 28117080; 30179222; 25558065
Phenotypes for gene: NUP107 were set to Galloway-Mowat syndrome 7, MIM# 618348
Review for gene: NUP107 was set to GREEN
gene: NUP107 was marked as current diagnostic
Added comment: Autosomal recessive disorder characterised by developmental delay, microcephaly (-5 to -9 SD), and early-onset nephrotic syndrome. Approx 10 families reported. Recurrent variant p.Met101Ile identified in several families, likely represents a South Asian founder allele.
Sources: Expert list
Severe microcephaly v2.19 VRK1 Zornitza Stark gene: VRK1 was added
gene: VRK1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to 19646678; 24126608; 27281532; 31560180
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A MIM#607596
Review for gene: VRK1 was set to GREEN
gene: VRK1 was marked as current diagnostic
Added comment: PMID 19646678: A homozygous nonsense variant was identified in an affected Ashkenazi Jewish family with 3 individuals with SMA-PCH. 2 had severe microcephaly (-6SD at 5yo and -7.9SD at 19mo). The third was noted to be microcephalic but no figures given. PMID 24126608: "Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly". 2 sibs from one family had head circumference -4SD and -6SD and were chet for missense variants. The third unrelated individual was -6SD and hom for a nonsense variant. PMID 27281532: reports another individual with microcephaly but no details provided.
Sources: Expert list
Severe microcephaly v2.19 BRD4 Zornitza Stark gene: BRD4 was added
gene: BRD4 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: BRD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRD4 were set to 29379197; 30302754
Phenotypes for gene: BRD4 were set to Cornelia de Lange-like syndrome
Review for gene: BRD4 was set to AMBER
Added comment: A mixture of evidence from SNVs and CNVs. Note the CNVs are large and only some individuals have documented OFC < -3SD.

PMID: 29379197;
- 4x patients reports however only 3 reported with occipitofrontal circumference of < -3 SD
- 1x microdeletion of 1.04Mb, 1x missense and 1x fs. All de novo

PMID: 30302754
- 1x proband with occipitofrontal circumference 28 cm (−2 SD)
- de novo interstitial deletion involving the short arm of a chromosome 19, 1.97 Mb in size, which included BRD4
Sources: Expert list
Severe microcephaly v2.19 WDR4 Zornitza Stark reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26416026, 28617965, 30079490, 29597095; Phenotypes: Galloway-Mowat syndrome 6 MIM#618347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark edited their review of gene: WDR37: Set current diagnostic: yes
Severe microcephaly v2.19 WDR37 Zornitza Stark gene: WDR37 was added
gene: WDR37 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR37 were set to 31327508; 31327510
Phenotypes for gene: WDR37 were set to Neurooculocardiogenitourinary syndrome MIM#618652
Review for gene: WDR37 was set to GREEN
Added comment: Summary: 7/9 individuals reported with neurooculocardiogenitourinary syndrome had microcephaly. 5 had measurements provided and were severe (-3SD).

PMID 31327510: 4 individuals with de novo missense variants reported, with Neurooculocardiogenitourinary syndrome. All four have microcephaly - 49.5cm at 21yo, 40.2cm at 22mo (-4.8SD), 47.4cm at 7.5yo.

PMID 31327508: 5 probands with de novo missense variants, 3 with microcephaly (0th centile, <3rd centile (-5SD), and 11th centile)
Sources: Expert list
Severe microcephaly v2.19 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204; 31608932
Phenotypes for gene: ATP1A2 were set to hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations
Review for gene: ATP1A2 was set to GREEN
gene: ATP1A2 was marked as current diagnostic
Added comment: This is a distinct phenotype from the one associated with mono-allelic variants.

PMID: 30690204;
- 2 families with severe microcephaly (-6 to -8 SD)
- both homozygous PTVs

PMID: 31608932;
- 4 patients from 2 families
- Family A, all 3 affecteds had severe microcephaly during ultrasound (-3 to -4 SD)
- Family B, no measurements were reported
- both homozygous PTVs
Sources: Expert list
Severe microcephaly v2.19 ARCN1 Zornitza Stark gene: ARCN1 was added
gene: ARCN1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARCN1 were set to 27476655
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay (MIM#617164)
Review for gene: ARCN1 was set to GREEN
gene: ARCN1 was marked as current diagnostic
Added comment: Borderline Amber/Green. Microcephaly is a key part of the phenotype but few exact measurements actually reported.
Sources: Expert list
Severe microcephaly v2.19 AP4S1 Zornitza Stark gene: AP4S1 was added
gene: AP4S1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4S1 were set to 21620353; 25552650; 27444738
Phenotypes for gene: AP4S1 were set to Spastic paraplegia 52, autosomal recessive (MIM#614067)
Review for gene: AP4S1 was set to GREEN
gene: AP4S1 was marked as current diagnostic
Added comment: Borderline Amber/Green as only one affected individual <-3SD; however, part of same gene family as other spastic paraplegias with microcephaly. Microcephaly in another family -2SD and precise information on the microcephaly not available for third family.
Sources: Expert list
Severe microcephaly v2.19 AP4M1 Zornitza Stark gene: AP4M1 was added
gene: AP4M1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4M1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4M1 were set to 28464862; 24700674
Phenotypes for gene: AP4M1 were set to Spastic paraplegia 50, autosomal recessive (MIM#612936)
Review for gene: AP4M1 was set to GREEN
gene: AP4M1 was marked as current diagnostic
Added comment: Despite the OMIM name, this is a complex neurological condition, where microcephaly is an early prominent presenting feature.

PMID: 28464862;
- 1x with severe progressive microcephaly (< - 4 SD)
- homozygous nonsense

PMID: 24700674;
- 2x unrelated patients (1 and 3) < -3 SD head circumference
- 2x homozygous nonsense
Sources: Expert list
Severe microcephaly v2.19 NSD2 Zornitza Stark gene: NSD2 was added
gene: NSD2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: NSD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSD2 were set to 30345613; 31171569
Phenotypes for gene: NSD2 were set to microcephaly; intellectual disability
Review for gene: NSD2 was set to GREEN
Added comment: Microcephaly reported in 6 of 7 individuals with LOF variants in this gene.
Sources: Expert list
Severe microcephaly v2.19 ZNF335 Zornitza Stark reviewed gene: ZNF335: Rating: GREEN; Mode of pathogenicity: None; Publications: 23178126, 27540107, 29652087; Phenotypes: Microcephaly 10, primary, autosomal recessive (MIM#615095); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 MED17 Zornitza Stark gene: MED17 was added
gene: MED17 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MED17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Phenotypes for gene: MED17 were set to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668
Review for gene: MED17 was set to GREEN
gene: MED17 was marked as current diagnostic
Added comment: Five individuals from four families reported initially, founder effect for p.Leu371Pro. Two additional families reported since with different variants, one family with milder phenotype.
Sources: Expert list
Severe microcephaly v2.19 MECP2 Zornitza Stark gene: MECP2 was added
gene: MECP2 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MECP2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: MECP2 were set to Rett syndrome, MIM# 312750; Encephalopathy, neonatal severe 300673
Review for gene: MECP2 was set to GREEN
gene: MECP2 was marked as current diagnostic
Added comment: Well established gene-disease association, microcephaly is a key phenotypic feature both in Rett syndrome and in males affected by severe neonatal encephalopathy.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark changed review comment from: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list; to: Activating variants in AKT3 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AKT3 Zornitza Stark gene: AKT3 was added
gene: AKT3 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AKT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT3 were set to 32827175; 31929334; 30853971; 30053339; 25424989
Phenotypes for gene: AKT3 were set to Microcephaly
Review for gene: AKT3 was set to AMBER
Added comment: Activating variants in AKT2 and micro duplications are associated with macrocephaly/megalencephaly. Note that deletions involving AKT3 have consistently been associated with microcephaly. However, most involve at least one other gene apart from AKT3. One family reported with only AKT3 deleted: deletion was inherited from a phenotypically normal parent, suggesting either additional effects in bigger deletions or incomplete penetrance. You may wish to consider adding the CNV region to this panel rather than AKT3 alone, in which case I suspect the region has enough evidence for a Green rating.
Sources: Expert list
Severe microcephaly v2.19 AP4E1 Zornitza Stark gene: AP4E1 was added
gene: AP4E1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4E1 were set to 20972249; 21620353; 21937992
Phenotypes for gene: AP4E1 were set to Spastic paraplegia 51, autosomal recessive, MIM# 613744
Review for gene: AP4E1 was set to GREEN
gene: AP4E1 was marked as current diagnostic
Added comment: Autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development. Microcephaly is a prominent, presenting feature. At least 3 families reported.
Sources: Expert list
Severe microcephaly v2.19 AP4B1 Zornitza Stark gene: AP4B1 was added
gene: AP4B1 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to 21620353; 22290197; 24700674; 24781758
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive, MIM# 614066
Review for gene: AP4B1 was set to GREEN
gene: AP4B1 was marked as current diagnostic
Added comment: Microcephaly is an early, prominent presenting feature of this progressive neurological disorder. At least 4 unrelated families reported.
Sources: Expert list
Severe microcephaly v2.19 ANKLE2 Zornitza Stark edited their review of gene: ANKLE2: Changed rating: GREEN
Severe microcephaly v2.19 ANKLE2 Zornitza Stark reviewed gene: ANKLE2: Rating: ; Mode of pathogenicity: None; Publications: 25259927, 30214071, 31735666; Phenotypes: Microcephaly 16, primary, autosomal recessive, MIM# 616681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe microcephaly v2.19 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: 31555905; Phenotypes: microcephaly, intellectual disability, epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32424323; Phenotypes: Congenital Disorder of Glycosylation, Type Iq (OMIM: 612379), Kahrizi Syndrome (OMIM: 612713); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer Deleted their review
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer changed review comment from: Comment on rating: At least 38 genetically confirmed patients (from 26 families) have been reported. The frequency and prevalence of the disease are not known. Most patients have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico, and Turkey.

Comment on the mode of pathogenicity: Loss-of-function; At least 15 variants have been reported: 11 nonsense variants, 3 missense variants, and a large deletion (www.lovd.nl/SRD5A3).

Comment on the mode of inheritance: AR (homozygous or compound heterozygous); to: Comment on rating: At least 38 genetically confirmed patients (from 26 families) have been reported. The frequency and prevalence of the disease are not known. Most patients have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico, and Turkey.

Comment on the mode of pathogenicity: Loss-of-function; At least 15 variants have been reported: 11 nonsense variants, 3 missense variants, and a large deletion (www.lovd.nl/SRD5A3).

Comment on the mode of inheritance: AR (homozygous or compound heterozygous)
Congenital disorders of glycosylation v2.14 SRD5A3 Mehdi Montazer reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 32424323; Phenotypes: Congenital Disorder of Glycosylation, Type Iq (OMIM: 612379 ), Kahrizi Syndrome (OMIM: 612713); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and platelet disorders v1.6 IKZF5 Carl Fratter reviewed gene: IKZF5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31217188, 32419556; Phenotypes: Thrombocytopenia (HP:0001873), Reduced platelet alpha granules (HP:0012528).; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Malformations of cortical development v2.13 TMX2 Zornitza Stark reviewed gene: TMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31735293, 31586943; Phenotypes: Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity MIM#618730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.13 SNAP29 Zornitza Stark gene: SNAP29 was added
gene: SNAP29 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: SNAP29 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAP29 were set to 29051910; 21073448; 30793783
Phenotypes for gene: SNAP29 were set to Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (MIM#609528)
Review for gene: SNAP29 was set to GREEN
gene: SNAP29 was marked as current diagnostic
Added comment: Associated with CEDNIK syndrome. Both pachygyria and polymicrogyria, and additionally dysgenesis of the corpus callosum, are reported in multiple patients from unrelated families with pathogenic variants in this gene (at least 5 patients from 3 families with both pachygyria and polymicrogyria, and at least 5 patients from 3 families with polymicrogyria alone (PMID: 29051910, 30793783)).
Sources: Expert list
Malformations of cortical development v2.13 SCN3A Zornitza Stark gene: SCN3A was added
gene: SCN3A was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: SCN3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SCN3A were set to 32515017; 30146301
Phenotypes for gene: SCN3A were set to Polymicrogyria; malformations of cortical development; epilepsy
Review for gene: SCN3A was set to GREEN
gene: SCN3A was marked as current diagnostic
Added comment: Six unrelated families reported with prominent speech and oral motor dysfunction but no epilepsy, some multiplex in PMID: 30146301. Additionally malformations of cortical development reported in ~75% of a cohort of 22 individuals with a broader neurodevelomental phenotype, including epilepsy, PMID: 32515017
Sources: Expert list
Malformations of cortical development v2.13 RAB3GAP2 Zornitza Stark gene: RAB3GAP2 was added
gene: RAB3GAP2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB3GAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB3GAP2 were set to 23420520; 20967465
Phenotypes for gene: RAB3GAP2 were set to Warburg micro syndrome 2, MIM# 614225
Review for gene: RAB3GAP2 was set to GREEN
gene: RAB3GAP2 was marked as current diagnostic
Added comment: Polymicrogyria is a well described phenotypic feature in Micro syndrome caused by variants in RAB3GAP2 and other genes.

PMID: 23420520 – at least 3 unrelated families with polymicrogyria
PMID: 20967465 - single proband with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 RAB3GAP1 Zornitza Stark gene: RAB3GAP1 was added
gene: RAB3GAP1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB3GAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB3GAP1 were set to 23420520
Phenotypes for gene: RAB3GAP1 were set to Warburg micro syndrome 1, MIM# 600118
Review for gene: RAB3GAP1 was set to GREEN
gene: RAB3GAP1 was marked as current diagnostic
Added comment: Polymicrogyria is a well described phenotypic feature of Micro syndrome, caused by RAB3GAP1 and other genes.

PMID: 23420520 - at least 4 unrelated families with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 RAB18 Zornitza Stark gene: RAB18 was added
gene: RAB18 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: RAB18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAB18 were set to 21473985; 23420520
Phenotypes for gene: RAB18 were set to Warburg micro syndrome 3, MIM# 614222
Review for gene: RAB18 was set to GREEN
Added comment: Polymicrogyria is a well described phenotypic feature in Micro syndrome, caused by RAB18 and other genes.

