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Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI was removed from gene: ACOX1.
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Deleted their review
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Deleted their comment
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong Tag Q3_21_MOI tag was added to gene: ACOX1.
Early onset or syndromic epilepsy v2.381 ACOX1 Ivone Leong reviewed gene: ACOX1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.188 ACOX1 Ivone Leong changed review comment from: PMID: 32169171. 3 unrelated patients with the same de novo variant (N237S) with a progressive disease. Age of onset is between 3-12 years old (cf to AR patients 0-3 years old), disease course is progressive (AR patients, early onset and severe) white matter demyelination is progressive, sensorineural hearing loss and ataxia. Authors found that the variant increased levels of ACOX1 protein and function which increased levels of ROS in glia of Drosphila and mouse Schwann cells leading to glial degeneration. The authors suggested that the variant caused a GOF effect.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID: 33805425 - Sawaguchi et al 2021 - using a mouse model they show that EPRS1 variant Arg339-to-Ter (R339X) (found in one of the patients in Mendes et al in heterozgyous state with another variant) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells. Wild-type proteins are distributed throughout the cell bodies. This seems to inhibit cell morphological differentiation.; Changed rating: GREEN; Changed publications to: 29576217, 33805425; Changed phenotypes to: Leukodystrophy, hypomyelinating, 15, OMIM:617951; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v2.38 SLC25A42 Ivone Leong Phenotypes for gene: SLC25A42 were changed from muscle weakness, lactic acidosis, and muscle changes suggestive of mitochondrial dysfunction to Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression, OMIM:618416
Congenital myopathy v2.37 SLC25A42 Ivone Leong Publications for gene: SLC25A42 were set to 26541337
Severe microcephaly v2.211 TP53RK Eleanor Williams Classified gene: TP53RK as Amber List (moderate evidence)
Severe microcephaly v2.211 TP53RK Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating following GMS review. Following consultation with the Genomics England clinical team it was decided that a green recommendation would be appropriate as primary microcephaly might be the presenting feature before renal issues appear.
Severe microcephaly v2.211 TP53RK Eleanor Williams Gene: tp53rk has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.210 TP53RK Eleanor Williams Tag Q2_21_rating tag was added to gene: TP53RK.
Severe microcephaly v2.210 TCF4 Eleanor Williams Classified gene: TCF4 as Red List (low evidence)
Severe microcephaly v2.210 TCF4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. After consultation with the Genomics England Clinical Team it was decided that patients with Pitt-Hopkins syndrome are more likely to be following a route for explanation of global developmental delay/intellectual disability than severe microcephaly.
Severe microcephaly v2.210 TCF4 Eleanor Williams Gene: tcf4 has been classified as Red List (Low Evidence).
Haematological malignancies cancer susceptibility v2.16 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553; MDS, AML; Oral and GI squamous cell carcinoma
Adult solid tumours cancer susceptibility v2.12 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Primary immunodeficiency or monogenic inflammatory bowel disease v2.440 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita 6, 616553; Dyskeratosis congenita 7, 616553; Hoyeraal-Hreidarsson syndrome to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Ductal plate malformation v1.17 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from ?Dyskeratosis congenita, autosomal dominant 6 (616553); ?Dyskeratosis congenita, autosomal recessive 7 (616553) to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Childhood solid tumours v2.21 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
COVID-19 research v1.78 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Dyskeratosis congenita 6, 616553; Dyskeratosis congenita 7, 616553; Hoyeraal-Hreidarsson syndrome to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Haematological malignancies for rare disease v1.2 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from Class: BM failure syndrome (typ AR); Dyskeratosis congenita; MDS, AML; Oral and GI squamous cell carcinoma to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553; MDS, AML; Oral and GI squamous cell carcinoma
Cytopenia - NOT Fanconi anaemia v1.39 ACD Arina Puzriakova Phenotypes for gene: ACD were changed from 616553 ?Dyskeratosis congenita 6 and 7 to Dyskeratosis congenita, autosomal dominant 6, OMIM:616553; Dyskeratosis congenita, autosomal recessive 7, OMIM:616553
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Classified gene: ACD as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Added comment: Comment on list classification: Only two families with DC who have variants in ACD have been reported since 2015 - one family with AD inheritance had only progressive bone marrow failure (PMID: 25205116) and one patient (patient B) with AR inheritance had a more severe phenotype (PMID: 25233904). However, this gene was rated Green on this and other panels following external clinical review - so this rating will be maintained at this time.
Cytopenia - NOT Fanconi anaemia v1.38 ACD Arina Puzriakova Gene: acd has been classified as Green List (High Evidence).
Severe microcephaly v2.209 PTPN23 Eleanor Williams Classified gene: PTPN23 as Amber List (moderate evidence)
Severe microcephaly v2.209 PTPN23 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. 1 confirmed case with severe microcephaly plus several further cases of microcephaly, not all of which have the degree of severity stated. Genomics England clinician confirms proposal for green rating.
Severe microcephaly v2.209 PTPN23 Eleanor Williams Gene: ptpn23 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.208 PTPN23 Eleanor Williams Tag Q2_21_rating tag was added to gene: PTPN23.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova changed review comment from: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_rating); to: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_expert_review)
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_rating was removed from gene: ADAMTS13.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: ADAMTS13.
Thrombophilia with a likely monogenic cause v1.19 ADAMTS13 Arina Puzriakova Tag Q2_21_NHS_review tag was added to gene: ADAMTS13.
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova commented on gene: ADAMTS13: This gene will be flagged for review at the next GMS panel update to highlight the recent review by Kate Downes (CUH) indicating that the phenotype associated with ADAMTS13 (MIM# 274150) may be out of scope for this panel (tagged Q2_21_rating)
Fetal anomalies v1.679 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
DDG2P v2.29 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
Childhood onset dystonia, chorea or related movement disorder v1.132 DMPK Dmitrijs Rots changed review comment from: Causes myotinic dystonia only due to STR expansion, not SNVs.; to: Causes myotinic dystrophy only due to STR expansion, not SNVs.
DDG2P v2.29 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.679 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v1.132 DMPK Dmitrijs Rots reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and platelet disorders v1.26 ADAMTS13 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ADAMTS13.
Tag Q2_21_NHS_review tag was added to gene: ADAMTS13.
Segmental overgrowth disorders - Deep sequencing v2.14 NLRP2 Sarah Leigh commented on gene: NLRP2: The Q2_21_expert_review tag has been added for the TEWG to consider whether or not the epigenetic effects of maternal variants in NLRP2 have in their children is appropriate for a Green gene rating.
Segmental overgrowth disorders - Deep sequencing v2.14 NLRP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: NLRP2.
Childhood onset dystonia, chorea or related movement disorder v1.132 FXN_GAA Sarah Leigh Publications for STR: FXN_GAA were set to
Intellectual disability v3.1149 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
Intellectual disability v3.1149 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Early onset or syndromic epilepsy v2.379 UFSP2 Sarah Leigh changed review comment from: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; to: The Q2_21_expert_review tag has been added to consider the evidence for the founder variant rs142500730, which appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.
Early onset or syndromic epilepsy v2.379 UFSP2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: UFSP2.
Childhood onset dystonia, chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh changed review comment from: Based on review by Zornitza Stark and opinion of Helen Brittain (Genomics England Clinical Fellow), the Q2_21_phenotype & Q2_21_expert_review tags have been added, in order to request the opinion of the TEWG regarding the relevance of phenotype associated with variants in ALDH18A1 for this panel (Childhood onset dystonia or chorea or related movement disorder).; to: Based on review by Zornitza Stark and the opinion of Helen Brittain (Genomics England Clinical Fellow), the Q2_21_phenotype & Q2_21_expert_review tags have been added, in order to request the opinion of the TEWG regarding the relevance of phenotype associated with variants in ALDH18A1 for this panel (Childhood onset dystonia or chorea or related movement disorder).
Childhood onset dystonia, chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh commented on gene: ALDH18A1
Childhood onset dystonia, chorea or related movement disorder v1.131 ALDH18A1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: ALDH18A1.
Intellectual disability v3.1149 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.439 OAS1 Arina Puzriakova Phenotypes for gene: OAS1 were changed from Autoinflammatory Disorders; Pulmonary alveolar proteinosis, skin rash; OAS1 GOF to Autoinflammatory Disorders; Pulmonary alveolar proteinosis; Recurrent fever; Dermatitis; Inflammatory bowel disease; Hypogammaglobulinemia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.438 OAS1 Arina Puzriakova Mode of pathogenicity for gene: OAS1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Primary immunodeficiency or monogenic inflammatory bowel disease v2.437 OAS1 Arina Puzriakova edited their review of gene: OAS1: Added comment: Additional publication identified by Boaz Palterer (PMID:34145065) supports the inclusion of this gene as Green on this panel. There are now at least 4 different gain-of-function heterozygous variants in the OAS1 gene identified in 8 unrelated families with 10 affected individuals (P5 in PMID:34145065 and C-II-1 in PMID:29455859 refer to the same individual).; Changed rating: GREEN; Changed publications to: 34145065, 29455859; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cerebral vascular malformations v2.55 CHD4 Sarah Leigh Classified gene: CHD4 as Amber List (moderate evidence)
Cerebral vascular malformations v2.55 CHD4 Sarah Leigh Gene: chd4 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.54 SETD5 Sarah Leigh Publications for gene: SETD5 were set to 31474762
Cerebral vascular malformations v2.53 SETD5 Sarah Leigh Classified gene: SETD5 as Amber List (moderate evidence)
Cerebral vascular malformations v2.53 SETD5 Sarah Leigh Gene: setd5 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh Tag watchlist tag was added to gene: SETD5.