PMID: 21473985 – two unrelated families with polymicrogyria
PMID: 23420520 – one proband with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 PTEN Zornitza Stark gene: PTEN was added
gene: PTEN was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTEN were set to 32162846
Phenotypes for gene: PTEN were set to Cowden syndrome 1 158350; Lhermitte-Duclos syndrome 158350; Macrocephaly/autism syndrome 605309
Review for gene: PTEN was set to GREEN
gene: PTEN was marked as current diagnostic
Added comment: PMID: 32162846 - 4 unrelated individuals with PTEN variants with polymicrogyria
Sources: Expert list
Malformations of cortical development v2.13 PI4KA Zornitza Stark gene: PI4KA was added
gene: PI4KA was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, MIM# 616531
Review for gene: PI4KA was set to AMBER
Added comment: One family reported, we are aware of additional cases.
Sources: Expert list
Malformations of cortical development v2.13 NPRL3 Zornitza Stark gene: NPRL3 was added
gene: NPRL3 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: NPRL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL3 were set to 27173016; 26285051
Phenotypes for gene: NPRL3 were set to Epilepsy, familial focal, with variable foci 3 (MIM#617118)
Review for gene: NPRL3 was set to GREEN
Added comment: Three families reported where focal cortical dysplasia is a feature, but also reduced penetrance noted. Borderline Amber/Green.
Sources: Expert list
Malformations of cortical development v2.13 NPRL2 Zornitza Stark gene: NPRL2 was added
gene: NPRL2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: NPRL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPRL2 were set to 29281825; 27173016; 31625153
Phenotypes for gene: NPRL2 were set to Epilepsy, familial focal, with variable foci 2, MIM# 617116
Review for gene: NPRL2 was set to AMBER
Added comment: Focal cortical dysplasia reported in some patients

PMID: 29281825 (2017) - LOF variant identified in a patient with left frontal focal cortical dysplasia

PMID: 27173016 (2016) - cohort of focal epilepsy patients. LOF function variant in a family with focal epilepsy and focal cortical dysplasia. Segregated with two affected individuals but reduced penetrance and variable expressivity was observed.

Summary: associated with focal cortical dysplasia in two families. Recent review (PMID: 31625153) also states, mutations in NPRL2 have been linked to focal epilepsy with a less clear association with Focal Cortical Dysplasia.
Sources: Expert list
Malformations of cortical development v2.13 MAPK8IP3 Zornitza Stark gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities OMIM# 605431
Review for gene: MAPK8IP3 was set to GREEN
gene: MAPK8IP3 was marked as current diagnostic
Added comment: 13 unrelated individuals reported, with de novo truncating or missense variants (one recurrent). Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants.
Sources: Expert list
Malformations of cortical development v2.13 MAP1B Zornitza Stark gene: MAP1B was added
gene: MAP1B was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: MAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1B were set to 31317654; 30150678; 30214071
Phenotypes for gene: MAP1B were set to Periventricular nodular heterotopia 9, MIM# 618918
Review for gene: MAP1B was set to GREEN
gene: MAP1B was marked as current diagnostic
Added comment: At least 5 families described with intellectual disability and variable brain malformation phenotypes.
Sources: Expert list
Malformations of cortical development v2.13 LAMA2 Zornitza Stark gene: LAMA2 was added
gene: LAMA2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: LAMA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LAMA2 were set to 20207543; 18406646
Phenotypes for gene: LAMA2 were set to Muscular dystrophy, congenital, merosin deficient or partially deficient, MIM# 607855
Review for gene: LAMA2 was set to GREEN
gene: LAMA2 was marked as current diagnostic
Added comment: Malformations of cortical development are seen in a small proportion of individuals with biallelic LAMA2 variants. These were initially described and characterised based on immunohistochemistry showing loss of the protein associated with LAMA2. Reports where genotyping has been performed include: PMID: 20207543 – 7 individuals with biallelic LAMA2 variants and occipital agyria / polymicrogyria with a further 2 individuals with cortical folding abnormalities in other sites. PMID: 18406646 – 1 individual with a homozygous nonsense LAMA2 variant with extensive bilateral occipital polymicrogyria.
Sources: Expert list
Malformations of cortical development v2.13 GRIN2B Zornitza Stark gene: GRIN2B was added
gene: GRIN2B was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: GRIN2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GRIN2B were set to 28377535
Phenotypes for gene: GRIN2B were set to Mental retardation, autosomal dominant 6, MIM# 613970
Review for gene: GRIN2B was set to GREEN
Added comment: PMID: 28377535 - Neuroimaging was performed in 44 of 58 individuals: six unrelated individuals (6/44, 14%) showed a consistent MCD intermediate between typical polymicrogyria (PMG) and the cortical appearance of tubulinopathies, consisting of mixed large and small gyri separated by shallow sulci, a smooth grey-white border and little infolding. These individuals also had hypoplastic corpus callosum of varying degrees, enlarged and mildly dysplastic basal ganglia, hippocampal dysplasia with thick leaves and open hilus as well as enlarged tecta. One had no septum pellucidum. Generalised cerebral volume loss, compatible with cerebral atrophy, was described in four additional patients (4/44; 9%).
Sources: Expert list
Malformations of cortical development v2.13 GRIN1 Zornitza Stark gene: GRIN1 was added
gene: GRIN1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: GRIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GRIN1 were set to 29365063
Phenotypes for gene: GRIN1 were set to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254
Review for gene: GRIN1 was set to GREEN
gene: GRIN1 was marked as current diagnostic
Added comment: PMID: 29365063 - series of 11 unrelated individuals with GRIN1 variants and polymicrogyria
Sources: Expert list
Intellectual disability v3.274 HARS Zornitza Stark edited their review of gene: HARS: Changed publications: 32333447
Inborn errors of metabolism v2.17 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Inborn errors of metabolism v2.17 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Inborn errors of metabolism v2.17 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Inborn errors of metabolism v2.16 TKFC Arina Puzriakova gene: TKFC was added
gene: TKFC was added to Inborn errors of metabolism. Sources: Literature
watchlist tags were added to gene: TKFC.
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446
Phenotypes for gene: TKFC were set to Triokinase and FMN cyclase deficiency syndrome, 618805
Review for gene: TKFC was set to AMBER
Added comment: Associated with phenotype in OMIM, and a possible gene for TKFC-related Cataracts and Multisystem Disease in G2P.

PMID: 32004446 (2020) - Two sib pairs from two unrelated consanguineous families with an inborn error of metabolism caused by distinct homozygous variants in TKFC. In Family 1, both sibs had congenital cataracts but otherwise presented disparate phenotypes. The older sister had DD (motor and speech) and cerebellar hypoplasia; while the younger sister had liver dysfunction and fatal cardiomyopathy at 11 weeks with severe lactic acidosis following a febrile illness. In Family 2, the brother exhibited global DD as well as bilateral cataracts at 22 months. He developed progressive non-cholestatic liver failure, and at 3yrs-10months he could not walk independently and had no words. His older sister, had delayed speech development and learning difficulties, but is otherwise well and did not have cataracts.

Both variants segregated with disease in each family, and some functional data of the variants using yeast cells.
Sources: Literature
Intellectual disability v3.274 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Intellectual disability v3.274 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Intellectual disability v3.274 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.273 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Intellectual disability v3.272 TKFC Arina Puzriakova Tag watchlist tag was added to gene: TKFC.
Intellectual disability v3.272 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.13 TKFC Arina Puzriakova Tag watchlist tag was added to gene: TKFC.
Cataracts v2.13 TKFC Arina Puzriakova Phenotypes for gene: TKFC were changed from Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, 618805
Cataracts v2.12 TKFC Arina Puzriakova Classified gene: TKFC as Amber List (moderate evidence)
Cataracts v2.12 TKFC Arina Puzriakova Added comment: Comment on list classification: Additional cases required before inclusion on a diagnostic panel (added to watchlist).
Cataracts v2.12 TKFC Arina Puzriakova Gene: tkfc has been classified as Amber List (Moderate Evidence).
Cataracts v2.11 TKFC Arina Puzriakova reviewed gene: TKFC: Rating: AMBER; Mode of pathogenicity: None; Publications: 32004446; Phenotypes: Triokinase and FMN cyclase deficiency syndrome, 618805; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.272 TP73 Arina Puzriakova Classified gene: TP73 as Red List (low evidence)
Intellectual disability v3.272 TP73 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene - patients display discordant phenotype and DD only reported in one patient.
Intellectual disability v3.272 TP73 Arina Puzriakova Gene: tp73 has been classified as Red List (Low Evidence).
Intellectual disability v3.271 TP73 Arina Puzriakova reviewed gene: TP73: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.271 SMG8 Arina Puzriakova Classified gene: SMG8 as Red List (low evidence)
Intellectual disability v3.271 SMG8 Arina Puzriakova Added comment: Comment on list classification: Rating Red as gene only distinguished due to multiple hits in same candidate gene; however, patients display discordant phenotype and ID only reported in one patient.
Intellectual disability v3.271 SMG8 Arina Puzriakova Gene: smg8 has been classified as Red List (Low Evidence).
Intellectual disability v3.270 SMG8 Arina Puzriakova reviewed gene: SMG8: Rating: RED; Mode of pathogenicity: None; Publications: 31130284; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Tag founder-effect tag was added to gene: RAP1GDS1.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Classified gene: RAP1GDS1 as Red List (low evidence)
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Added comment: Comment on list classification: The same variant identified in two families from the region, indicating a possible founder effect. Therefore rated Red as there is not currently enough evidence that other variants in the RAP1GDS1 gene are disease causing.
Intellectual disability v3.270 RAP1GDS1 Arina Puzriakova Gene: rap1gds1 has been classified as Red List (Low Evidence).
Intellectual disability v3.269 RAP1GDS1 Arina Puzriakova reviewed gene: RAP1GDS1: Rating: ; Mode of pathogenicity: None; Publications: 32431071; Phenotypes: Intellectual disability, Global developmental delay, Hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.
Intellectual disability v3.269 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.146 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.146 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four unrelated individuals with three distinct TUBGCP2 variants, associated with generalised seizures.
Genetic epilepsy syndromes v2.146 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Genetic epilepsy syndromes v2.145 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Genetic epilepsy syndromes. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), generalised seizures (4/5, onset at 6yrs-9m, 5m, and 7m). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least three families with distinct TUBGCP2 variants, presenting progressive severe microcephaly.
Severe microcephaly v2.19 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.18 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive severe microcephaly (4/4, Z score: -4.0 to -9.0), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova changed review comment from: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).; to: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy/Microcephaly), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Malformations of cortical development v2.13 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 18758830; 24598713
Phenotypes for gene: FIG4 were set to Polymicrogyria with epilepsy MIM# 612691
Review for gene: FIG4 was set to AMBER
Added comment: One family and a supportive mouse model:

PMID 18758830 – Ben Cheikh et al (2009) studied a large consanguineous Moroccan family in which bilateral occipital polymicrogyria segregated as an autosomal recessive trait, establishing linkage to 6q16-q22 by homozygosity mapping. Three affected individuals had epilepsy and polymicrogyria (other siblings had variable phenotypes).

PMID 24598713 – Baulac et al (2014) analysed the consanguineous Moroccan family and detected a homozygous missense variant in FIG4, which was homozygous in each of the affected siblings with polymicrogyria, heterozygous in one healthy sibling, not present in three healthy siblings, heterozygous in both parents and not tested in a further four siblings. They went on to study transfected fibroblasts from FIG4 deficient mice and examined histologically brains from FIG4-null mice which had findings that included changes “reminiscent of human cortical malformations”.
Sources: Expert list
Malformations of cortical development v2.13 FAT4 Zornitza Stark gene: FAT4 was added
gene: FAT4 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: FAT4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT4 were set to 22473091; 24056717
Phenotypes for gene: FAT4 were set to Van Maldergem syndrome 2, MIM# 615546
Review for gene: FAT4 was set to AMBER
Added comment: PVNH reported in two families.
Sources: Expert list
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least four families with three distinct TUBGCP2 variants, associated with a lissencephaly-spectrum phenotype.
Malformations of cortical development v2.13 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.12 TUBGCP2 Arina Puzriakova Tag for-review tag was added to gene: TUBGCP2.
Malformations of cortical development v2.12 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive microcephaly (4/4), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Deleted their comment
Malformations of cortical development v2.11 EML1 Zornitza Stark gene: EML1 was added
gene: EML1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: EML1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EML1 were set to 31710781
Phenotypes for gene: EML1 were set to Band heterotopia (MIM# 600348)
Review for gene: EML1 was set to GREEN
gene: EML1 was marked as current diagnostic
Added comment: PMID: 31710781; Review of 5 families with patients characterised by severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging of 4 patients, there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation.
Sources: Expert list
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as Amber List (moderate evidence)
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Classified gene: TUBGCP2 as No list
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Added comment: Comment on list classification: Although the phenotype is relevant for this panel, additional cases would help determine the aetiology of the ID presentation. This gene has been added to other panels (Malformations of cortical development/Epilepsy), in view of which these patients are more likely to be recognised.

Rating Amber, awaiting further publications (added to watchlist).
Intellectual disability v3.268 TUBGCP2 Arina Puzriakova Gene: tubgcp2 has been removed from the panel.
Malformations of cortical development v2.11 DEPDC5 Zornitza Stark gene: DEPDC5 was added
gene: DEPDC5 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: DEPDC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DEPDC5 were set to 31444548
Phenotypes for gene: DEPDC5 were set to Epilepsy, familial focal, with variable foci 1 (MIM#604364)
Review for gene: DEPDC5 was set to GREEN
gene: DEPDC5 was marked as current diagnostic
Added comment: PMID: 31444548
- 5x focal cortical dysplasia patients
Sources: Expert list
Malformations of cortical development v2.11 DCHS1 Zornitza Stark gene: DCHS1 was added
gene: DCHS1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: DCHS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DCHS1 were set to 27262615; 22473091
Phenotypes for gene: DCHS1 were set to Van Maldergem syndrome 1 (MIM#601390)
Review for gene: DCHS1 was set to GREEN
gene: DCHS1 was marked as current diagnostic
Added comment: PMID: 27262615;
- cohort of 26x periventricular band heterotopias and 2x had additional phenotype of pachygyria
- 2nd cohort of 10x band heterotopias

PMID: 22473091;
- 1x patient with localised areas of cortical thickening and gyral simplification
Sources: Literature
Sources: Expert list
Malformations of cortical development v2.11 DAG1 Zornitza Stark reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: 24052401; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (MIM#616538); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.11 CTNNA2 Zornitza Stark gene: CTNNA2 was added
gene: CTNNA2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTNNA2 were set to 30013181
Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9, MIM#618174
Review for gene: CTNNA2 was set to GREEN
gene: CTNNA2 was marked as current diagnostic
Added comment: 13 children from three unrelated families reported.
Sources: Expert list
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova Tag watchlist tag was added to gene: TUBGCP2.
Intellectual disability v3.267 TUBGCP2 Arina Puzriakova reviewed gene: TUBGCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31630790; Phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.11 CSNK2A1 Zornitza Stark reviewed gene: CSNK2A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27048600, 29240241; Phenotypes: Okur-Chung neurodevelopmental syndrome (MIM#617062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 5 unrelated cases reported with brain malformations associated with PPP1R12A variants.