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh changed review comment from: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761.; to: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761, two further variants were found, but it was not possible to report their inheritance (PMID 31474762). Eight de novo SETD5 variants have been reported in Mental retardation, autosomal dominant 23 OMIM:615761 (PMIDs 24680889, 23020937, 25138099). However, none of these reported detailed neurological examinations that could have diagnosed Moyamoya disease.
Cerebral vascular malformations v2.52 SETD5 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: SETD5.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.437 OAS1 Arina Puzriakova Publications for gene: OAS1 were set to 32086639; 29455859; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.436 IKZF3 Arina Puzriakova Publications for gene: IKZF3 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.435 IKZF3 Arina Puzriakova Classified gene: IKZF3 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.435 IKZF3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer (University of Florence). Rating Red as only a single family with B cell deficiency has been reported at this time. Includes supportive mouse model showing B cell developmental defects and T cell abnormalities (PMID:34155405).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.435 IKZF3 Arina Puzriakova Gene: ikzf3 has been classified as Red List (Low Evidence).
Hereditary ataxia with onset in adulthood v2.80 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.80 XRCC1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: XRCC1.
Hereditary ataxia with onset in adulthood v2.80 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.80 XRCC1 Arina Puzriakova Added comment: Comment on list classification: This gene will be flagged for GMS review to determine whether there is enough evidence to include XRCC1 on this panel as Green. Only one case with adult onset and the other two with onset in childhood, however inclusion may be justified to ensure identification of edge cases.
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Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia with onset in adulthood v2.80 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed rating: GREEN; Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova edited their review of gene: XRCC1: Changed rating: GREEN; Changed publications to: 28002403, 29472272; Changed phenotypes to: Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova changed review comment from: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
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Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when biallelic. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.; to: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
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Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Green List (high evidence)
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene from Red to Green.
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Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when in trans with a second variant. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Hereditary ataxia v1.231 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Green List (High Evidence).
Hereditary ataxia v1.230 XRCC1 Arina Puzriakova Tag founder-effect tag was added to gene: XRCC1.
Hereditary ataxia with onset in adulthood v2.79 XRCC1 Arina Puzriakova Tag watchlist was removed from gene: XRCC1.
Tag founder-effect tag was added to gene: XRCC1.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Tag founder-effect tag was added to gene: XRCC1.
Tag Q2_21_rating tag was added to gene: XRCC1.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Classified gene: XRCC1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is enough evidence to promote this gene to Green at the next GMS panel update (see details below).
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Three individuals from unrelated families all from South Asian descent with cerebellar ataxia and peripheral neuropathy and a recurrent variant (c.1293G>C, 2 homozygotes and a comp het) in the XRCC1 gene. Homozygosity mapping in 2 families confirmed a shared haplotype and the recurrent variant is found in a heterozygous state in an unaffected sib and 4 individuals of South Asian descent in ExAC - indicating that this is a founder variant that is pathogenic when biallelic. There is some strong functional evidence that supports pathogenicity, including an animal model that recapitulated human phenotypes such as cerebellar ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.214 XRCC1 Arina Puzriakova Gene: xrcc1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia v1.230 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Hereditary ataxia with onset in adulthood v2.79 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Ataxia and cerebellar anomalies - narrow panel v2.213 XRCC1 Arina Puzriakova Publications for gene: XRCC1 were set to 28002403
Adult onset neurodegenerative disorder v2.175 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Adult onset neurodegenerative disorder v2.175 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Congenital myopathy v2.36 ACTN2 Ivone Leong Publications for gene: ACTN2 were set to 24692096; 30701273
Hereditary ataxia v1.229 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary neuropathy v1.386 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Spinocerebellar ataxia, autosomal recessive 26, 617633; Ataxia, developmental delay, azoospermia and hypogonadism, myotonia, sensory and motor axonal neuropathy to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary ataxia with onset in adulthood v2.78 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia; Autosomal recessive spinocerebellar ataxia 26, 617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Ataxia and cerebellar anomalies - narrow panel v2.212 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Hereditary neuropathy or pain disorder v1.29 XRCC1 Arina Puzriakova Phenotypes for gene: XRCC1 were changed from Ataxia, developmental delay, azoospermia and hypogonadism, myotonia, sensory and motor axonal neuropathy; Spinocerebellar ataxia, autosomal recessive 26, 617633 to Spinocerebellar ataxia, autosomal recessive 26, OMIM:617633
Congenital myopathy v2.35 MYH8 Ivone Leong Tag Q2_21_phenotype tag was added to gene: MYH8.
Congenital myopathy v2.35 MYH8 Ivone Leong reviewed gene: MYH8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Congenital myopathy v2.35 MYH8 Ivone Leong Publications for gene: MYH8 were set to 17041932
Congenital myopathy v2.34 MYH8 Ivone Leong Phenotypes for gene: MYH8 were changed from Trismus-pseudocamptodactyly syndrome, 158300 to Trismus-pseudocamptodactyly syndrome, OMIM:158300
Congenital myopathy v2.33 MYL2 Ivone Leong Classified gene: MYL2 as Amber List (moderate evidence)
Congenital myopathy v2.33 MYL2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a variant in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Congenital myopathy v2.33 MYL2 Ivone Leong Gene: myl2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v2.32 MYL2 Ivone Leong Tag Q2_21_rating tag was added to gene: MYL2.
Congenital myopathy v2.32 MYL2 Ivone Leong Added comment: Comment on publications: PMID:33731536 third case from Japan
Congenital myopathy v2.32 MYL2 Ivone Leong Publications for gene: MYL2 were set to 23365102; 27378946; 33731536
Intellectual disability v3.1149 JMJD1C Arina Puzriakova changed review comment from: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.; to: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges (added watchlist tag).
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Tag watchlist tag was added to gene: JMJD1C.
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Classified gene: JMJD1C as Amber List (moderate evidence)
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that there is currently not enough evidence to support this gene-disease association. Rating Amber until further evidence emerges.
Intellectual disability v3.1149 JMJD1C Arina Puzriakova Gene: jmjd1c has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1148 JMJD1C Arina Puzriakova Phenotypes for gene: JMJD1C were changed from Intellectual disability to Intellectual disability; Autism
Intellectual disability v3.1147 JMJD1C Arina Puzriakova Publications for gene: JMJD1C were set to 26181491; 32996679
Intellectual disability v3.1146 JMJD1C Arina Puzriakova reviewed gene: JMJD1C: Rating: AMBER; Mode of pathogenicity: None; Publications: 26181491, 31954878, 32996679, 28378413, 22495311, 25363768, 17290275, 33591602; Phenotypes: Intellectual disability, Autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Monogenic hearing loss v2.177 KDM3B Ivone Leong changed review comment from: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.; to: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to this panel. However, there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Monogenic hearing loss v2.177 KDM3B Ivone Leong Tag Q2_21_rating was removed from gene: KDM3B.
Tag watchlist tag was added to gene: KDM3B.
Monogenic hearing loss v2.177 KDM3B Ivone Leong Entity copied from Intellectual disability v3.1146
Monogenic hearing loss v2.177 KDM3B Ivone Leong gene: KDM3B was added
gene: KDM3B was added to Hearing loss. Sources: Victorian Clinical Genetics Services,Expert Review Amber
Q2_21_rating tags were added to gene: KDM3B.
Mode of inheritance for gene: KDM3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KDM3B were set to 30929739
Phenotypes for gene: KDM3B were set to Global developmental delay; Intellectual disability; Short stature; Behavioral abnormality; Seizures
Intellectual disability v3.1146 KDM3B Ivone Leong Added comment: Comment on publications: PMID: 30929739. 8/16 patients had short stature (< -2.5 SD) and 9/15 had neonatal feeding difficulties. 5/16 had joint hypermobility, 4/17 had hearing loss.
Intellectual disability v3.1146 KDM3B Ivone Leong Publications for gene: KDM3B were set to 30929739
Intellectual disability v3.1145 KDM3B Ivone Leong Tag Q2_21_rating tag was added to gene: KDM3B.
Intellectual disability v3.1145 KDM3B Ivone Leong commented on gene: KDM3B: After consulting with the Genomics England Clinical Team it was decided that this gene should be promoted to Green status at the next review.
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 Ivone Leong Classified gene: KIAA1161 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.186 KIAA1161 Ivone Leong Gene: kiaa1161 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Tag Q2_21_rating tag was added to gene: KIAA1161.
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Added comment: Comment on mode of inheritance: MOI has been changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "Biallelic, autosomal or pseudoautosomal" after consulting the Genomics England Clinical Team. As not all carriers exhibit the phenotype and the age of for the carriers that do exhibit the phenotype is not appropriate for this panel. Therefore the Biallelic MOI was assigned.
White matter disorders and cerebral calcification - narrow panel v1.185 KIAA1161 Ivone Leong Mode of inheritance for gene: KIAA1161 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.184 KIAA1161 Ivone Leong Added comment: Comment on publications: PMID: 31951047 - "89.5% (34 of 38) of individuals with heterozygous mutations remained asymptomatic at the time of examination and 4 of them exhibited symptoms with uncertain clinical significance (nonspecific depression, epilepsy, and late‐onset parkinsonism)". Age at CT scans range from 28-84. "brain calcifications of varying severity, from mild calcifications limited to the basal ganglia that were hard to differentiate from physiological calcifications to diffuse and moderate calcium deposits".

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

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

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

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

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

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

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

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

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

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

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

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

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

GEMIN5 is associated with a relevant phenotype in OMIM (Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333) but is not yet listed in G2P.
Intellectual disability v3.1145 GEMIN5 Arina Puzriakova Gene: gemin5 has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v1.22 COL4A2 Ivone Leong Phenotypes for gene: COL4A2 were changed from Brain small vessel disease 2, 614483 to Brain small vessel disease 2, OMIM:614483
White matter disorders and cerebral calcification - narrow panel v1.182 AUH Ivone Leong Entity copied from White matter disorders - adult onset v1.21
White matter disorders and cerebral calcification - narrow panel v1.182 AUH Ivone Leong gene: AUH was added
gene: AUH was added to White matter disorders and cerebral calcification - narrow panel. Sources: Expert list,Expert Review Amber
Q2_21_rating tags were added to gene: AUH.
Mode of inheritance for gene: AUH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AUH were set to 20855850; 17130438
Phenotypes for gene: AUH were set to 3-methylglutaconic aciduria, type I, OMIM:250950
Hereditary ataxia with onset in adulthood v2.77 AUH Ivone Leong Entity copied from White matter disorders - adult onset v1.21
Hereditary ataxia with onset in adulthood v2.77 AUH Ivone Leong gene: AUH was added
gene: AUH was added to Hereditary ataxia - adult onset. Sources: Expert list,Expert Review Amber
Q2_21_rating tags were added to gene: AUH.
Mode of inheritance for gene: AUH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AUH were set to 20855850; 17130438
Phenotypes for gene: AUH were set to 3-methylglutaconic aciduria, type I, OMIM:250950
Adult onset leukodystrophy v1.21 AUH Ivone Leong Tag Q2_21_rating tag was added to gene: AUH.
Adult onset leukodystrophy v1.21 AUH Ivone Leong Classified gene: AUH as Amber List (moderate evidence)
Adult onset leukodystrophy v1.21 AUH Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. The age of onset is between 1 to 52 years of age. Childhood onset patients have psychomotor retardation and white matter changes. There are 3 cases of adult onset of this phenotype. Patients presented with ataxia (3/3), dementia (2/3) and spasticity (2/3) and all had white matter changes. This gene should be rated Green at the next review.
Adult onset leukodystrophy v1.21 AUH Ivone Leong Gene: auh has been classified as Amber List (Moderate Evidence).
Adult onset leukodystrophy v1.20 AUH Ivone Leong Phenotypes for gene: AUH were changed from 3-methylglutaconic aciduria, type I, MIM# 250950 to 3-methylglutaconic aciduria, type I, OMIM:250950
Adult onset leukodystrophy v1.19 AUH Ivone Leong Publications for gene: AUH were set to 20855850
Intellectual disability v3.1144 GEMIN5 Arina Puzriakova Phenotypes for gene: GEMIN5 were changed from Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, MIM# 619333 to Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, OMIM:619333
Childhood onset hereditary spastic paraplegia v2.41 BCAS3 Arina Puzriakova Entity copied from Intellectual disability v3.1143
Childhood onset hereditary spastic paraplegia v2.41 BCAS3 Arina Puzriakova gene: BCAS3 was added
gene: BCAS3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: BCAS3.
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Tag Q2_21_rating tag was added to gene: BCAS3.
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Classified gene: BCAS3 as Amber List (moderate evidence)
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update (see details below).
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Hengel et al. 2021 (PMID: 34022130) report 8 unrelated families, all with different biallelic variants in the BCAS3 gene. All affected individuals (15 total, +1 additional proband but with unphased variants but consistent phenotype) had severe GDD and ID, with 10 subjects having minimal vocabulary and 4 never learning to speak. All probands had a severe motor disorder with pyramidal tract involvement resulting in hyperreflexia and spasticity of the lower limbs (15/15). Other variable features observed in the cohort include microcephaly, short stature, seizures, and dysmorphic facial features.
Intellectual disability v3.1143 BCAS3 Arina Puzriakova Gene: bcas3 has been classified as Amber List (Moderate Evidence).
Holoprosencephaly - NOT chromosomal v2.18 DISP1 Sarah Leigh Phenotypes for gene: DISP1 were changed from Holoprosencephaly to holoprosencephaly MONDO:0016296
Holoprosencephaly - NOT chromosomal v2.17 DISP1 Sarah Leigh reviewed gene: DISP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset leukodystrophy v1.18 ASPA Ivone Leong Classified gene: ASPA as Red List (low evidence)
Adult onset leukodystrophy v1.18 ASPA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Age of onset for Canavan disease is reported range from congenital, infantile to childhood onset. PMID: 2512436 indicated that there are late-onset forms of Canavan disease; however, I cannot access this article. There is enough evidence to support a gene-disease association; however, due to lack of evidence about age of onset being in adulthood, this gene has been given a Red rating on this panel.