PPP1R12A has been added to this panel following discussion with the clinical team.
Malformations of cortical development v2.11 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.10 PPP1R12A Arina Puzriakova gene: PPP1R12A was added
gene: PPP1R12A was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: PPP1R12A.
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Genitourinary and/or/brain malformation syndrome, 618820
Review for gene: PPP1R12A was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 5/12 individuals presented structural CNS anomalies; however, the phenotype was variable and included dysgenesis of the corpus callosum, polymicrogyria, leukomalacia, and acrania.
Sources: Literature
Disorders of sex development v2.6 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Disorders of sex development v2.6 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with significant genitourinary malformations.
Disorders of sex development v2.6 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Disorders of sex development v2.5 PPP1R12A Arina Puzriakova gene: PPP1R12A was added
gene: PPP1R12A was added to Disorders of sex development. Sources: Literature
for-review tags were added to gene: PPP1R12A.
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Genitourinary and/or/brain malformation syndrome, 618820
Review for gene: PPP1R12A was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). Out of the 12 patients, 4 were XY females and 3 were XY males with significant anomalies.
Sources: Literature
Holoprosencephaly v2.7 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Tag watchlist tag was added to gene: PPP1R12A.
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further publications/clinical evidence as currently only two cases reported (added to watchlist).
Holoprosencephaly v2.6 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Holoprosencephaly v2.5 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.267 PPP1R12A Arina Puzriakova Phenotypes for gene: PPP1R12A were changed from Intellectual disability; holoprosencephaly; disorder of sex development to Genitourinary and/or/brain malformation syndrome, 618820
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Classified gene: PPP1R12A as Amber List (moderate evidence)
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - DD reported in at least 7 unrelated patients with PPP1R12A variants.
Intellectual disability v3.266 PPP1R12A Arina Puzriakova Gene: ppp1r12a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.265 PPP1R12A Arina Puzriakova Tag for-review tag was added to gene: PPP1R12A.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova changed review comment from: PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.; to: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). 7/12 individuals exhibited developmental delay, which warrants inclusion on this panel.
Intellectual disability v3.265 PPP1R12A Arina Puzriakova reviewed gene: PPP1R12A: Rating: GREEN; Mode of pathogenicity: None; Publications: 31883643; Phenotypes: Genitourinary and/or/brain malformation syndrome, 618820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hearing loss v2.42 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Hearing loss v2.42 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - added to this panel following suggestion from the clinical team.
Hearing loss v2.42 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Hearing loss v2.41 MN1 Arina Puzriakova gene: MN1 was added
gene: MN1 was added to Hearing loss. Sources: Literature
for-review tags were added to gene: MN1.
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Review for gene: MN1 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum). 20/25 individuals had conductive and/or sensorineural hearing loss (no report on hearing status in a further 6 individuals across the two studies).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect.
Sources: Literature
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Classified gene: MNS1 as Amber List (moderate evidence)
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Added comment: Comment on list classification: This gene has been added as an Amber gene and will be promoted to a Green gene at the next major update. It has been tagged with "for-review".
Laterality disorders and isomerism v1.11 MNS1 Ivone Leong Gene: mns1 has been classified as Amber List (Moderate Evidence).
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong reviewed gene: MNS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong Tag for-review tag was added to gene: MNS1.
Laterality disorders and isomerism v1.10 MNS1 Ivone Leong Publications for gene: MNS1 were set to 31534215; 30148830
Malformations of cortical development v2.9 MN1 Arina Puzriakova changed review comment from: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature; to: Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Malformations of cortical development v2.9 MN1 Arina Puzriakova Classified gene: MN1 as Amber List (moderate evidence)
Malformations of cortical development v2.9 MN1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - added to this panel following suggestion from the clinical team.
Malformations of cortical development v2.9 MN1 Arina Puzriakova Gene: mn1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.8 MN1 Arina Puzriakova gene: MN1 was added
gene: MN1 was added to Malformations of cortical development. Sources: Literature
for-review tags were added to gene: MN1.
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Review for gene: MN1 was set to GREEN
Added comment: Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.18 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Infantile enterocolitis & monogenic inflammatory bowel disease v1.17 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; Haemorrhagic diarrhoea; Dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Intestinal failure v1.5 ANO1 Arina Puzriakova Classified gene: ANO1 as Amber List (moderate evidence)
Intestinal failure v1.5 ANO1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber, awaiting further cases and review of phenotype associated with variants in this gene.
Intestinal failure v1.5 ANO1 Arina Puzriakova Gene: ano1 has been classified as Amber List (Moderate Evidence).
Intestinal failure v1.4 ANO1 Arina Puzriakova gene: ANO1 was added
gene: ANO1 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: ANO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANO1 were set to 32487539
Phenotypes for gene: ANO1 were set to Impaired intestinal peristalsis; Haemorrhagic diarrhoea; Dysmorphic features
Review for gene: ANO1 was set to AMBER
Added comment: PMID: 32487539 (2020) - Two affected sibs presenting in early infancy with impaired intestinal peristalsis, intestinal pneumatosis and dysmorphic features. Delayed motor and language development was reported in one sibling, however, the other sibling died at 5 months from cardiac arrest and therefore a psychomotor assessment was not performed. Exome sequencing identified a homozygous truncating variant (c.897+3_897+6delAAGT, p.L300Vfs*58) in ANO1 which segregated with disease in the family. Functional data revealed that the variant led to lack of expression of functional TMEM16A in patient cells, which in turn abolished calcium-activated Cl- currents. Also supportive mouse model.
Sources: Literature
Laterality disorders and isomerism v1.9 MNS1 Ivone Leong Phenotypes for gene: MNS1 were changed from Heterotaxy; male infertility to Heterotaxy, visceral, 9, autosomal, with male infertility, 618948
Arrhythmogenic cardiomyopathy v2.9 CDH2 Ivone Leong commented on gene: CDH2: Tagged with "for-review" for the specialist group to review whether this gene should remain Green.
Arrhythmogenic cardiomyopathy v2.9 CDH2 Ivone Leong Tag for-review tag was added to gene: CDH2.
Parkinson Disease and Complex Parkinsonism v1.68 COASY Zornitza Stark gene: COASY was added
gene: COASY was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 28489334; 24360804
Phenotypes for gene: COASY were set to Neurodegeneration with brain iron accumulation 6, MIM# 615643
Review for gene: COASY was set to AMBER
Added comment: Extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism are prominent due to iron accumulation in the basal ganglia. 2 families reported.
Sources: Expert list
Genetic epilepsy syndromes v2.144 DDC Sarah Leigh Classified gene: DDC as Amber List (moderate evidence)
Genetic epilepsy syndromes v2.144 DDC Sarah Leigh Added comment: Comment on list classification: This is a metabolic gene and is green on the Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/DDC/), therefore it is rated as amber on the Genetic epilepsy syndromes panel.
Genetic epilepsy syndromes v2.144 DDC Sarah Leigh Gene: ddc has been classified as Amber List (Moderate Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 CLN3 Zornitza Stark gene: CLN3 was added
gene: CLN3 was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: CLN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN3 were set to 19489875; 11342698
Phenotypes for gene: CLN3 were set to Ceroid lipofuscinosis, neuronal, 3 MIM#204200
Review for gene: CLN3 was set to GREEN
gene: CLN3 was marked as current diagnostic
Added comment: Parkinsonism is a prominent feature of this condition.
Sources: Expert list
Genetic epilepsy syndromes v2.143 DDC Sarah Leigh Tag for-review tag was added to gene: DDC.
Optic neuropathy v2.27 AFG3L2 Ivone Leong reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Parkinson Disease and Complex Parkinsonism v1.68 CHCHD2 Zornitza Stark reviewed gene: CHCHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32068847, 25662902, 31600778, 26705026; Phenotypes: Parkinson disease 22, autosomal dominant MIM#616710; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Optic neuropathy v2.27 AFG3L2 Ivone Leong Tag for-review tag was added to gene: AFG3L2.
Optic neuropathy v2.27 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to 29181157; 26539208; 30544562; 30252181; 30389403; 30252181; 30389403; 32219868
Parkinson Disease and Complex Parkinsonism v1.68 ATP7B Zornitza Stark gene: ATP7B was added
gene: ATP7B was added to Parkinson Disease and Complex Parkinsonism. Sources: Expert list
Mode of inheritance for gene: ATP7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP7B were set to 17435591
Phenotypes for gene: ATP7B were set to Wilson disease MIM#277900
Review for gene: ATP7B was set to GREEN
gene: ATP7B was marked as current diagnostic
Added comment: Parkinsonism is a prominent neurological feature of Wilson disease.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 TRIM22 Zornitza Stark gene: TRIM22 was added
gene: TRIM22 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIM22 were set to 26836588
Phenotypes for gene: TRIM22 were set to Inflammatory bowel disease
Review for gene: TRIM22 was set to GREEN
gene: TRIM22 was marked as current diagnostic
Added comment: Three unrelated families reported with bi-allelic variants in this gene, and very early onset IBD, some functional data.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 RIPK1 Zornitza Stark gene: RIPK1 was added
gene: RIPK1 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: RIPK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK1 were set to 30026316; 30591564; 31213653
Phenotypes for gene: RIPK1 were set to Immunodeficiency 57, MIM#618108
Review for gene: RIPK1 was set to GREEN
Added comment: Ten families reported, inflammatory bowel disease/enteropathy is a common feature of this immune dysregulation syndrome.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 NOD2 Zornitza Stark gene: NOD2 was added
gene: NOD2 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: NOD2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NOD2 were set to 11385576; 17804789; 32463623
Phenotypes for gene: NOD2 were set to {Inflammatory bowel disease 1, Crohn disease} 266600; {Yao syndrome} 617321
Review for gene: NOD2 was set to GREEN
gene: NOD2 was marked as current diagnostic
Added comment: Variants in NOD2 (particularly bi-allelic ones) are associated with increased risk of Crohn's disease. 7% of a cohort of 401 patients with Crohn's had NOD2 bi-allelic variants.
Sources: Expert list
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 FERMT1 Zornitza Stark reviewed gene: FERMT1: Rating: RED; Mode of pathogenicity: None; Publications: 19057668, 27537055, 32463623; Phenotypes: Kindler syndrome, MIM# 173650; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Optic neuropathy v2.26 AFG3L2 Ivone Leong Publications for gene: AFG3L2 were set to 29181157; 26539208; 30544562; 30252181; 30389403; 30252181; 30389403
Optic neuropathy v2.25 AFG3L2 Ivone Leong Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487; Spinocerebellar ataxia 28, 610246 to Optic atrophy 12, 618977
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 BACH2 Zornitza Stark gene: BACH2 was added
gene: BACH2 was added to Infantile enterocolitis & monogenic inflammatory bowel disease. Sources: Expert list
Mode of inheritance for gene: BACH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BACH2 were set to 28530713
Phenotypes for gene: BACH2 were set to Immunodeficiency 60, MIM# 618394; inflammatory bowel disease; recurrent sinopulmonary infections
Review for gene: BACH2 was set to GREEN
Added comment: Two families and a mouse model.
Sources: Expert list
Hypertrophic cardiomyopathy - teen and adult v2.8 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Hypertrophic cardiomyopathy - teen and adult v2.8 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy - teen and adult v2.7 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Hypertrophic cardiomyopathy - teen and adult. Sources: Literature
watchlist tags were added to gene: ATAD3A.
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28652416; 28158749; 31727539
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to AMBER
Added comment: Added new gene as Amber based on the available literature. As not every patient with a monoallelic/biallelic variant in this gene presented with HCM, this gene has been rated Amber until further evidence is available.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have HCM. The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Sources: Literature
Optic neuropathy v2.24 ATAD3A Ivone Leong Tag watchlist tag was added to gene: ATAD3A.
Cataracts v2.11 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Cataracts v2.11 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Cataracts v2.10 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Cataracts. Sources: Literature
for-review tags were added to gene: ATAD3A.
Mode of inheritance for gene: ATAD3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307; 28652416; 28158749; 31727539
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to AMBER
Added comment: Added new gene as Amber for now, but should be promoted to Green (as there is enough evidence for it to be a Green gene) at the next major review.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have hypertrophic cardiomyopathy (HCM). The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Sources: Literature
Hereditary spastic paraplegia - childhood onset v2.15 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATAD3A were set to 28158749
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to RED
Added comment: Added as a Red gene based on the available literature. There is only one case. PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.
Sources: Literature
Optic neuropathy v2.24 ATAD3A Ivone Leong Classified gene: ATAD3A as Amber List (moderate evidence)
Optic neuropathy v2.24 ATAD3A Ivone Leong Added comment: Comment on list classification: Promoted gene from Red to Amber based on the available literature. As not every patient with a monoallelic variant in this gene presented with optic atrophy, this gene has been rated Amber until further evidence is available.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have hypertrophic cardiomyopathy (HCM). The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.
Optic neuropathy v2.24 ATAD3A Ivone Leong Gene: atad3a has been classified as Amber List (Moderate Evidence).
Optic neuropathy v2.23 ATAD3A Ivone Leong Publications for gene: ATAD3A were set to 27640307; 28652416
Intellectual disability v3.265 TRNT1 Arina Puzriakova Tag for-review tag was added to gene: TRNT1.
Intellectual disability v3.265 TRNT1 Arina Puzriakova Publications for gene: TRNT1 were set to 25193871; 23553769; 29170023; 27389523
Intellectual disability v3.264 TRNT1 Arina Puzriakova Classified gene: TRNT1 as Amber List (moderate evidence)
Intellectual disability v3.264 TRNT1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - sufficient number of cases with (mild-profound) developmental delay, associated with biallelic variants in TRNT1.
Intellectual disability v3.264 TRNT1 Arina Puzriakova Gene: trnt1 has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.7 B4GAT1 Zornitza Stark reviewed gene: B4GAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359570, 23877401, 23359570, 23217742; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13 MIM# 615287; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Malformations of cortical development v2.7 ATP1A2 Zornitza Stark gene: ATP1A2 was added
gene: ATP1A2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 31608932
Phenotypes for gene: ATP1A2 were set to hydrops fetalis; microcephaly; arthrogryposis; extensive cortical malformations
Review for gene: ATP1A2 was set to GREEN
gene: ATP1A2 was marked as current diagnostic
Added comment: Three individuals from two unrelated families reported with balleliic LoF variants in this gene and hydrops/congenital abnormalities including extensive cortical malformations. Mouse model is perinatal lethal. This is a distinct phenotype from the mono allelic variants associated with alternating hemiplegia.
Sources: Expert list
Malformations of cortical development v2.7 ARF1 Zornitza Stark gene: ARF1 was added
gene: ARF1 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: ARF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARF1 were set to 28868155
Phenotypes for gene: ARF1 were set to Periventricular nodular heterotopia 8, MIM# 618185
Review for gene: ARF1 was set to GREEN
gene: ARF1 was marked as current diagnostic
Added comment: Three unrelated individuals reported with de novo missense in this gene.
Sources: Expert list
Malformations of cortical development v2.7 APC2 Zornitza Stark gene: APC2 was added
gene: APC2 was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108
Phenotypes for gene: APC2 were set to Cortical dysplasia, complex, with other brain malformations 10, MIM#618677
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: 12 individuals from 8 unrelated families; intellectual disability, seizures, cortical dysplasia including posterior to anterior predominant pattern of lissencephaly, heterotopias, paucity of white matter, thin corpus callosum.
Sources: Expert list
Structural eye disease v1.9 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ocular coloboma v1.38 TENM3 Arina Puzriakova Publications for gene: TENM3 were set to 22766609, 27103084, 24859618
Ocular coloboma v1.37 TENM3 Arina Puzriakova Classified gene: TENM3 as Green List (high evidence)
Ocular coloboma v1.37 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Green List (High Evidence).
Ocular coloboma v1.36 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.28 TENM3 Arina Puzriakova Phenotypes for gene: TENM3 were changed from Microphthalmia isolated with coloboma 9 to Microphthalmia, syndromic 15, 615145; ?Microphthalmia, isolated, with coloboma 9, 615145
Anophthalmia or microphthalmia v1.27 TENM3 Arina Puzriakova Mode of inheritance for gene: TENM3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Anophthalmia or microphthalmia v1.26 TENM3 Arina Puzriakova Classified gene: TENM3 as Green List (high evidence)
Anophthalmia or microphthalmia v1.26 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Green List (High Evidence).
Malformations of cortical development v2.7 CRADD Zornitza Stark gene: CRADD was added
gene: CRADD was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: CRADD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRADD were set to 27773430
Phenotypes for gene: CRADD were set to Mental retardation, autosomal recessive 34, with variant lissencephaly, MIM# 614499
Review for gene: CRADD was set to GREEN
gene: CRADD was marked as current diagnostic
Added comment: At least 5 families reported though some were from the Pennsylvania Mennonite population, and had same founder variant (but at least 4 unique variants reported). Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex.
Sources: Expert list
Anophthalmia or microphthalmia v1.25 TENM3 Arina Puzriakova changed review comment from: PMID: 22766609 (2012) - Two affected sibs from a consanguineous Saudi family, with nonsyndromic bilateral microphthalmia, iris and retinal coloboma, and microcornea. Normal cognitive development was noted in both sibs. A homozygous 1 bp insertion (c.2083dup, p.T695Nfs*5) in the TENM3 gene, causing a frameshift predicted to result in premature truncation of the resulting protein, segregated with the phenotype. No other pathogenic variant were identified in any of the known microphthalmia genes.