This gene is Green on White matter disorders and cerebral calcification - narrow panel (Version 1.181).
Adult onset leukodystrophy v1.18 ASPA Ivone Leong Gene: aspa has been classified as Red List (Low Evidence).
Hypogonadotropic hypogonadism (GMS) v1.43 CPE Arina Puzriakova Entity copied from Intellectual disability v3.1142
Hypogonadotropic hypogonadism (GMS) v1.43 CPE Arina Puzriakova gene: CPE was added
gene: CPE was added to Hypogonadotropic hypogonadism idiopathic. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: CPE.
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
Intellectual disability v3.1142 CPE Arina Puzriakova Tag watchlist tag was added to gene: CPE.
Intellectual disability v3.1142 CPE Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag); to: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature to date with different homozygous variants in the CPE gene (PMIDs: 26120850; 32936766). Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Classified gene: CPE as Amber List (moderate evidence)
Intellectual disability v3.1142 CPE Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Two consanguineous families in literature with different homozygous variants in the CPE gene. Affected individuals presented with obesity, intellectual disability and hypogonadotropic hypogonadism. Rating Amber, awaiting further cases (added watchlist tag)
Intellectual disability v3.1142 CPE Arina Puzriakova Gene: cpe has been classified as Amber List (Moderate Evidence).
Severe early-onset obesity v2.39 CPE Arina Puzriakova Added comment: Comment on phenotypes: CPE is now associated with a relevant phenotype in OMIM - Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Severe early-onset obesity v2.39 CPE Arina Puzriakova Phenotypes for gene: CPE were changed from obesity to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
Intellectual disability v3.1141 CPE Arina Puzriakova Phenotypes for gene: CPE were changed from Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326 to Intellectual developmental disorder and hypogonadotropic hypogonadism, OMIM:619326
Adult onset leukodystrophy v1.17 ASPA Ivone Leong Phenotypes for gene: ASPA were changed from to Canavan disease, OMIM:271900
Paroxysmal central nervous system disorders v1.15 ATP1A4 Ivone Leong Classified gene: ATP1A4 as Red List (low evidence)
Paroxysmal central nervous system disorders v1.15 ATP1A4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Paroxysmal central nervous system disorders v1.15 ATP1A4 Ivone Leong Gene: atp1a4 has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v1.14 ATP1A4 Ivone Leong Phenotypes for gene: ATP1A4 were changed from Hemiplegic migraine to familial hemiplegic migraine, MONDO:0000700
Congenital myopathy v2.28 TNNC2 Dmitrijs Rots reviewed gene: TNNC2: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 33755597; Phenotypes: Myopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hydrocephalus v2.114 ERF Ivone Leong Tag Q2_21_expert_review tag was added to gene: ERF.
Hydrocephalus v2.114 TNFRSF11A Ivone Leong Phenotypes for gene: TNFRSF11A were changed from Osteopetrosis, autosomal recessive 7, MIM# 612301 to Osteopetrosis, autosomal recessive 7, OMIM:612301
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: POU4F1.
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Classified gene: POU4F1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.210 POU4F1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update - sufficient number of unrelated cases (>3), supported by an animal model (see details below)
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Webb et al. 2021 (PMID:33783914) identified four unrelated individuals with different de novo POU4F1 variants. All presented with ataxia, hypotonia, and intention tremor. 3/4 also had strabismus and a history of paroxysmal tonic upgaze. Pou4f1−/− mice are known to have uncoordinated movements consistent with the ataxia phenotype seen in this patient cohort.

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

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

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

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

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

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

Another study (PMID: 22452945) investigating contribution of MAX variants to PCC stated the age of diagnosis ranged between 13-58 years in a cohort of 23 probands.
Sources: NHS GMS
Adult solid tumours cancer susceptibility v2.11 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Familial Pheochromocytoma, adrenal to {Pheochromocytoma, susceptibility to}, OMIM:171300; Familial Pheochromocytoma, adrenal
Inherited phaeochromocytoma and paraganglioma excluding NF1 v1.16 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from {Pheochromocytoma, susceptibility to}, 171300; Hereditary Paraganglioma-Pheochromocytoma Syndrome; pheochromocytomas (PHEOs), paragangliomas (PGLs) to {Pheochromocytoma, susceptibility to}, OMIM:171300; Hereditary Paraganglioma-Pheochromocytoma Syndrome
Multiple endocrine tumours v1.10 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Endocrine Cancer to {Pheochromocytoma, susceptibility to}, OMIM:171300
Adult solid tumours for rare disease v1.23 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Familial Pheochromocytoma, adrenal to {Pheochromocytoma, susceptibility to}, OMIM:171300
Neuroendocrine cancer pertinent cancer susceptibility v1.1 MAX Arina Puzriakova Phenotypes for gene: MAX were changed from Neuroendocrine cancer to {Pheochromocytoma, susceptibility to}, OMIM:171300
Hydrocephalus v2.109 TRIM71 Ivone Leong Tag Q2_21_rating tag was added to gene: TRIM71.
Hydrocephalus v2.109 TRIM71 Ivone Leong Classified gene: TRIM71 as Amber List (moderate evidence)
Hydrocephalus v2.109 TRIM71 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hydrocephalus v2.109 TRIM71 Ivone Leong Gene: trim71 has been classified as Amber List (Moderate Evidence).
Hydrocephalus v2.108 TRIM71 Ivone Leong Added comment: Comment on publications: PMID: 33077954. 3 additional cases with different variants.
Hydrocephalus v2.108 TRIM71 Ivone Leong Publications for gene: TRIM71 were set to 29983323; 32168371; 30975633
Hydrocephalus v2.107 TRIM71 Ivone Leong Phenotypes for gene: TRIM71 were changed from Hydrocephalus, congenital communicating, 1, MIM# 618667 to Hydrocephalus, congenital communicating, 1, OMIM:618667
Proteinuric renal disease v2.50 CD151 Natalie Forrester reviewed gene: CD151: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15265795, 29138120, 17015618, 32641585, 22338088, 18787104, 22201679; Phenotypes: Nephropathy with pretibial epidermolysis bullosa and deafness #609057; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v2.18 POPDC3 Agnese Zarina gene: POPDC3 was added
gene: POPDC3 was added to Limb girdle muscular dystrophy. Sources: Literature
Mode of inheritance for gene: POPDC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POPDC3 were set to https://doi.org/10.1002/ana.25620
Phenotypes for gene: POPDC3 were set to Muscular dystrophy, limb-girdle, autosomal recessive 26
Review for gene: POPDC3 was set to AMBER
Added comment: Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 SQSTM1 Agnese Zarina gene: SQSTM1 was added
gene: SQSTM1 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: SQSTM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SQSTM1 were set to doi:10.1001/archneurol.2011.250
Phenotypes for gene: SQSTM1 were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Penetrance for gene: SQSTM1 were set to Complete
Review for gene: SQSTM1 was set to AMBER
Added comment: The gene is included in other panels, but one of the phenotypes is also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 SPG11 Agnese Zarina gene: SPG11 was added
gene: SPG11 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: SPG11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPG11 were set to https://doi.org/10.1093/brain/awp325
Phenotypes for gene: SPG11 were set to Amyotrophic lateral sclerosis 5, juvenile
Penetrance for gene: SPG11 were set to Complete
Review for gene: SPG11 was set to AMBER
Added comment: The gene is included in other panels (e.g., spastic paraplegia), but one of the phenotypes could be also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 ANXA11 Agnese Zarina gene: ANXA11 was added
gene: ANXA11 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: ANXA11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANXA11 were set to DOI: 10.1126/scitranslmed.aad9157
Phenotypes for gene: ANXA11 were set to Amyotrophic lateral sclerosis 23
Penetrance for gene: ANXA11 were set to Complete
Review for gene: ANXA11 was set to AMBER
Added comment: gene is added to "Neurodegenerative disorders - adult onset" panel, but one of the phenotype is also ALS
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 TUBA4A Agnese Zarina gene: TUBA4A was added
gene: TUBA4A was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA4A were set to https://doi.org/10.1016/j.neuron.2014.09.027
Phenotypes for gene: TUBA4A were set to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia
Penetrance for gene: TUBA4A were set to Complete
Review for gene: TUBA4A was set to AMBER
Added comment: Gene is added to "Neurodegenerative disorders - adult onset" panel, but the phenotype can be also amyotrophic lateral sclerosis with or without frontotemporal dementia
Sources: Literature
Amyotrophic lateral sclerosis/motor neuron disease v1.29 MATR3 Agnese Zarina gene: MATR3 was added
gene: MATR3 was added to Amyotrophic lateral sclerosis/motor neuron disease. Sources: Literature
Mode of inheritance for gene: MATR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MATR3 were set to https://doi.org/10.1038/nn.3688 https://doi.org/10.1002/ana.24255
Phenotypes for gene: MATR3 were set to Amyotrophic lateral sclerosis 21
Penetrance for gene: MATR3 were set to Complete
Review for gene: MATR3 was set to AMBER
Added comment: Gene is added to the "Neuromuscular diseases" super panel and "Dystal myopathies" sub-panel, but it should be added also to the "ALS" panel.
Sources: Literature
Monogenic hearing loss v2.176 ADGRV1 Ivone Leong Publications for gene: ADGRV1 were set to PMID:10234513; 10976914; 11545713; 11606593; 12095917; 12402266; 14740321; 15820310; 18854872; 19357116; 19357117; 20440071; 22147658; 9598305; 9734811
Intellectual disability v3.1136 RUBCN Arina Puzriakova edited their review of gene: RUBCN: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1136 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: ; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1136 RUBCN Arina Puzriakova Tag founder-effect tag was added to gene: RUBCN.