PMID: 27103084 (2016) - In a patient with bilateral colobomatous microphthalmia authors identified a segregating homozygous splice site variant (c.2968‐2A>T, p.Val990Cysfs*13) in the TENM3 gene. His development was delayed, and he entered a specialised institution at the age of eight because of his apparent ID.

PMID: 30513139 (2018) - In two sisters with ocular coloboma and microcornea, but without microphthalmia, WES revealed a homozygous TENM3 variant (c.1857T>A, p. Cys619*). Sanger sequencing confirmed the parents were heterozygous carriers. Patient cells were not available for functional study of the variant. The older child (5.5 years old) was said to have global developmental delay; while the younger child (4 years 3 months old) had mild motor delay and spoke only few words, but cognition was reported normal.

PMID: 29753094 (2019) - 9-year-old boy with right eye microphthalmia, sclerocornea of both eyes, anterior segment dysgenesis, and severe global developmental delay, associated with compound heterozygous variants ([c.4046C>G, p.Ala1349Gly] ; [c.7687C>T, p.Arg2563Trp]) in the TENM3 gene. The p.Ala1349Gly variant was found in a heterozygous state in the proband's unaffected father and brother; however, the p.Arg2563Trp variant was not present in either parent, suggesting mosaicism in the mother or a de novo occurrence in the proband.; to: Associated with phenotype in OMIM, and a probable gene for Colobomatous microphthalmia in G2P.

PMID: 22766609 (2012) - Two affected sibs from a consanguineous Saudi family, with nonsyndromic bilateral microphthalmia, iris and retinal coloboma, and microcornea. Normal cognitive development was noted in both sibs. A homozygous 1 bp insertion (c.2083dup, p.T695Nfs*5) in the TENM3 gene, causing a frameshift predicted to result in premature truncation of the resulting protein, segregated with the phenotype. No other pathogenic variant were identified in any of the known microphthalmia genes.

PMID: 27103084 (2016) - In a patient with bilateral colobomatous microphthalmia authors identified a segregating homozygous splice site variant (c.2968‐2A>T, p.Val990Cysfs*13) in the TENM3 gene. His development was delayed, and he entered a specialised institution at the age of eight because of his apparent ID.

PMID: 30513139 (2018) - In two sisters with ocular coloboma and microcornea, but without microphthalmia, WES revealed a homozygous TENM3 variant (c.1857T>A, p. Cys619*). Sanger sequencing confirmed the parents were heterozygous carriers. Patient cells were not available for functional study of the variant. The older child (5.5 years old) was said to have global developmental delay; while the younger child (4 years 3 months old) had mild motor delay and spoke only few words, but cognition was reported normal.

PMID: 29753094 (2019) - 9-year-old boy with right eye microphthalmia, sclerocornea of both eyes, anterior segment dysgenesis, and severe global developmental delay, associated with compound heterozygous variants ([c.4046C>G, p.Ala1349Gly] ; [c.7687C>T, p.Arg2563Trp]) in the TENM3 gene. The p.Ala1349Gly variant was found in a heterozygous state in the proband's unaffected father and brother; however, the p.Arg2563Trp variant was not present in either parent, suggesting mosaicism in the mother or a de novo occurrence in the proband.
Anophthalmia or microphthalmia v1.25 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.263 TENM3 Arina Puzriakova Classified gene: TENM3 as Amber List (moderate evidence)
Intellectual disability v3.263 TENM3 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - sufficient unrelated cases with an ID phenotype.
Intellectual disability v3.263 TENM3 Arina Puzriakova Gene: tenm3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.262 TENM3 Arina Puzriakova Tag for-review tag was added to gene: TENM3.
Intellectual disability v3.262 TENM3 Arina Puzriakova reviewed gene: TENM3: Rating: ; Mode of pathogenicity: None; Publications: 22766609, 27103084, 30513139, 29753094; Phenotypes: Microphthalmia, syndromic 15, 615145, ?Microphthalmia, isolated, with coloboma 9, 615145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Holoprosencephaly v2.5 RAD21 Zornitza Stark gene: RAD21 was added
gene: RAD21 was added to Holoprosencephaly. Sources: Literature
Mode of inheritance for gene: RAD21 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAD21 were set to 31334757
Phenotypes for gene: RAD21 were set to Holoprosencephaly; Septo-optic dysplasia
Review for gene: RAD21 was set to GREEN
gene: RAD21 was marked as current diagnostic
Added comment: Three individuals reported with variants in this gene and HPE phenotype
Sources: Literature
Holoprosencephaly v2.5 PPP1R12A Zornitza Stark gene: PPP1R12A was added
gene: PPP1R12A was added to Holoprosencephaly. Sources: Expert list
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Intellectual disability; holoprosencephaly; disorder of sex development
Review for gene: PPP1R12A was set to GREEN
gene: PPP1R12A was marked as current diagnostic
Added comment: 12 individuals reported.
Sources: Expert list
Malformations of cortical development v2.7 CDK13 Zornitza Stark reviewed gene: CDK13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, MIM# 617360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Malformations of cortical development v2.7 PEX7 Zornitza Stark reviewed gene: PEX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 9B (MIM#614879), Rhizomelic chondrodysplasia punctata, type 1 (MIM#215100); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Malformations of cortical development v2.7 VLDLR Zornitza Stark gene: VLDLR was added
gene: VLDLR was added to Malformations of cortical development. Sources: Expert list
Mode of inheritance for gene: VLDLR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VLDLR were set to 16080122; 18364738; 18326629; 22700954; 22973972
Phenotypes for gene: VLDLR were set to Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1 (MIM#224050)
Review for gene: VLDLR was set to GREEN
gene: VLDLR was marked as current diagnostic
Added comment: Gyral simplification/pachygyria reported in this condition.
Sources: Expert list
Neurotransmitter disorders v1.4 ALDH7A1 Zornitza Stark gene: ALDH7A1 was added
gene: ALDH7A1 was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ALDH7A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALDH7A1 were set to Epilepsy, pyridoxine-dependent, MIM# 266100
Review for gene: ALDH7A1 was set to GREEN
gene: ALDH7A1 was marked as current diagnostic
Added comment: Well established gene-disease association, condition is considered a disorder of neurotransmitter metabolism by some expert groups: deficiency of antiquitin leads to the buildup of α-aminoadipic semialdehyde, resulting in a disruption in the activity of pyridoxine, which in turn is required for the breakdown of neurotransmitters. Metabolic findings: increased serum and CSF levels of pipecolic acid; increased serum, CSF and urinary levels of alpha-aminoadipic semialdehyde. Treatable disorder.
Sources: Expert list
Neurotransmitter disorders v1.4 PNPO Zornitza Stark gene: PNPO was added
gene: PNPO was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: PNPO was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PNPO were set to Pyridoxamine 5'-phosphate oxidase deficiency, MIM# 610090
Review for gene: PNPO was set to GREEN
Added comment: Well established gene-disease association. Pyridoxal 5′-phosphate is a co-factor in the synthesis of dopamine and serotonin. Multiple CSF abnormalities reported including decreased HVA and 5HIAA. Treatable disorder, typically manifesting as neonatal seizures.
Sources: Expert list
Neurotransmitter disorders v1.4 ALDH5A1 Zornitza Stark gene: ALDH5A1 was added
gene: ALDH5A1 was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ALDH5A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH5A1 were set to 9683595; 14635103; 32402538
Phenotypes for gene: ALDH5A1 were set to Succinic semialdehyde dehydrogenase deficiency, MIM# 271980
Review for gene: ALDH5A1 was set to GREEN
gene: ALDH5A1 was marked as current diagnostic
Added comment: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder in which an enzyme defect in the GABA degradation pathway causes a consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA. The clinical features include developmental delay, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances. Over 50 unrelated families reported.
Sources: Expert list
Neurotransmitter disorders v1.4 ABAT Zornitza Stark edited their review of gene: ABAT: Set current diagnostic: yes
Neurotransmitter disorders v1.4 ABAT Zornitza Stark gene: ABAT was added
gene: ABAT was added to Neurotransmitter disorders. Sources: Expert list
Mode of inheritance for gene: ABAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABAT were set to 28411234; 27596361; 20052547; 10407778; 6148708
Phenotypes for gene: ABAT were set to GABA-transaminase deficiency, MIM# 613163
Review for gene: ABAT was set to GREEN
Added comment: Over ten families reported. Disorder is is characterised by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most individuals have profound developmental impairment and some die in infancy.
Sources: Expert list
Intellectual disability v3.262 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Genetic epilepsy syndromes v2.143 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: 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: 32822602; Phenotypes: Severe global developmental delay, Intellectual disability, Seizures, Microcephaly, Behavioral abnormality, Sleep disturbance, Morphological abnormality of the central nervous system, Short stature, Oral cleft, Abnormality of the face; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Clefting v2.3 KAT5 Konstantinos Varvagiannis gene: KAT5 was added
gene: KAT5 was added to Clefting. Sources: Literature
Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KAT5 were set to 32822602
Phenotypes for gene: KAT5 were set to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face
Mode of pathogenicity for gene: KAT5 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: KAT5 was set to AMBER
Added comment: Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants.

Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects).

KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development.

3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420).

Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism.

As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a
syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited).

RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc).

Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies).

Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber.
Sources: Literature
Intellectual disability v3.262 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Review for gene: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Genetic epilepsy syndromes v2.143 LMBRD2 Konstantinos Varvagiannis gene: LMBRD2 was added
gene: LMBRD2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Penetrance for gene: LMBRD2 were set to unknown
Mode of pathogenicity for gene: LMBRD2 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: LMBRD2 was set to AMBER
Added comment: You may consider inclusion with green (13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies) or amber rating (role of the gene not known, no variant studies, animal model probably not available).

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants.

Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific).

All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity.

5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect.

There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H).

The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely.

As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation.