Intellectual disability v3.1136 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to 20826435
Early onset or syndromic epilepsy v2.374 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: RED; Mode of pathogenicity: None; Publications: 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia v1.225 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to PMID: 20826435
Hereditary ataxia with onset in adulthood v2.74 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from Autosomal recessive spinocerebellar ataxia 15, 615705 to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Hereditary ataxia v1.224 RUBCN Arina Puzriakova reviewed gene: RUBCN: Rating: RED; Mode of pathogenicity: None; Publications: 20826435, 32450808; Phenotypes: Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.201 RUBCN Arina Puzriakova Publications for gene: RUBCN were set to PMID: 20826435
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Classified gene: RUBCN as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Added comment: Comment on list classification: Gene was reassessed following a Green review by Zornitza Stark. Five individuals from two consanguineous Saudi families have been identified (PMID: 20826435; 32450808) who presented with early-onset ataxia, dysarthria, and developmental delay. All harboured the same c.2624delC variant, which was confirmed to be a founder variant by autozygosity mapping. Limited functional data showing the variant results in mislocalisation of the mutant protein from the late endosome and lysosomes to diffuse cytosolic distribution.

*Note the third publication identified by Zornitza (PMID:30237576) refers to the same sib pair as in PMID:32450808. The variants appeared distinct as the two papers refer to different reference sequences (NM_014687 vs NM_001145642.2) but the variant/case are in fact the same.
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Overall as there is only a single variant in a single population with only limited in vitro functional support, maintaining Red rating on this panel until further evidence on the gene/variants emerges.
Ataxia and cerebellar anomalies - narrow panel v2.200 RUBCN Arina Puzriakova Gene: rubcn has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.199 RUBCN Arina Puzriakova Tag founder-effect tag was added to gene: RUBCN.
Monogenic hearing loss v2.175 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Monogenic hearing loss v2.175 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Hearing loss. Sources: Literature,Expert Review Red
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Optic neuropathy v2.44 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Optic neuropathy v2.44 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Optic neuropathy. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Hydrocephalus v2.106 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Hydrocephalus v2.106 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Hydrocephalus. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Retinal disorders v2.187 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Retinal disorders v2.187 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Retinal disorders. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Severe microcephaly v2.208 ZPR1 Ivone Leong Entity copied from Growth failure in early childhood v1.70
Severe microcephaly v2.208 ZPR1 Ivone Leong gene: ZPR1 was added
gene: ZPR1 was added to Severe microcephaly. Sources: Expert Review Red,Literature
founder-effect tags were added to gene: ZPR1.
Mode of inheritance for gene: ZPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZPR1 were set to 29851065
Phenotypes for gene: ZPR1 were set to ?Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, OMIM:619321
Thoracic aortic aneurysm or dissection v1.118 COL5A1 Ivone Leong Publications for gene: COL5A1 were set to 26188975; 10946364; 28868310; 25845371; 239975631; 2180144; 29543232
Thoracic aortic aneurysm or dissection v1.117 COL5A1 Ivone Leong reviewed gene: COL5A1: Rating: ; Mode of pathogenicity: None; Publications: 32938213; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1135 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from SYNDROMIC MR WITH ATAXIA, DYSARTHRIA AND EPILEPSY to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm or dissection v1.117 COL5A1 Ivone Leong Phenotypes for gene: COL5A1 were changed from Ehlers-Danlos syndrome vascular type; Ehlers-Danlos syndrome, classic type, 130000 to Ehlers-Danlos syndrome, classic type, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329
Early onset or syndromic epilepsy v2.374 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from ?Spinocerebellar ataxia, autosomal recessive 15 615705 to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm or dissection (GMS) v1.12 COL5A1 Ivone Leong Added comment: Comment on phenotypes: Added Fibromuscular dysplasia, multifocal, OMIM:619329
Thoracic aortic aneurysm or dissection (GMS) v1.12 COL5A1 Ivone Leong Phenotypes for gene: COL5A1 were changed from Ehlers-Danlos syndrome, classic type, 130000; Ehlers-Danlos syndrome vascular type to Ehlers-Danlos syndrome, classic type, OMIM:130000; Fibromuscular dysplasia, multifocal, OMIM:619329
Hereditary ataxia v1.224 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Ataxia and cerebellar anomalies - narrow panel v2.199 RUBCN Arina Puzriakova Phenotypes for gene: RUBCN were changed from to Spinocerebellar ataxia, autosomal recessive 15, OMIM:615705
Thoracic aortic aneurysm or dissection v1.116 IPO8 Ivone Leong Classified gene: IPO8 as Green List (high evidence)
Thoracic aortic aneurysm or dissection v1.116 IPO8 Ivone Leong Gene: ipo8 has been classified as Green List (High Evidence).
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong Tag Q2_21_rating was removed from gene: IPO8.
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong Entity copied from Thoracic aortic aneurysm and dissection v1.11
Thoracic aortic aneurysm or dissection v1.115 IPO8 Ivone Leong gene: IPO8 was added
gene: IPO8 was added to Thoracic aortic aneurysm or dissection. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: IPO8.
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604; 34010605
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Thoracic aortic aneurysm or dissection (GMS) v1.11 IPO8 Ivone Leong Tag Q2_21_rating tag was added to gene: IPO8.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.434 IPO8 Ivone Leong changed review comment from: Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8):

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

"12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression. Sources: Literature
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Hereditary neuropathy or pain disorder v1.27 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Ataxia, spasticity, and demyelinating neuropathy to POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Thoracic aortic aneurysm or dissection (GMS) v1.11 IPO8 Ivone Leong commented on gene: IPO8: Boaz Palterer also left a Green review on the Primary immunodeficiency panel (Version 2.434):

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

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

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

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

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype.
Thoracic aortic aneurysm or dissection (GMS) v1.10 IPO8 Ivone Leong Classified gene: IPO8 as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.10 IPO8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Thoracic aortic aneurysm or dissection (GMS) v1.10 IPO8 Ivone Leong Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1134 POLR3B Arina Puzriakova Publications for gene: POLR3B were set to
Thoracic aortic aneurysm or dissection (GMS) v1.9 IPO8 Ivone Leong Added comment: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

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

Recently, heterozygous variants were also linked to ID. Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. The majority had some degree of DD, with 5/6 participants being diagnosed with intellectual disability ranging from mild to moderate severity. Four individuals required assistance with basic activities of daily living, however none had developmental regression. Protein modelling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Intellectual disability v3.1133 POLR3B Arina Puzriakova Mode of inheritance for gene: POLR3B was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1132 POLR3B Arina Puzriakova Tag Q2_21_MOI tag was added to gene: POLR3B.
Intellectual disability v3.1132 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381; POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Hereditary neuropathy or pain disorder v1.26 POLR3B Arina Puzriakova Classified gene: POLR3B as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.26 POLR3B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. EMG/NCSs for 5/6 individuals revealed predominantly demyelinating sensory and motor neuropathy. Other features included ID, ataxia, spasticity.

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

Overall, there is sufficient evidence to warrant a Green rating on this panel.
Hereditary neuropathy or pain disorder v1.26 POLR3B Arina Puzriakova Gene: polr3b has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.25 POLR3B Arina Puzriakova Tag Q2_21_rating tag was added to gene: POLR3B.
Ataxia and cerebellar anomalies - narrow panel v2.197 POLR3B Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Progressive childhood-onset cerebellar ataxia is a feature in a subset of cases with biallelic variants in this gene. There are sufficient unrelated families in literature to warrant a Green rating on this panel (>10 individuals reported with ataxia)

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


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

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


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

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


Comment on mode of inheritance: Both biallelic and monoallelic variants have been linked to ataxia - enough evidence for a Green rating for both allelic requirements
Ataxia and cerebellar anomalies - narrow panel v2.195 POLR3B Arina Puzriakova Gene: polr3b has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.101 ARCN1 Andžela Lazdāne edited their review of gene: ARCN1: Changed rating: GREEN
IUGR and IGF abnormalities v1.35 ARCN1 Andžela Lazdāne edited their review of gene: ARCN1: Changed rating: GREEN
DDG2P v2.28 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM 607694; AUTOSOMAL RECESSIVE MENTAL RETARDATION to Autosomal recessive mental retardation; Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism; POLR3B-related neurodevelopmental disorder
Intellectual disability v3.1131 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropichypogonadism, 614381; LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Fetal anomalies v1.678 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION; LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Inherited white matter disorders v1.126 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Adult onset leukodystrophy v1.16 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Ataxia and cerebellar anomalies - narrow panel v2.194 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 614381 to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
White matter disorders and cerebral calcification - narrow panel v1.181 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, 614381; Pol III-Related Leukodystrophy; General Leukodystrophy & Mitochondrial Leukoencephalopathy to Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:614381
Intellectual disability v3.1130 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures, intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Early onset or syndromic epilepsy v2.373 RORB Arina Puzriakova Phenotypes for gene: RORB were changed from generalized epilepsies with predominant absence seizures to {Epilepsy, idiopathic generalized, susceptibility to, 15}, OMIM:618357
Intellectual disability v3.1129 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures:Epileptic encephalopathy, early infantile, 70 618298; PHACTR1-associated neurodevelopment disorder to Developmental and epileptic encephalopathy 70, OMIM:618298
Early onset or syndromic epilepsy v2.372 PHACTR1 Arina Puzriakova Phenotypes for gene: PHACTR1 were changed from Global developmental delay; Intellectual disability; Seizures to Developmental and epileptic encephalopathy 70, OMIM:618298
Intellectual disability v3.1128 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Early onset or syndromic epilepsy v2.371 EIF3F Arina Puzriakova Phenotypes for gene: EIF3F were changed from Intellectual disability; Seizures; Behavioral abnormality; Sensorineural hearing impairment to Mental retardation, autosomal recessive 67, OMIM:618295
Intellectual disability v3.1127 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior to Developmental and epileptic encephalopathy 67, OMIM:618141; Seizures; Intellectual disability; Autistic behaviour
Early onset or syndromic epilepsy v2.370 CUX2 Arina Puzriakova Phenotypes for gene: CUX2 were changed from Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy to Developmental and epileptic encephalopathy 67, OMIM:618141; Infantile onset myoclonic epileptic encephalopathy
Skeletal dysplasia v2.101 FAM46A Arina Puzriakova Phenotypes for gene: FAM46A were changed from Osteogenesis imperfecta, type XVIII 617952 to Osteogenesis imperfecta, type XVIII, OMIM:617952
Osteogenesis imperfecta v2.14 FAM46A Arina Puzriakova Phenotypes for gene: FAM46A were changed from osteogenesis imperfecta to Osteogenesis imperfecta, type XVIII, OMIM:617952
Fetal anomalies v1.677 SPTBN5 Arina Puzriakova Phenotypes for gene: SPTBN5 were changed from Multicystic kidney; Oligohydramnios to Multicystic kidney; Oligohydramnios; Sacral agenesis
Fetal anomalies v1.676 SPTBN5 Arina Puzriakova Publications for gene: SPTBN5 were set to 32732226
Fetal anomalies v1.675 SPTBN5 Arina Puzriakova Mode of inheritance for gene: SPTBN5 was changed from BIALLELIC, autosomal or pseudoautosomal to Unknown
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: PITRM1.
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Classified gene: PITRM1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence for PITRM1 to be classified as Green at the next GMS panel update. Three unrelated families including 2 consanguineous Palestinian families each with 2 affected boys (PMID: 29764912) and a consanguineous Norwegian family also with 2 affected sibs (PMID: 26697887). Phenotypes include ataxia although severity is variable. Supported by functional work and mouse model also exhibiting progressive ataxia.
Ataxia and cerebellar anomalies - narrow panel v2.193 PITRM1 Arina Puzriakova Gene: pitrm1 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.8 COL5A1 Ivone Leong Publications for gene: COL5A1 were set to
Fetal hydrops v1.29 SLC30A5 Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.45
Fetal hydrops v1.29 SLC30A5 Ivone Leong gene: SLC30A5 was added
gene: SLC30A5 was added to Fetal hydrops. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: SLC30A5.
Mode of inheritance for gene: SLC30A5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC30A5 were set to 33547425; 12095919
Phenotypes for gene: SLC30A5 were set to Perinatal lethal cardiomyopathy; cardiomyopathy, MONDO:0004994
Paediatric or syndromic cardiomyopathy v1.45 SLC30A5 Ivone Leong Classified gene: SLC30A5 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.45 SLC30A5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Paediatric or syndromic cardiomyopathy v1.45 SLC30A5 Ivone Leong Gene: slc30a5 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.44 SLC30A5 Ivone Leong Tag watchlist tag was added to gene: SLC30A5.
Paediatric or syndromic cardiomyopathy v1.44 SLC30A5 Ivone Leong Phenotypes for gene: SLC30A5 were changed from Perinatal lethal cardiomyopathy to Perinatal lethal cardiomyopathy; cardiomyopathy, MONDO:0004994
Stickler syndrome v2.22 BMP4 Ivone Leong Added comment: Comment on publications: Added publication and removed PMID: 25663169; 30362103, which were for LOXL3 and not BMP4
Stickler syndrome v2.22 BMP4 Ivone Leong Publications for gene: BMP4 were set to 30568244
Stickler syndrome v2.21 BMP4 Ivone Leong Publications for gene: BMP4 were set to 25663169; 30362103; 30568244
Stickler syndrome v2.20 LOXL3 Ivone Leong Publications for gene: LOXL3 were set to 25663169
Stickler syndrome v2.19 BMP4 Ivone Leong Publications for gene: BMP4 were set to 25663169; 30362103
Monogenic hearing loss v2.174 COL9A3 Ivone Leong reviewed gene: COL9A3: Rating: ; Mode of pathogenicity: None; Publications: 33633367; Phenotypes: ; Mode of inheritance: None
Stickler syndrome v2.18 COL9A3 Ivone Leong changed review comment from: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.; to: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 variant associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong changed review comment from: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with Stickler syndrome, the MOI will be kept as "Biallelic" until more evidence is available.; to: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with peripheral vitreoretinal degeneration and retinal detachment, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong Added comment: Comment on mode of inheritance: As there are currently only 2 unrelated cases of autosomal dominant COL9A3 associated with Stickler syndrome, the MOI will be kept as "Biallelic" until more evidence is available.
Stickler syndrome v2.18 COL9A3 Ivone Leong Mode of inheritance for gene: COL9A3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Stickler syndrome v2.17 COL9A3 Ivone Leong Publications for gene: COL9A3 were set to 24273071 and unpublished observation; 30450842
Structural eye disease v1.73 KIF17 Ivone Leong Classified gene: KIF17 as Red List (low evidence)
Structural eye disease v1.73 KIF17 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support gene-disease association. This gene has been given a Red rating.
Structural eye disease v1.73 KIF17 Ivone Leong Gene: kif17 has been classified as Red List (Low Evidence).
Structural eye disease v1.72 KIF17 Ivone Leong Phenotypes for gene: KIF17 were changed from Microphthalmia; Coloboma to Microphthalmia, MONDO:0021129; Coloboma, MONDO:0001476
Primary immunodeficiency or monogenic inflammatory bowel disease v2.432 MYOF Arina Puzriakova Penetrance for gene MYOF was set from to None
IUGR and IGF abnormalities v1.35 ARCN1 Andžela Lazdāne gene: ARCN1 was added
gene: ARCN1 was added to IUGR and IGF abnormalities. Sources: Literature
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARCN1 were set to PMID: 27476655; PMID: 33154040
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
Penetrance for gene: ARCN1 were set to Complete
Review for gene: ARCN1 was set to AMBER
Added comment: Pathogenic loss-of-function variants in ARCN1 represent an emerging disorder of developmental delay and skeletal manifestations. Phenotype corresponds to IUGR such as craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, cleft palate, microcephalic dwarfism and mild developmental delay.
Sources: Literature
Skeletal dysplasia v2.100 ARCN1 Andžela Lazdāne gene: ARCN1 was added
gene: ARCN1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ARCN1 were set to PMID: 27476655
Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay
Penetrance for gene: ARCN1 were set to Complete
Review for gene: ARCN1 was set to AMBER
Added comment: Clinical features like short stature, rhizomelia, laxity of the small joints, cleft palete and developmental delay also tend to occur in Skeletal dysplasia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