It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Fetal anomalies v1.93 Catherine Snow Panel version has been signed off
Fetal anomalies v1.91 SRY Eleanor Williams Mode of inheritance for gene: SRY 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
Fetal anomalies v1.90 SRY Eleanor Williams Added comment: Comment on mode of inheritance: Reverting to X-LINKED MOI as OMIM has XLD and YL inheritance listed.
Fetal anomalies v1.90 SRY Eleanor Williams Mode of inheritance for gene: SRY was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Osteopetrosis v0.6 Catherine Snow Panel types changed to GMS Rare Disease
Osteopetrosis v0.5 Catherine Snow Panel status changed from internal to public
Osteopetrosis v0.4 Catherine Snow List of related panels changed from to R104.4
Thrombocythaemia v0.6 Catherine Snow Panel types changed to GMS Rare Disease Virtual
Osteopetrosis v0.3 TYROBP Eleanor Williams commented on gene: TYROBP
Osteopetrosis v0.3 TNFSF11 Eleanor Williams commented on gene: TNFSF11
Osteopetrosis v0.3 TNFRSF11A Eleanor Williams commented on gene: TNFRSF11A
Osteopetrosis v0.3 TGFB1 Eleanor Williams commented on gene: TGFB1
Osteopetrosis v0.3 TCIRG1 Eleanor Williams commented on gene: TCIRG1
Osteopetrosis v0.3 SOST Eleanor Williams commented on gene: SOST
Osteopetrosis v0.3 SNX10 Eleanor Williams commented on gene: SNX10
Osteopetrosis v0.3 RASGRP2 Eleanor Williams commented on gene: RASGRP2
Osteopetrosis v0.3 PTH1R Eleanor Williams commented on gene: PTH1R
Osteopetrosis v0.3 PLEKHM1 Eleanor Williams commented on gene: PLEKHM1
Osteopetrosis v0.3 OSTM1 Eleanor Williams commented on gene: OSTM1
Osteopetrosis v0.3 LRP5 Eleanor Williams commented on gene: LRP5
Osteopetrosis v0.3 LEMD3 Eleanor Williams commented on gene: LEMD3
Osteopetrosis v0.3 IKBKG Eleanor Williams commented on gene: IKBKG
Osteopetrosis v0.3 FERMT3 Eleanor Williams commented on gene: FERMT3
Osteopetrosis v0.3 FAM20C Eleanor Williams commented on gene: FAM20C
Osteopetrosis v0.3 CTSK Eleanor Williams commented on gene: CTSK
Osteopetrosis v0.3 CLCN7 Eleanor Williams commented on gene: CLCN7
Osteopetrosis v0.3 CA2 Eleanor Williams commented on gene: CA2
Osteopetrosis v0.3 ANKH Eleanor Williams commented on gene: ANKH
Osteopetrosis v0.3 AMER1 Eleanor Williams commented on gene: AMER1
Thrombocythaemia v0.5 Catherine Snow Panel status changed from internal to public
Fetal anomalies v1.89 SRY Eleanor Williams Added comment: Comment on mode of inheritance: Changing mode of inheritance to "Other" has this gene is on the Y chromosome.
Fetal anomalies v1.89 SRY Eleanor Williams Mode of inheritance for gene: SRY was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to Other
Thrombocythaemia v0.4 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Thrombocythaemia v0.3 Arina Puzriakova Panel types changed to GMS Rare Disease Virtual; GMS Rare Disease; GMS signed-off
Thrombocythaemia v0.2 Arina Puzriakova List of related panels changed from to R406
Panel types changed to GMS signed-off
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova Tag somatic tag was added to gene: SH2B3.
Thrombocythaemia v0.1 CALR Arina Puzriakova Tag somatic tag was added to gene: CALR.
Thrombocythaemia v0.1 CALR Arina Puzriakova reviewed gene: CALR: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thrombocythaemia v0.1 SH2B3 Arina Puzriakova reviewed gene: SH2B3: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thrombocythaemia v0.1 JAK2 Arina Puzriakova reviewed gene: JAK2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thrombocythaemia v0.1 THPO Arina Puzriakova reviewed gene: THPO: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thrombocythaemia v0.1 MPL Arina Puzriakova reviewed gene: MPL: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Osteopetrosis v0.1 TYROBP Catherine Snow gene: TYROBP was added
gene: TYROBP was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TYROBP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TYROBP were set to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 221770
Osteopetrosis v0.1 TNFSF11 Catherine Snow gene: TNFSF11 was added
gene: TNFSF11 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TNFSF11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TNFSF11 were set to Osteopetrosis, autosomal recessive 2 259710
Osteopetrosis v0.1 TNFRSF11A Catherine Snow gene: TNFRSF11A was added
gene: TNFRSF11A was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TNFRSF11A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: TNFRSF11A were set to Osteolysis, familial expansile 174810; {Paget disease of bone 2, early-onset} 602080; Osteopetrosis, autosomal recessive 7 612301
Osteopetrosis v0.1 TGFB1 Catherine Snow gene: TGFB1 was added
gene: TGFB1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TGFB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TGFB1 were set to Camurati-Engelmann disease 131300
Osteopetrosis v0.1 TCIRG1 Catherine Snow gene: TCIRG1 was added
gene: TCIRG1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: TCIRG1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TCIRG1 were set to Osteopetrosis, autosomal recessive 1 259700
Osteopetrosis v0.1 SOST Catherine Snow gene: SOST was added
gene: SOST was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SOST was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: SOST were set to Sclerosteosis 1 269500; Craniodiaphyseal dysplasia, autosomal dominant 122860; Van Buchem disease 239100
Osteopetrosis v0.1 SNX10 Catherine Snow gene: SNX10 was added
gene: SNX10 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 615085
Osteopetrosis v0.1 RASGRP2 Catherine Snow gene: RASGRP2 was added
gene: RASGRP2 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: RASGRP2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RASGRP2 were set to ?Bleeding disorder, platelet-type, 18 615888
Osteopetrosis v0.1 PTH1R Catherine Snow gene: PTH1R was added
gene: PTH1R was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PTH1R was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PTH1R were set to Chondrodysplasia, Blomstrand type 215045; Metaphyseal chondrodysplasia, Murk Jansen type 156400
Osteopetrosis v0.1 PLEKHM1 Catherine Snow gene: PLEKHM1 was added
gene: PLEKHM1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: PLEKHM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PLEKHM1 were set to ?Osteopetrosis, autosomal recessive 6 611497; Osteopetrosis, autosomal dominant 3 618107
Osteopetrosis v0.1 OSTM1 Catherine Snow gene: OSTM1 was added
gene: OSTM1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: OSTM1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OSTM1 were set to Osteopetrosis, autosomal recessive 5 259720
Osteopetrosis v0.1 LRP5 Catherine Snow gene: LRP5 was added
gene: LRP5 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: LRP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LRP5 were set to Osteopetrosis, autosomal dominant 1 607634; Osteosclerosis 144750; Hyperostosis, endosteal 144750; [Bone mineral density variability 1] 601884; van Buchem disease, type 2 607636
Osteopetrosis v0.1 LEMD3 Catherine Snow gene: LEMD3 was added
gene: LEMD3 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: LEMD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: LEMD3 were set to Osteopoikilosis with or without melorheostosis 166700; Buschke-Ollendorff syndrome 166700
Osteopetrosis v0.1 IKBKG Catherine Snow gene: IKBKG was added
gene: IKBKG was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: IKBKG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: IKBKG were set to Ectodermal dysplasia and immunodeficiency 1 300291
Osteopetrosis v0.1 FERMT3 Catherine Snow gene: FERMT3 was added
gene: FERMT3 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FERMT3 were set to 18709451
Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III 612840
Osteopetrosis v0.1 FAM20C Catherine Snow gene: FAM20C was added
gene: FAM20C was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: FAM20C was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FAM20C were set to Raine syndrome 259775
Osteopetrosis v0.1 CTSK Catherine Snow gene: CTSK was added
gene: CTSK was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CTSK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTSK were set to Pycnodysostosis 265800
Osteopetrosis v0.1 CLCN7 Catherine Snow gene: CLCN7 was added
gene: CLCN7 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CLCN7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: CLCN7 were set to Osteopetrosis, autosomal recessive 4 611490; Osteopetrosis, autosomal dominant 2 166600
Osteopetrosis v0.1 CA2 Catherine Snow gene: CA2 was added
gene: CA2 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis 259730
Osteopetrosis v0.1 ANKH Catherine Snow gene: ANKH was added
gene: ANKH was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ANKH were set to Chondrocalcinosis 2 118600; Craniometaphyseal dysplasia 123000
Osteopetrosis v0.1 AMER1 Catherine Snow gene: AMER1 was added
gene: AMER1 was added to Osteopetrosis. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: AMER1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: AMER1 were set to Osteopathia striata with cranial sclerosis 300373
Thrombocythaemia v0.0 CALR Arina Puzriakova gene: CALR was added
gene: CALR was added to Thrombocythaemia. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: CALR was set to Unknown
Phenotypes for gene: CALR were set to Thrombocythemia, somatic, 187950
Thrombocythaemia v0.0 SH2B3 Arina Puzriakova gene: SH2B3 was added
gene: SH2B3 was added to Thrombocythaemia. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: SH2B3 was set to Unknown
Phenotypes for gene: SH2B3 were set to Thrombocythemia, somatic, 187950
Thrombocythaemia v0.0 JAK2 Arina Puzriakova gene: JAK2 was added
gene: JAK2 was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: JAK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: JAK2 were set to Thrombocythemia 3, 614521
Thrombocythaemia v0.0 THPO Arina Puzriakova gene: THPO was added
gene: THPO was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: THPO was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: THPO were set to Thrombocythemia 1, 187950
Thrombocythaemia v0.0 MPL Arina Puzriakova gene: MPL was added
gene: MPL was added to Thrombocythaemia. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: MPL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MPL were set to Thrombocythemia 2, 601977
Thrombocythaemia v0.0 Arina Puzriakova Added panel Thrombocythaemia
Osteopetrosis v0.0 Catherine Snow Added Panel Osteopetrosis
Sudden cardiac death v9.72 Ivone Leong Panel version has been signed off
Dilated cardiomyopathy - adult and teen v1.5 Ivone Leong Panel version has been signed off
Progressive cardiac conduction disease v1.6 Ivone Leong Panel version has been signed off
Brugada syndrome v2.5 Ivone Leong Panel version has been signed off
Short QT syndrome v2.6 Ivone Leong Panel version has been signed off
Catecholaminergic polymorphic VT v2.6 Ivone Leong Panel version has been signed off
Hypertrophic cardiomyopathy - teen and adult v2.6 Ivone Leong Panel version has been signed off
Arrhythmogenic cardiomyopathy v2.9 Ivone Leong Panel version has been signed off
Long QT syndrome v2.21 Ivone Leong Panel version has been signed off
Intellectual disability v3.262 SPOP Arina Puzriakova changed review comment from: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.; to: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to differences in additional clinical manifestations.
Intellectual disability v3.262 TASP1 Arina Puzriakova Tag for-review tag was added to gene: TASP1.
Intellectual disability v3.262 TASP1 Arina Puzriakova Classified gene: TASP1 as Amber List (moderate evidence)
Intellectual disability v3.262 TASP1 Arina Puzriakova Added comment: Comment on list classification: Sufficient cases for a GREEN rating at the next major review.

Associated with phenotype in OMIM, and a possible gene for Developmental delay, happy demeanor, distinctive facial features, and congenital anomalies in G2P.

Four unrelated patients with homozygous LOF variants in this gene all exhibited a consistent phenotype which included global developmental delay. All variants segregated with disease, but no functional studies of the variants or patient cells were not performed.
Intellectual disability v3.262 TASP1 Arina Puzriakova Gene: tasp1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.88 PSAT1 Sarah Leigh commented on gene: PSAT1: There is enough evidence for this gene to be rated GREEN at the next major review.
Fetal anomalies v1.88 PSAT1 Sarah Leigh Deleted their comment
Fetal anomalies v1.88 PSAT1 Sarah Leigh reviewed gene: PSAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.88 PSAT1 Sarah Leigh Tag for-review tag was added to gene: PSAT1.
Fetal anomalies v1.88 POLE Sarah Leigh Tag for-review tag was added to gene: POLE.
Neurodegenerative disorders - adult onset v2.12 ISCA-37478-Gain Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders - adult onset v2.12 ISCA-37468-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders - adult onset v2.12 ISCA-37404-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders - adult onset v2.12 ISCA-37478-Loss Arina Puzriakova changed review comment from: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Removed as testing for this region is not achievable using currently available methodology.
Neurodegenerative disorders - adult onset v2.12 Arina Puzriakova Panel version has been signed off
Intellectual disability v3.261 SPOP Arina Puzriakova Phenotypes for gene: SPOP were changed from Intellectual disability; dysmorphism; microcephaly; macrocephaly to Nabais Sa-de Vries syndrome, type 1, 618828; Nabais Sa-de Vries syndrome, type 2, 618829
Neurodegenerative disorders - adult onset v2.10 Arina Puzriakova Panel version has been signed off
Cholestasis v1.22 Ivone Leong Panel version has been signed off
Childhood onset dystonia or chorea or related movement disorder v1.49 Eleanor Williams Panel version has been signed off
Intellectual disability v3.260 SPOP Arina Puzriakova Tag for-review tag was added to gene: SPOP.
Intellectual disability v3.260 SPOP Arina Puzriakova Classified gene: SPOP as Amber List (moderate evidence)
Intellectual disability v3.260 SPOP Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Associated with Nabais Sa-de Vries syndrome in OMIM, and a probable gene for SPOP-related Neurodevelopmental Disorder in G2P.

At least 7 unrelated individuals with mild-severe ID, associated with de novo missense variants in the SPOP gene. Additional variable features include craniofacial dysmorphisms, cardiovascular abnormalities, hearing impairment, and endocrine abnormalities. Functional studies show differing effects of the variants (gain-of-function or dominant-negative) that correspond to the different clinical manifestations.
Intellectual disability v3.260 SPOP Arina Puzriakova Gene: spop has been classified as Amber List (Moderate Evidence).
Skeletal muscle channelopathy v1.4 SLC2A1 Zornitza Stark reviewed gene: SLC2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dystonia 9, MIM# 601042; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 SLC1A3 Zornitza Stark reviewed gene: SLC1A3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Episodic ataxia, type 6, MIM# 612656; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 PYGM Zornitza Stark reviewed gene: PYGM: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: McArdle disease, 232600; Mode of inheritance: None
Skeletal muscle channelopathy v1.4 CACNA1A Zornitza Stark reviewed gene: CACNA1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Episodic ataxia, type 2, MIM# 108500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal muscle channelopathy v1.4 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: RED; Mode of pathogenicity: None; Publications: 30423015; Phenotypes: Hypokalaemic periodic paralysis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain channelopathy v1.55 KCNMA1 Zornitza Stark gene: KCNMA1 was added
gene: KCNMA1 was added to Brain channelopathy. Sources: Expert list
Mode of inheritance for gene: KCNMA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNMA1 were set to 15937479; 26195193
Phenotypes for gene: KCNMA1 were set to Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy, MIM# 609446
Review for gene: KCNMA1 was set to GREEN
gene: KCNMA1 was marked as current diagnostic
Added comment: Potassium channel gene which is associated with several phenotypes, including paroxysmal dyskinesia in at least three unrelated families.
Sources: Expert list
Brain channelopathy v1.55 KCNJ2 Zornitza Stark gene: KCNJ2 was added
gene: KCNJ2 was added to Brain channelopathy. Sources: Expert list
Mode of inheritance for gene: KCNJ2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ2 were set to 16217063; 16571646; 16419128; 17324964
Phenotypes for gene: KCNJ2 were set to Andersen syndrome, MIM# 170390
Review for gene: KCNJ2 was set to GREEN
Added comment: Multisystem channelopathy characterised by periodic paralysis as well as ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. > 10 families reported, well established gene-disease association.
Sources: Expert list
Fetal anomalies v1.88 TUBA8 Catherine Snow Classified gene: TUBA8 as Green List (high evidence)
Fetal anomalies v1.88 TUBA8 Catherine Snow Added comment: Comment on list classification: Change from Amber to Green, as requested by NHSE for signed-off panel.
Fetal anomalies v1.88 TUBA8 Catherine Snow Gene: tuba8 has been classified as Green List (High Evidence).
Fetal anomalies v1.87 SMG9 Catherine Snow Tag for-review tag was added to gene: SMG9.
Fetal anomalies v1.87 SMG9 Catherine Snow Classified gene: SMG9 as Amber List (moderate evidence)
Fetal anomalies v1.87 SMG9 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.87 SMG9 Catherine Snow Gene: smg9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.86 PSAT1 Catherine Snow Classified gene: PSAT1 as Amber List (moderate evidence)
Fetal anomalies v1.86 PSAT1 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.86 PSAT1 Catherine Snow Gene: psat1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.85 POLE Catherine Snow Classified gene: POLE as Amber List (moderate evidence)
Fetal anomalies v1.85 POLE Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.85 POLE Catherine Snow Gene: pole has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.84 GREB1L Catherine Snow Classified gene: GREB1L as Amber List (moderate evidence)
Fetal anomalies v1.84 GREB1L Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.84 GREB1L Catherine Snow Gene: greb1l has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Tag for-review tag was added to gene: EXOC3L2.
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Classified gene: EXOC3L2 as Amber List (moderate evidence)
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.83 EXOC3L2 Catherine Snow Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.82 CEP55 Catherine Snow Tag for-review tag was added to gene: CEP55.
Fetal anomalies v1.82 CEP55 Catherine Snow Classified gene: CEP55 as Amber List (moderate evidence)
Fetal anomalies v1.82 CEP55 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber, as requested by NHSE for signed-off panel.
Fetal anomalies v1.82 CEP55 Catherine Snow Gene: cep55 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.81 ALG9 Catherine Snow Tag for-review tag was added to gene: ALG9.
Fetal anomalies v1.81 ALG9 Catherine Snow Classified gene: ALG9 as Amber List (moderate evidence)
Fetal anomalies v1.81 ALG9 Catherine Snow Added comment: Comment on list classification: Change from Green to Amber as requested by NHSE for sign-off panel
Fetal anomalies v1.81 ALG9 Catherine Snow Gene: alg9 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.80 TMEM94 Catherine Snow Classified gene: TMEM94 as Green List (high evidence)
Fetal anomalies v1.80 TMEM94 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.80 TMEM94 Catherine Snow Gene: tmem94 has been classified as Green List (High Evidence).
Fetal anomalies v1.79 GDF1 Catherine Snow Classified gene: GDF1 as Green List (high evidence)
Fetal anomalies v1.79 GDF1 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.79 GDF1 Catherine Snow Gene: gdf1 has been classified as Green List (High Evidence).
Fetal anomalies v1.78 COL3A1 Catherine Snow Classified gene: COL3A1 as Green List (high evidence)
Fetal anomalies v1.78 COL3A1 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.78 COL3A1 Catherine Snow Gene: col3a1 has been classified as Green List (High Evidence).
Fetal anomalies v1.77 CFAP53 Catherine Snow Classified gene: CFAP53 as Green List (high evidence)
Fetal anomalies v1.77 CFAP53 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.77 CFAP53 Catherine Snow Gene: cfap53 has been classified as Green List (High Evidence).
Fetal anomalies v1.76 CEP120 Catherine Snow Classified gene: CEP120 as Green List (high evidence)
Fetal anomalies v1.76 CEP120 Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.76 CEP120 Catherine Snow Gene: cep120 has been classified as Green List (High Evidence).
Intellectual disability v3.259 POMK Arina Puzriakova Publications for gene: POMK were set to
Intellectual disability v3.258 POMK Arina Puzriakova Classified gene: POMK as Amber List (moderate evidence)
Intellectual disability v3.258 POMK Arina Puzriakova Added comment: Comment on list classification: Sufficient cases to support causation; however, ID is unlikely to be the main presenting feature of this phenotype - therefore, rating Amber on this panel.

POMK is rated Green on other relevant panels including Congenital muscular dystrophy, Hydrocephalus, and Arthrogryposis.
Intellectual disability v3.258 POMK Arina Puzriakova Gene: pomk has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.75 ACVR2B Catherine Snow Classified gene: ACVR2B as Green List (high evidence)
Fetal anomalies v1.75 ACVR2B Catherine Snow Added comment: Comment on list classification: Rating as Green following expert review from Rhiannon Mellis (Great Ormond Street Hospital)
Fetal anomalies v1.75 ACVR2B Catherine Snow Gene: acvr2b has been classified as Green List (High Evidence).
Cataracts v2.9 PISD Arina Puzriakova changed review comment from: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affects sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.; to: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affected sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.
Skeletal dysplasia v2.13 PISD Arina Puzriakova Classified gene: PISD as Amber List (moderate evidence)
Skeletal dysplasia v2.13 PISD Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN on the next major review - at least five unrelated families (three with the same founder variant) presenting skeletal dysplasia associated with biallelic variants in this gene.
Skeletal dysplasia v2.13 PISD Arina Puzriakova Gene: pisd has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.12 PISD Arina Puzriakova gene: PISD was added
gene: PISD was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: PISD.
Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PISD were set to 31263216; 30858161; 30488656; 3561949
Phenotypes for gene: PISD were set to Liberfarb syndrome, 618889
Review for gene: PISD was set to GREEN
Added comment: Associated with Liberfarb syndrome in OMIM, but not in G2P.

PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by skeletal dysplasia, short stature, early-onset retinal degeneration, developmental delay, microcephaly, and hearing loss. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.
Sources: Literature
Intellectual disability v3.257 PISD Arina Puzriakova Classified gene: PISD as Amber List (moderate evidence)
Intellectual disability v3.257 PISD Arina Puzriakova Added comment: Comment on list classification: Four families presenting a DD/ID phenotype, but three share the same founder variant - Rating Amber until further cases are reported (added to watchlist).
Intellectual disability v3.257 PISD Arina Puzriakova Gene: pisd has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.256 PISD Arina Puzriakova Tag watchlist tag was added to gene: PISD.
Intellectual disability v3.256 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656, 3561949; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cataracts v2.9 PISD Arina Puzriakova Publications for gene: PISD were set to 31263216; 30858161
Cataracts v2.8 PISD Arina Puzriakova Phenotypes for gene: PISD were changed from Intellectual disability; cataracts; retinal degeneration; microcephaly; deafness; short stature; white matter abnormalities to Liberfarb syndrome, 618889
Cataracts v2.7 PISD Arina Puzriakova Classified gene: PISD as Red List (low evidence)
Cataracts v2.7 PISD Arina Puzriakova Added comment: Comment on list classification: Rating Red, as cataracts (congenital) only reported in a single family with two affects sibs - additional cases required to ascertain the contribution of PISD variants to this phenotype.
Cataracts v2.7 PISD Arina Puzriakova Gene: pisd has been classified as Red List (Low Evidence).
Cataracts v2.6 PISD Arina Puzriakova edited their review of gene: PISD: Changed publications: 31263216, 30858161, 30488656, 3561949
Cataracts v2.6 PISD Arina Puzriakova changed review comment from: PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by early-onset retinal degeneration, skeletal dysplasia, short stature, developmental delay, microcephaly, and hearing loss. There was a concern for bilateral cataracts in one patient (patient 3), but a formal ophthalmological evaluation could not be performed. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.; to: Associated with Liberfarb syndrome in OMIM, but not in G2P.

PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by early-onset retinal degeneration, skeletal dysplasia, short stature, developmental delay, microcephaly, and hearing loss. There was a concern for bilateral cataracts in one patient (patient 3), but a formal ophthalmological evaluation could not be performed. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals.

PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene.

PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts.
Cataracts v2.6 PISD Arina Puzriakova reviewed gene: PISD: Rating: ; Mode of pathogenicity: None; Publications: 31263216, 30858161, 30488656; Phenotypes: Liberfarb syndrome, 618889; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.256 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Renal ciliopathies v1.28 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Red List (low evidence)
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Added comment: Comment on list classification: Keeping rating Red, as renal manifestation only reported in a single patient - awaiting further publications/clinical evidence to ascertain the contribution of variants in PIBF1 to this phenotype.
Renal ciliopathies v1.27 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Red List (Low Evidence).
Renal ciliopathies v1.26 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: ; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurological ciliopathies v1.9 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Neurological ciliopathies v1.9 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Amber List (moderate evidence)
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Added comment: Comment on list classification: With the addition of the two recent reports, there are now at least 7 total families (4 with same founder variant) with Joubert syndrome associated with biallelic variants in this gene.
Neurological ciliopathies v1.8 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v1.7 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Red List (low evidence)
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Added comment: Comment on list classification: Keeping rating Red as ophthalmological phenotype has been absent from all cases reported to date.
Ophthalmological ciliopathies v1.8 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Red List (Low Evidence).
Ophthalmological ciliopathies v1.7 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Ophthalmological ciliopathies v1.6 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: ; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: None
Hereditary Erythrocytosis v1.11 Sarah Leigh List of related panels changed from to R405
Panel types changed to Rare Disease 100K; GMS signed-off
Long QT syndrome v2.17 TRDN Ivone Leong Classified gene: TRDN as Amber List (moderate evidence)
Long QT syndrome v2.17 TRDN Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Amber at the request of NHS England following discussion at a Rare Disease workshop.
Long QT syndrome v2.17 TRDN Ivone Leong Gene: trdn has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Classified gene: BPGM as Amber List (moderate evidence)
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in 3 unrelated cases, although two of the cases are biallelic (PMID 25015942, 15054810), one case appears to monoallelic (PMID 25015942).
Hereditary Erythrocytosis v1.10 BPGM Sarah Leigh Gene: bpgm has been classified as Amber List (Moderate Evidence).
Hereditary Erythrocytosis v1.9 BPGM Sarah Leigh Added comment: Comment on phenotypes: Erythrocytosis due to bisphosphoglycerate mutase deficiency
Hereditary Erythrocytosis v1.9 BPGM Sarah Leigh Phenotypes for gene: BPGM were changed from Erythrocytosis due to bisphosphoglycerate mutase deficiency to Erythrocytosis, familial, 8 222800
Long QT syndrome v2.16 TRDN Ivone Leong Tag for-review tag was added to gene: TRDN.
Neurodegenerative disorders - adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Classified Region: ISCA-37478-Loss as No list
Neurodegenerative disorders - adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders - adult onset v2.8 ISCA-37478-Loss Arina Puzriakova Region: isca-37478-loss has been removed from the panel.
Neurodegenerative disorders - adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Classified Region: ISCA-37478-Gain as No list
Neurodegenerative disorders - adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders - adult onset v2.7 ISCA-37478-Gain Arina Puzriakova Region: isca-37478-gain has been removed from the panel.
Neurodegenerative disorders - adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Classified Region: ISCA-37404-Loss as No list
Neurodegenerative disorders - adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders - adult onset v2.6 ISCA-37404-Loss Arina Puzriakova Region: isca-37404-loss has been removed from the panel.
Neurodegenerative disorders - adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Classified Region: ISCA-37468-Loss as No list
Neurodegenerative disorders - adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Added comment: Comment on list classification: This region has been removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Neurodegenerative disorders - adult onset v2.5 ISCA-37468-Loss Arina Puzriakova Region: isca-37468-loss has been removed from the panel.
Palmoplantar keratodermas v1.3 ARSE Zornitza Stark reviewed gene: ARSE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Chondrodysplasia punctata, X-linked recessive, MIM# 302950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Palmoplantar keratodermas v1.3 CASP14 Zornitza Stark reviewed gene: CASP14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 CLDN1 Zornitza Stark reviewed gene: CLDN1: Rating: RED; Mode of pathogenicity: None; Publications: 15521008; Phenotypes: Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (MIM#607626); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 MVK Zornitza Stark reviewed gene: MVK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porokeratosis 3, multiple types, MIM# 175900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratodermas v1.3 PEX7 Zornitza Stark reviewed gene: PEX7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peroxisome biogenesis disorder 9B (AR), Rhizomelic chondrodysplasia punctata, type 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 PHYH Zornitza Stark reviewed gene: PHYH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Refsum disease (MIM#266500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 SLC27A4 Zornitza Stark reviewed gene: SLC27A4: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis prematurity syndrome (MIM#608649); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 ST14 Zornitza Stark reviewed gene: ST14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ichthyosis, congenital, autosomal recessive 11 (MIM#602400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Palmoplantar keratodermas v1.3 STK11 Zornitza Stark reviewed gene: STK11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Peutz-Jeghers syndrome (MIM#175200); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia or chorea or related movement disorder v1.45 COL6A3 Eleanor Williams Tag for-review tag was added to gene: COL6A3.
Childhood onset dystonia or chorea or related movement disorder v1.45 COL6A3 Eleanor Williams reviewed gene: COL6A3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Rare multisystem ciliopathy disorders v1.129 PIBF1 Arina Puzriakova Publications for gene: PIBF1 were set to 26167768
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Added comment: Comment on list classification: With the addition of the two recent reports, there are now at least 7 total families (4 with same founder variant) with Joubert syndrome associated with biallelic variants in this gene.
Rare multisystem ciliopathy disorders v1.128 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Green List (High Evidence).
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova Tag for-review was removed from gene: PIBF1.
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova Tag for-review tag was added to gene: PIBF1.
Rare multisystem ciliopathy disorders v1.127 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary Erythrocytosis v1.8 JAK2 Sarah Leigh changed review comment from: GMS Expert list Green
Sources: Expert list, NHS GMS; to: GMS Expert review Green
Sources: Expert review, NHS GMS
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh changed review comment from: GMS Expert list Green
Sources: NHS GMS, Expert list; to: GMS Expert review Green
Sources: NHS GMS, Expert review
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh Classified gene: SH2B3 as Green List (high evidence)
Hereditary Erythrocytosis v1.8 SH2B3 Sarah Leigh Gene: sh2b3 has been classified as Green List (High Evidence).
Hereditary Erythrocytosis v1.7 SH2B3 Sarah Leigh gene: SH2B3 was added
gene: SH2B3 was added to Hereditary Erythrocytosis. Sources: NHS GMS,Expert list
somatic tags were added to gene: SH2B3.
Mode of inheritance for gene: SH2B3 was set to Unknown
Phenotypes for gene: SH2B3 were set to Erythrocytosis, somatic 133100
Review for gene: SH2B3 was set to GREEN
Added comment: GMS Expert list Green
Sources: NHS GMS, Expert list
Hereditary Erythrocytosis v1.6 JAK2 Sarah Leigh Classified gene: JAK2 as Green List (high evidence)
Hereditary Erythrocytosis v1.6 JAK2 Sarah Leigh Gene: jak2 has been classified as Green List (High Evidence).
Hereditary Erythrocytosis v1.5 JAK2 Sarah Leigh gene: JAK2 was added
gene: JAK2 was added to Hereditary Erythrocytosis. Sources: Expert list,NHS GMS
somatic tags were added to gene: JAK2.
Mode of inheritance for gene: JAK2 was set to Unknown
Phenotypes for gene: JAK2 were set to Erythrocytosis, somatic 133100
Review for gene: JAK2 was set to GREEN
Added comment: GMS Expert list Green
Sources: Expert list, NHS GMS
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TY Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TW Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TV Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TT Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TS2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TS1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TR Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TQ Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TP Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TN Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TM Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TL2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TL1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TI Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TH Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TG Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TF Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TE Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TD Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TA Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-RNR2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-RNR1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND4L Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-CYB Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-CO2 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-CO1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ATP8 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from red to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TK Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TC Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND6 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND5 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND4 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND3 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ND1 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-CO3 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-ATP6 Eleanor Williams changed review comment from: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.; to: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop. Rating changed from green to grey.
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TY Eleanor Williams Classified gene: MT-TY as No list
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TY Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.45 MT-TY Eleanor Williams Gene: mt-ty has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.44 MT-TW Eleanor Williams Classified gene: MT-TW as No list
Childhood onset dystonia or chorea or related movement disorder v1.44 MT-TW Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.44 MT-TW Eleanor Williams Gene: mt-tw has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.43 MT-TV Eleanor Williams Classified gene: MT-TV as No list
Childhood onset dystonia or chorea or related movement disorder v1.43 MT-TV Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.43 MT-TV Eleanor Williams Gene: mt-tv has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.42 MT-TT Eleanor Williams Classified gene: MT-TT as No list
Childhood onset dystonia or chorea or related movement disorder v1.42 MT-TT Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.42 MT-TT Eleanor Williams Gene: mt-tt has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.41 MT-TS2 Eleanor Williams Classified gene: MT-TS2 as No list
Childhood onset dystonia or chorea or related movement disorder v1.41 MT-TS2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.41 MT-TS2 Eleanor Williams Gene: mt-ts2 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.40 MT-TS1 Eleanor Williams Classified gene: MT-TS1 as No list
Childhood onset dystonia or chorea or related movement disorder v1.40 MT-TS1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.40 MT-TS1 Eleanor Williams Gene: mt-ts1 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.39 MT-TR Eleanor Williams Classified gene: MT-TR as No list
Childhood onset dystonia or chorea or related movement disorder v1.39 MT-TR Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.39 MT-TR Eleanor Williams Gene: mt-tr has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.38 MT-TQ Eleanor Williams Classified gene: MT-TQ as No list
Childhood onset dystonia or chorea or related movement disorder v1.38 MT-TQ Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.38 MT-TQ Eleanor Williams Gene: mt-tq has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.37 MT-TP Eleanor Williams Classified gene: MT-TP as No list
Childhood onset dystonia or chorea or related movement disorder v1.37 MT-TP Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.37 MT-TP Eleanor Williams Gene: mt-tp has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.36 MT-TN Eleanor Williams Classified gene: MT-TN as No list
Childhood onset dystonia or chorea or related movement disorder v1.36 MT-TN Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.36 MT-TN Eleanor Williams Gene: mt-tn has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.35 MT-TM Eleanor Williams Classified gene: MT-TM as No list
Childhood onset dystonia or chorea or related movement disorder v1.35 MT-TM Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.35 MT-TM Eleanor Williams Gene: mt-tm has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.34 MT-TL2 Eleanor Williams Classified gene: MT-TL2 as No list
Childhood onset dystonia or chorea or related movement disorder v1.34 MT-TL2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.34 MT-TL2 Eleanor Williams Gene: mt-tl2 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.33 MT-TL1 Eleanor Williams Classified gene: MT-TL1 as No list
Childhood onset dystonia or chorea or related movement disorder v1.33 MT-TL1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.33 MT-TL1 Eleanor Williams Gene: mt-tl1 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.32 MT-TI Eleanor Williams Classified gene: MT-TI as No list
Childhood onset dystonia or chorea or related movement disorder v1.32 MT-TI Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.32 MT-TI Eleanor Williams Gene: mt-ti has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.31 MT-TH Eleanor Williams Classified gene: MT-TH as No list
Childhood onset dystonia or chorea or related movement disorder v1.31 MT-TH Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.31 MT-TH Eleanor Williams Gene: mt-th has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.30 MT-TG Eleanor Williams Classified gene: MT-TG as No list
Childhood onset dystonia or chorea or related movement disorder v1.30 MT-TG Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.30 MT-TG Eleanor Williams Gene: mt-tg has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.29 MT-TF Eleanor Williams Classified gene: MT-TF as No list
Childhood onset dystonia or chorea or related movement disorder v1.29 MT-TF Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.29 MT-TF Eleanor Williams Gene: mt-tf has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.28 MT-TE Eleanor Williams Classified gene: MT-TE as No list
Childhood onset dystonia or chorea or related movement disorder v1.28 MT-TE Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.28 MT-TE Eleanor Williams Gene: mt-te has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.27 MT-TD Eleanor Williams Classified gene: MT-TD as No list
Childhood onset dystonia or chorea or related movement disorder v1.27 MT-TD Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.27 MT-TD Eleanor Williams Gene: mt-td has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.26 MT-TA Eleanor Williams Classified gene: MT-TA as No list
Childhood onset dystonia or chorea or related movement disorder v1.26 MT-TA Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.26 MT-TA Eleanor Williams Gene: mt-ta has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.25 MT-RNR2 Eleanor Williams Classified gene: MT-RNR2 as No list
Childhood onset dystonia or chorea or related movement disorder v1.25 MT-RNR2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.25 MT-RNR2 Eleanor Williams Gene: mt-rnr2 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.24 MT-RNR1 Eleanor Williams Classified gene: MT-RNR1 as No list
Childhood onset dystonia or chorea or related movement disorder v1.24 MT-RNR1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.24 MT-RNR1 Eleanor Williams Gene: mt-rnr1 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.23 MT-ND4L Eleanor Williams Classified gene: MT-ND4L as No list
Childhood onset dystonia or chorea or related movement disorder v1.23 MT-ND4L Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.23 MT-ND4L Eleanor Williams Gene: mt-nd4l has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.22 MT-ND2 Eleanor Williams Classified gene: MT-ND2 as No list
Childhood onset dystonia or chorea or related movement disorder v1.22 MT-ND2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.22 MT-ND2 Eleanor Williams Gene: mt-nd2 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.21 MT-CYB Eleanor Williams Classified gene: MT-CYB as No list
Childhood onset dystonia or chorea or related movement disorder v1.21 MT-CYB Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.21 MT-CYB Eleanor Williams Gene: mt-cyb has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.20 MT-CO2 Eleanor Williams Classified gene: MT-CO2 as No list
Childhood onset dystonia or chorea or related movement disorder v1.20 MT-CO2 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.20 MT-CO2 Eleanor Williams Gene: mt-co2 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.19 MT-CO1 Eleanor Williams Classified gene: MT-CO1 as No list
Childhood onset dystonia or chorea or related movement disorder v1.19 MT-CO1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.19 MT-CO1 Eleanor Williams Gene: mt-co1 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.18 MT-ATP8 Eleanor Williams Classified gene: MT-ATP8 as No list
Childhood onset dystonia or chorea or related movement disorder v1.18 MT-ATP8 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.18 MT-ATP8 Eleanor Williams Gene: mt-atp8 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.17 MT-TK Eleanor Williams Classified gene: MT-TK as No list
Childhood onset dystonia or chorea or related movement disorder v1.17 MT-TK Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.17 MT-TK Eleanor Williams Gene: mt-tk has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.16 MT-TC Eleanor Williams Classified gene: MT-TC as No list
Childhood onset dystonia or chorea or related movement disorder v1.16 MT-TC Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.16 MT-TC Eleanor Williams Gene: mt-tc has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.15 MT-ND6 Eleanor Williams Classified gene: MT-ND6 as No list
Childhood onset dystonia or chorea or related movement disorder v1.15 MT-ND6 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.15 MT-ND6 Eleanor Williams Gene: mt-nd6 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.14 MT-ND5 Eleanor Williams Classified gene: MT-ND5 as No list
Childhood onset dystonia or chorea or related movement disorder v1.14 MT-ND5 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.14 MT-ND5 Eleanor Williams Gene: mt-nd5 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.13 MT-ND4 Eleanor Williams Classified gene: MT-ND4 as No list
Childhood onset dystonia or chorea or related movement disorder v1.13 MT-ND4 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.13 MT-ND4 Eleanor Williams Gene: mt-nd4 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.12 MT-ND3 Eleanor Williams Classified gene: MT-ND3 as No list
Childhood onset dystonia or chorea or related movement disorder v1.12 MT-ND3 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.12 MT-ND3 Eleanor Williams Gene: mt-nd3 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.11 MT-ND1 Eleanor Williams Classified gene: MT-ND1 as No list
Childhood onset dystonia or chorea or related movement disorder v1.11 MT-ND1 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.11 MT-ND1 Eleanor Williams Gene: mt-nd1 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.10 MT-CO3 Eleanor Williams Classified gene: MT-CO3 as No list
Childhood onset dystonia or chorea or related movement disorder v1.10 MT-CO3 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop
Childhood onset dystonia or chorea or related movement disorder v1.10 MT-CO3 Eleanor Williams Gene: mt-co3 has been removed from the panel.
Childhood onset dystonia or chorea or related movement disorder v1.9 MT-ATP6 Eleanor Williams Classified gene: MT-ATP6 as No list
Childhood onset dystonia or chorea or related movement disorder v1.9 MT-ATP6 Eleanor Williams Added comment: Comment on list classification: Mitochondrial gene removed from the panel at the request of NHS England following discussion at a Rare Disease workshop.
Childhood onset dystonia or chorea or related movement disorder v1.9 MT-ATP6 Eleanor Williams Gene: mt-atp6 has been removed from the panel.
Hereditary Erythrocytosis v1.4 EPO Sarah Leigh Added comment: Comment on mode of inheritance: Biallelic variants have been associated with ?Diamond-Blackfan anemia-like 617911
Hereditary Erythrocytosis v1.4 EPO Sarah Leigh Mode of inheritance for gene: EPO was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary Erythrocytosis v1.3 EPO Sarah Leigh Phenotypes for gene: EPO were changed from Hereditary Erythrocytosis to Erythrocytosis, familial, 5 617907
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Classified gene: EPO as Green List (high evidence)
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Added comment: Comment on list classification: GMS, Expert list Green
Hereditary Erythrocytosis v1.2 EPO Sarah Leigh Gene: epo has been classified as Green List (High Evidence).
Sudden cardiac death v9.48 Ivone Leong List of related panels changed from Molecular autopsy; R138 to Molecular autopsy; R138; R408
Cholestasis v1.19 CC2D2A Ivone Leong Classified gene: CC2D2A as No list
Cholestasis v1.19 CC2D2A Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.19 CC2D2A Ivone Leong Gene: cc2d2a has been removed from the panel.
Cholestasis v1.18 TMEM67 Ivone Leong Classified gene: TMEM67 as No list
Cholestasis v1.18 TMEM67 Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.18 TMEM67 Ivone Leong Gene: tmem67 has been removed from the panel.
Cholestasis v1.17 TMEM67 Ivone Leong Tag for-review was removed from gene: TMEM67.
Cholestasis v1.17 RPGRIP1L Ivone Leong Classified gene: RPGRIP1L as No list
Cholestasis v1.17 RPGRIP1L Ivone Leong Added comment: Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).
Cholestasis v1.17 RPGRIP1L Ivone Leong Gene: rpgrip1l has been removed from the panel.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Classified gene: PIBF1 as Amber List (moderate evidence)
Intellectual disability v3.256 PIBF1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - at least 7 families (4 with same founder variant) with Joubert syndrome, which is associated with global DD/ID.
Intellectual disability v3.256 PIBF1 Arina Puzriakova Gene: pibf1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.255 PIBF1 Arina Puzriakova reviewed gene: PIBF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26167768, 29695797, 30858804; Phenotypes: Joubert syndrome 33, 617767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.255 TAF1C Konstantinos Varvagiannis gene: TAF1C was added
gene: TAF1C was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Penetrance for gene: TAF1C were set to Complete
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants.

Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual).

Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1).

The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele.

TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit.

RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs).

A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data).

The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).

As a result, TAF1C may be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Intellectual disability v3.255 ZMPSTE24 Arina Puzriakova commented on gene: ZMPSTE24
Intellectual disability v3.255 ZIC3 Arina Puzriakova commented on gene: ZIC3
Intellectual disability v3.255 XPC Arina Puzriakova commented on gene: XPC
Intellectual disability v3.255 WRAP53 Arina Puzriakova commented on gene: WRAP53
Intellectual disability v3.255 WNT7A Arina Puzriakova commented on gene: WNT7A
Intellectual disability v3.255 WNT3 Arina Puzriakova commented on gene: WNT3
Intellectual disability v3.255 WNT10B Arina Puzriakova commented on gene: WNT10B
Intellectual disability v3.255 WDR35 Arina Puzriakova commented on gene: WDR35
Intellectual disability v3.254 WDR34 Arina Puzriakova commented on gene: WDR34
Intellectual disability v3.254 WDR19 Arina Puzriakova commented on gene: WDR19
Intellectual disability v3.254 VSX2 Arina Puzriakova commented on gene: VSX2
Intellectual disability v3.254 UVSSA Arina Puzriakova commented on gene: UVSSA
Intellectual disability v3.254 USB1 Arina Puzriakova commented on gene: USB1
Intellectual disability v3.254 UROS Arina Puzriakova commented on gene: UROS
Intellectual disability v3.254 UGT1A1 Arina Puzriakova commented on gene: UGT1A1
Intellectual disability v3.254 TYRP1 Arina Puzriakova commented on gene: TYRP1
Intellectual disability v3.254 TYR Arina Puzriakova commented on gene: TYR
Intellectual disability v3.254 TXNL4A Arina Puzriakova commented on gene: TXNL4A
Intellectual disability v3.254 TUBA8 Arina Puzriakova commented on gene: TUBA8
Intellectual disability v3.254 TSHR Arina Puzriakova commented on gene: TSHR
Intellectual disability v3.254 TRPV4 Arina Puzriakova commented on gene: TRPV4
Intellectual disability v3.254 TRPS1 Arina Puzriakova commented on gene: TRPS1
Intellectual disability v3.254 TRPM1 Arina Puzriakova commented on gene: TRPM1
Intellectual disability v3.254 TRIP11 Arina Puzriakova commented on gene: TRIP11
Intellectual disability v3.254 TRAPPC2 Arina Puzriakova commented on gene: TRAPPC2
Intellectual disability v3.254 TP63 Arina Puzriakova commented on gene: TP63
Intellectual disability v3.254 TMPRSS6 Arina Puzriakova commented on gene: TMPRSS6
Intellectual disability v3.254 TMEM126B Arina Puzriakova commented on gene: TMEM126B
Intellectual disability v3.254 TGFB3 Arina Puzriakova commented on gene: TGFB3
Intellectual disability v3.254 TGFB2 Arina Puzriakova commented on gene: TGFB2
Intellectual disability v3.254 TEK Arina Puzriakova commented on gene: TEK
Intellectual disability v3.254 TCF12 Arina Puzriakova commented on gene: TCF12
Intellectual disability v3.254 TBXAS1 Arina Puzriakova commented on gene: TBXAS1
Intellectual disability v3.254 TBX5 Arina Puzriakova commented on gene: TBX5
Intellectual disability v3.254 TBX4 Arina Puzriakova commented on gene: TBX4
Intellectual disability v3.254 TBX3 Arina Puzriakova commented on gene: TBX3
Intellectual disability v3.254 TBX22 Arina Puzriakova commented on gene: TBX22
Intellectual disability v3.254 TBX20 Arina Puzriakova commented on gene: TBX20
Intellectual disability v3.254 TBX15 Arina Puzriakova commented on gene: TBX15
Intellectual disability v3.254 TAB2 Arina Puzriakova commented on gene: TAB2
Intellectual disability v3.254 STS Arina Puzriakova commented on gene: STS
Intellectual disability v3.254 STAT1 Arina Puzriakova commented on gene: STAT1
Intellectual disability v3.254 STAR Arina Puzriakova commented on gene: STAR
Intellectual disability v3.254 SRY Arina Puzriakova commented on gene: SRY
Intellectual disability v3.254 SPEG Arina Puzriakova commented on gene: SPEG
Intellectual disability v3.254 SPAG1 Arina Puzriakova commented on gene: SPAG1
Intellectual disability v3.254 SOX17 Arina Puzriakova commented on gene: SOX17
Intellectual disability v3.254 SMCHD1 Arina Puzriakova commented on gene: SMCHD1
Intellectual disability v3.254 SCN4A Arina Puzriakova commented on gene: SCN4A
Intellectual disability v3.254 RUNX2 Arina Puzriakova commented on gene: RUNX2
Intellectual disability v3.254 RSPO4 Arina Puzriakova commented on gene: RSPO4
Intellectual disability v3.254 RSPH3 Arina Puzriakova commented on gene: RSPH3
Intellectual disability v3.254 RSPH1 Arina Puzriakova commented on gene: RSPH1
Intellectual disability v3.254 RPS19 Arina Puzriakova commented on gene: RPS19
Intellectual disability v3.254 RPGRIP1 Arina Puzriakova commented on gene: RPGRIP1
Intellectual disability v3.254 RPE65 Arina Puzriakova commented on gene: RPE65
Intellectual disability v3.254 ROBO3 Arina Puzriakova commented on gene: ROBO3
Intellectual disability v3.254 RETREG1 Arina Puzriakova commented on gene: RETREG1
Intellectual disability v3.253 RASA1 Arina Puzriakova commented on gene: RASA1
Intellectual disability v3.253 PGM1 Arina Puzriakova commented on gene: PGM1
Intellectual disability v3.253 PDE6G Arina Puzriakova commented on gene: PDE6G
Intellectual disability v3.253 PAX9 Arina Puzriakova commented on gene: PAX9
Intellectual disability v3.253 PAX3 Arina Puzriakova commented on gene: PAX3
Intellectual disability v3.253 PAPSS2 Arina Puzriakova commented on gene: PAPSS2
Intellectual disability v3.253 OTULIN Arina Puzriakova commented on gene: OTULIN
Intellectual disability v3.253 OTOGL Arina Puzriakova commented on gene: OTOGL
Intellectual disability v3.253 ORC6 Arina Puzriakova commented on gene: ORC6
Intellectual disability v3.253 NRXN2 Arina Puzriakova commented on gene: NRXN2
Intellectual disability v3.253 NR5A1 Arina Puzriakova commented on gene: NR5A1
Intellectual disability v3.253 NR2F2 Arina Puzriakova commented on gene: NR2F2
Intellectual disability v3.253 NPR2 Arina Puzriakova commented on gene: NPR2
Intellectual disability v3.253 NPHS1 Arina Puzriakova commented on gene: NPHS1
Intellectual disability v3.253 NPHP4 Arina Puzriakova commented on gene: NPHP4
Intellectual disability v3.253 NOTCH2 Arina Puzriakova commented on gene: NOTCH2
Intellectual disability v3.253 NOG Arina Puzriakova commented on gene: NOG
Intellectual disability v3.253 NODAL Arina Puzriakova commented on gene: NODAL
Intellectual disability v3.253 NMNAT1 Arina Puzriakova commented on gene: NMNAT1
Intellectual disability v3.253 NKX3-2 Arina Puzriakova commented on gene: NKX3-2
Intellectual disability v3.253 NEK1 Arina Puzriakova commented on gene: NEK1
Intellectual disability v3.253 MYO5B Arina Puzriakova commented on gene: MYO5B
Intellectual disability v3.253 MYH9 Arina Puzriakova commented on gene: MYH9
Intellectual disability v3.253 MYH8 Arina Puzriakova commented on gene: MYH8
Intellectual disability v3.253 MYH6 Arina Puzriakova commented on gene: MYH6
Intellectual disability v3.253 MSX2 Arina Puzriakova commented on gene: MSX2
Intellectual disability v3.253 MSX1 Arina Puzriakova commented on gene: MSX1
Intellectual disability v3.253 MNX1 Arina Puzriakova commented on gene: MNX1
Intellectual disability v3.253 MMP13 Arina Puzriakova commented on gene: MMP13
Intellectual disability v3.253 MFRP Arina Puzriakova commented on gene: MFRP
Intellectual disability v3.253 MESP2 Arina Puzriakova commented on gene: MESP2
Intellectual disability v3.253 MC2R Arina Puzriakova commented on gene: MC2R
Intellectual disability v3.253 MATN3 Arina Puzriakova commented on gene: MATN3
Intellectual disability v3.253 MAPK10 Arina Puzriakova commented on gene: MAPK10
Intellectual disability v3.253 MAP3K1 Arina Puzriakova commented on gene: MAP3K1
Intellectual disability v3.253 LTBP3 Arina Puzriakova commented on gene: LTBP3
Intellectual disability v3.253 LTBP2 Arina Puzriakova commented on gene: LTBP2
Intellectual disability v3.253 LRRC6 Arina Puzriakova commented on gene: LRRC6
Intellectual disability v3.253 LRP4 Arina Puzriakova commented on gene: LRP4
Intellectual disability v3.253 LMX1B Arina Puzriakova commented on gene: LMX1B
Intellectual disability v3.253 LMNA Arina Puzriakova commented on gene: LMNA
Intellectual disability v3.253 LHX4 Arina Puzriakova commented on gene: LHX4
Intellectual disability v3.253 LHX3 Arina Puzriakova commented on gene: LHX3
Intellectual disability v3.253 LFNG Arina Puzriakova commented on gene: LFNG
Intellectual disability v3.253 LEMD3 Arina Puzriakova commented on gene: LEMD3
Intellectual disability v3.253 LDB3 Arina Puzriakova commented on gene: LDB3
Intellectual disability v3.253 KLHL40 Arina Puzriakova commented on gene: KLHL40
Intellectual disability v3.253 KLF1 Arina Puzriakova commented on gene: KLF1
Intellectual disability v3.253 KIT Arina Puzriakova commented on gene: KIT
Intellectual disability v3.253 KIRREL3 Arina Puzriakova commented on gene: KIRREL3
Intellectual disability v3.252 KIF22 Arina Puzriakova commented on gene: KIF22
Intellectual disability v3.252 KCTD1 Arina Puzriakova commented on gene: KCTD1
Intellectual disability v3.252 KCNQ1 Arina Puzriakova commented on gene: KCNQ1
Intellectual disability v3.252 KCND3 Arina Puzriakova commented on gene: KCND3
Intellectual disability v3.252 KBTBD13 Arina Puzriakova commented on gene: KBTBD13
Intellectual disability v3.252 JAK3 Arina Puzriakova commented on gene: JAK3
Intellectual disability v3.252 JAGN1 Arina Puzriakova commented on gene: JAGN1
Intellectual disability v3.252 JAG1 Arina Puzriakova commented on gene: JAG1
Intellectual disability v3.252 IRF6 Arina Puzriakova commented on gene: IRF6
Intellectual disability v3.252 INPPL1 Arina Puzriakova commented on gene: INPPL1
Intellectual disability v3.252 IMPAD1 Arina Puzriakova commented on gene: IMPAD1
Intellectual disability v3.252 IL11RA Arina Puzriakova commented on gene: IL11RA
Intellectual disability v3.252 IHH Arina Puzriakova commented on gene: IHH
Intellectual disability v3.252 IGF2 Arina Puzriakova commented on gene: IGF2
Intellectual disability v3.252 IFT80 Arina Puzriakova commented on gene: IFT80
Intellectual disability v3.252 IFT122 Arina Puzriakova commented on gene: IFT122
Intellectual disability v3.252 IFITM5 Arina Puzriakova commented on gene: IFITM5
Intellectual disability v3.252 HYDIN Arina Puzriakova commented on gene: HYDIN
Intellectual disability v3.252 HYAL1 Arina Puzriakova commented on gene: HYAL1
Intellectual disability v3.252 HSF4 Arina Puzriakova commented on gene: HSF4
Intellectual disability v3.252 HSD3B7 Arina Puzriakova commented on gene: HSD3B7
Intellectual disability v3.252 HR Arina Puzriakova commented on gene: HR
Intellectual disability v3.252 HPSE2 Arina Puzriakova commented on gene: HPSE2
Intellectual disability v3.252 HPS1 Arina Puzriakova commented on gene: HPS1
Intellectual disability v3.252 HPGD Arina Puzriakova commented on gene: HPGD
Intellectual disability v3.252 HOXD13 Arina Puzriakova commented on gene: HOXD13
Intellectual disability v3.252 HOXC13 Arina Puzriakova commented on gene: HOXC13
Intellectual disability v3.252 HOXA13 Arina Puzriakova commented on gene: HOXA13
Intellectual disability v3.252 HNF4A Arina Puzriakova commented on gene: HNF4A
Intellectual disability v3.252 HMGCS2 Arina Puzriakova commented on gene: HMGCS2
Intellectual disability v3.252 GUCY2C Arina Puzriakova commented on gene: GUCY2C
Intellectual disability v3.252 GRM6 Arina Puzriakova commented on gene: GRM6
Intellectual disability v3.252 GRHL3 Arina Puzriakova commented on gene: GRHL3
Intellectual disability v3.252 GPR179 Arina Puzriakova commented on gene: GPR179
Intellectual disability v3.252 GNAI3 Arina Puzriakova commented on gene: GNAI3
Intellectual disability v3.252 GLMN Arina Puzriakova commented on gene: GLMN
Intellectual disability v3.252 GLE1 Arina Puzriakova commented on gene: GLE1
Intellectual disability v3.252 GJB1 Arina Puzriakova commented on gene: GJB1
Intellectual disability v3.252 GJA8 Arina Puzriakova commented on gene: GJA8
Intellectual disability v3.252 GJA3 Arina Puzriakova commented on gene: GJA3
Intellectual disability v3.252 GJA1 Arina Puzriakova commented on gene: GJA1
Intellectual disability v3.252 GHR Arina Puzriakova commented on gene: GHR
Intellectual disability v3.252 GDF6 Arina Puzriakova commented on gene: GDF6
Intellectual disability v3.252 GDF5 Arina Puzriakova commented on gene: GDF5
Intellectual disability v3.252 GBA2 Arina Puzriakova commented on gene: GBA2
Intellectual disability v3.252 GATA4 Arina Puzriakova commented on gene: GATA4
Intellectual disability v3.252 GATA2 Arina Puzriakova commented on gene: GATA2
Intellectual disability v3.252 GAS8 Arina Puzriakova commented on gene: GAS8
Intellectual disability v3.252 GALK1 Arina Puzriakova commented on gene: GALK1
Intellectual disability v3.252 GAA Arina Puzriakova commented on gene: GAA
Intellectual disability v3.251 FZD6 Arina Puzriakova commented on gene: FZD6
Intellectual disability v3.251 FYCO1 Arina Puzriakova commented on gene: FYCO1
Intellectual disability v3.251 FXN Arina Puzriakova commented on gene: FXN
Intellectual disability v3.251 FTL Arina Puzriakova commented on gene: FTL
Intellectual disability v3.251 FOXN1 Arina Puzriakova commented on gene: FOXN1
Intellectual disability v3.251 FOXF1 Arina Puzriakova commented on gene: FOXF1
Intellectual disability v3.251 FOXE3 Arina Puzriakova commented on gene: FOXE3
Intellectual disability v3.251 FOXE1 Arina Puzriakova commented on gene: FOXE1
Intellectual disability v3.251 FOXC2 Arina Puzriakova commented on gene: FOXC2
Intellectual disability v3.251 FOXC1 Arina Puzriakova commented on gene: FOXC1
Intellectual disability v3.251 FLT4 Arina Puzriakova commented on gene: FLT4
Intellectual disability v3.251 FLNB Arina Puzriakova commented on gene: FLNB
Intellectual disability v3.251 FKBP14 Arina Puzriakova commented on gene: FKBP14
Intellectual disability v3.251 FHL1 Arina Puzriakova commented on gene: FHL1
Intellectual disability v3.251 FGF3 Arina Puzriakova commented on gene: FGF3
Intellectual disability v3.251 FGF10 Arina Puzriakova commented on gene: FGF10
Intellectual disability v3.251 FBXW4 Arina Puzriakova commented on gene: FBXW4
Intellectual disability v3.251 FBP1 Arina Puzriakova commented on gene: FBP1
Intellectual disability v3.251 FBN1 Arina Puzriakova commented on gene: FBN1
Intellectual disability v3.251 FAM20A Arina Puzriakova commented on gene: FAM20A
Intellectual disability v3.251 FAM161A Arina Puzriakova commented on gene: FAM161A
Intellectual disability v3.251 FAAH2 Arina Puzriakova commented on gene: FAAH2
Intellectual disability v3.251 EYA1 Arina Puzriakova commented on gene: EYA1
Intellectual disability v3.251