30 individuals from 22 unrelated families reported.
Sources: Literature
Thoracic aortic aneurysm or dissection (GMS) v1.7 IPO8 Zornitza Stark gene: IPO8 was added
gene: IPO8 was added to Thoracic aortic aneurysm and dissection. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604
Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Review for gene: IPO8 was set to GREEN
gene: IPO8 was marked as current diagnostic
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Literature
Intellectual disability v3.1120 PARP6 Zornitza Stark gene: PARP6 was added
gene: PARP6 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PARP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PARP6 were set to 34067418
Phenotypes for gene: PARP6 were set to Intellectual disability; Epilepsy; Microcephaly
Review for gene: PARP6 was set to GREEN
Added comment: Four unrelated individuals reported with de novo variants in this gene and a neurodevelopmental phenotype. Supportive functional data. One pair of siblings with a homozygous missense: limited evidence for bi-allelic variants causing disease.
Sources: Literature
Intellectual disability v3.1120 MYCN Zornitza Stark reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 21224895, 8470948; Phenotypes: Feingold syndrome 1, Megalencephaly, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Thoracic aortic aneurysm or dissection (GMS) v1.7 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32938213; Phenotypes: Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital disorders of glycosylation v2.70 SLC37A4 Zornitza Stark edited their review of gene: SLC37A4: Added comment: PMID 33964207: 7 patients from 4 families, additional to the two reported previously, described with the same recurrent c.1267C>T (p.R423*) variant with liver dysfunction multifactorial coagulation deficiency and cardiac issues. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans. Hepatoma cell-line studies support the pathogenicity of the variant.; Changed publications to: 32884905, 33964207
Intellectual disability v3.1120 CPE Zornitza Stark gene: CPE was added
gene: CPE was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CPE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPE were set to 26120850; 32936766
Phenotypes for gene: CPE were set to Intellectual developmental disorder and hypogonadotropic hypogonadism, MIM# 619326
Review for gene: CPE was set to AMBER
Added comment: Four affected individuals from two unrelated families reported, bi-allelic LoF variants.
Sources: Literature
Intellectual disability v3.1120 SMARCA5 Zornitza Stark reviewed gene: SMARCA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33980485; Phenotypes: Neurodevelopmental disorder, microcephaly, dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal ciliopathies v1.10 INTU Zornitza Stark gene: INTU was added
gene: INTU was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: INTU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTU were set to 27158779; 29451301; 20067783
Phenotypes for gene: INTU were set to Orofaciodigital syndrome XVII MIM#617926; Short-rib thoracic dysplasia 20 with polydactyly MIM#617925
Review for gene: INTU was set to GREEN
Added comment: Three families and a mouse model:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Note that a different homozygous founder variant was also found in 2 families with GDD, cleft palate, and proliferative retinopathy (PMID: 30976112) - none of these features were evident in the two cases discussed here.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.426 LRRC32 Arina Puzriakova Gene: lrrc32 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Tag Q2_21_rating tag was added to gene: SPG11.
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Classified gene: SPG11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green in the next review.
White matter disorders and cerebral calcification - narrow panel v1.169 SPG11 Ivone Leong Gene: spg11 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.168 SPG11 Ivone Leong Added comment: Comment on publications: PMID: 33581793. A total of 339 patients were analysed, their mean age at onset was 13.10 +/- 3.65 years.
White matter disorders and cerebral calcification - narrow panel v1.168 SPG11 Ivone Leong Publications for gene: SPG11 were set to 14745065; 18067136
Intellectual disability v3.1116 LRRC32 Arina Puzriakova Phenotypes for gene: LRRC32 were changed from Intellectual disability; cleft palate; proliferative retinopathy to Cleft palate, proliferative retinopathy, and developmental delay, OMIM:619074
White matter disorders and cerebral calcification - narrow panel v1.167 SPG11 Ivone Leong Phenotypes for gene: SPG11 were changed from Spastic paralplegia 11, autosomal recessive, MIM#604360 to Spastic paralplegia 11, autosomal recessive, OMIM:604360
White matter disorders and cerebral calcification - narrow panel v1.166 SPG11 Ivone Leong Publications for gene: SPG11 were set to 14745065
Likely inborn error of metabolism v2.141 NAXD Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.165
Likely inborn error of metabolism v2.141 NAXD Ivone Leong gene: NAXD was added
gene: NAXD was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 33224489; 31755961
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321
Monogenic hearing loss v2.166 STXBP3 Arina Puzriakova Entity copied from Primary immunodeficiency v2.425
Monogenic hearing loss v2.166 STXBP3 Arina Puzriakova gene: STXBP3 was added
gene: STXBP3 was added to Hearing loss. Sources: Expert Review Amber,Expert Review
Mode of inheritance for gene: STXBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STXBP3 were set to 33346580; https://doi.org/10.1053/j.gastro.2017.11.120; 33891011
Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Sensorineural hearing loss
Penetrance for gene: STXBP3 were set to unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.425 STXBP3 Arina Puzriakova Classified gene: STXBP3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.425 STXBP3 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of cases presenting a relevant phenotype with some functional data. However, given that several families carried potentially contributory variants in other genes, going to maintain an Amber rating at this time in anticipation of further cases/clinical evidence to validate the pathogenicity of this gene.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.425 STXBP3 Arina Puzriakova Gene: stxbp3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.424 STXBP3 Arina Puzriakova changed review comment from: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID: 27899912. 3 affected families (1 - 3), with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
White matter disorders and cerebral calcification - narrow panel v1.149 CLPP Ivone Leong Publications for gene: CLPP were set to 27899912
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova commented on gene: APOPT1: Added new-gene-name tag, new approved HGNC gene symbol for APOPT1 is COA8
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova Tag new-gene-name tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - narrow panel v1.148 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, MIM# 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Classified gene: APOPT1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of white matter disease from unrelated families to warrant a Green rating at the next GMS panel update.
White matter disorders and cerebral calcification - narrow panel v1.147 APOPT1 Arina Puzriakova Gene: apopt1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.146 APOPT1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: APOPT1.
White matter disorders and cerebral calcification - narrow panel v1.146 APOPT1 Arina Puzriakova reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.165 APOPT1 Arina Puzriakova Publications for gene: APOPT1 were set to
Paediatric or syndromic cardiomyopathy v1.43 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Mitochondrial disorders v2.40 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Monogenic hearing loss v2.164 APOPT1 Arina Puzriakova Mode of inheritance for gene: APOPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1112 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from MITOCHONDRIAL COMPLEX IV DEFICIENCY, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Monogenic hearing loss v2.163 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial Complex IV Deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Likely inborn error of metabolism v2.140 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110; Isolated complex IV deficiency to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Possible mitochondrial disorder - nuclear genes v1.46 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Undiagnosed metabolic disorders v1.460 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Isolated complex IV deficiency; Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061; Isolated complex IV deficiency
Mitochondrial disorder with complex IV deficiency v1.12 APOPT1 Arina Puzriakova Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 to Mitochondrial complex IV deficiency, nuclear type 17, OMIM:619061
Inherited white matter disorders v1.113 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 23472759; 17525174; 25925986
White matter disorders and cerebral calcification - narrow panel v1.146 LAMB1 Arina Puzriakova Publications for gene: LAMB1 were set to 25925986; 17525174; 23472759
White matter disorders and cerebral calcification - narrow panel v1.145 LAMB1 Arina Puzriakova reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23472759, 25925986, 29888467; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.25 PIGB Dmitrijs Rots gene: PIGB was added
gene: PIGB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to intellectual disability; developmental delay; epilepsy; axonal neuropathy
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
gene: PIGB was marked as current diagnostic
Added comment: Murakami et al., reported 10 cases with biallelic PIGB variants with complex and severe phenotype, of whom 4 had peripheral neuropathy.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.145 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191; Cystic leukoencephalopathy
Intellectual disability v3.1111 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from COBBLESTONE BRAIN MALFORMATION WITHOUT MUSCULAR OR OCULAR ABNORMALITIES to Lissencephaly 5, OMIM:615191
Inherited white matter disorders v1.112 LAMB1 Arina Puzriakova Phenotypes for gene: LAMB1 were changed from Lissencephaly 5, 615191 to Lissencephaly 5, OMIM:615191
Adult onset leukodystrophy v1.12 LAMB1 Arina Puzriakova Classified gene: LAMB1 as Red List (low evidence)
Adult onset leukodystrophy v1.12 LAMB1 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only a single adult-onset case of leukoencephalopathy reported (PMID: 32548278). Additional cases required prior to inclusion on this panel. All other publications to date report congenital or infantile- to childhood-onset leukoencephalopathy.
Adult onset leukodystrophy v1.12 LAMB1 Arina Puzriakova Gene: lamb1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.144 CLPP Ivone Leong Phenotypes for gene: CLPP were changed from Perrault syndrome 3, MIM# 614129 to Perrault syndrome 3, OMIM:614129
Hydrocephalus v2.105 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Fetal anomalies v1.674 SMARCC1 Arina Puzriakova commented on gene: SMARCC1: Penetrance for gene SMARCC1 was set from None to Incomplete
Rare anaemia v1.23 SLC19A1 Arina Puzriakova Phenotypes for gene: SLC19A1 were changed from Megaloblastic anemia, folate-responsive, MIM# 601775 to Megaloblastic anemia, folate-responsive, OMIM:601775
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Classified gene: SLC19A1 as Red List (low evidence)
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Red as only a single case reported at this time. Additional cases required to validate pathogenicity of variants in this gene.
Rare anaemia v1.22 SLC19A1 Arina Puzriakova Gene: slc19a1 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Classified gene: SPI1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (6) presenting a relevant phenotype, supported by some functional data (PMID: 33951726). However, only able to access the publication abstract at this time - Rating Amber with a watchlist tag until the full text becomes available (on 2022-01-05)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 SPI1 Arina Puzriakova Gene: spi1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.422 SPI1 Arina Puzriakova Phenotypes for gene: SPI1 were changed from agammaglobulinemia to Agammaglobulinemia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SPI1 Arina Puzriakova Tag watchlist tag was added to gene: SPI1.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Tag watchlist tag was added to gene: PDCD6IP.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Classified gene: PDCD6IP as Amber List (moderate evidence)
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Added comment: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Severe microcephaly v2.202 PDCD6IP Arina Puzriakova Gene: pdcd6ip has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.; to: Comment on list classification: Phenotype is relevant to this panel with a supportive animal model that recapitulates features such as microcephaly. However, additional cases required to validate pathogenicity prior to inclusion as diagnostic-grade. Therefore Rating Amber, awaiting further publications.
Intellectual disability v3.1110 PDCD6IP Arina Puzriakova changed review comment from: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene.; to: Comment on list classification: Phenotype is relevant to this panel but additional cases required to validate pathogenicity of variants in this gene. Therefore Rating Amber, awaiting further publications.
Severe microcephaly v2.201 POGZ Arina Puzriakova Publications for gene: POGZ were set to 26942287
Severe microcephaly v2.200 POGZ Arina Puzriakova Tag Q2_21_rating tag was added to gene: POGZ.
Severe microcephaly v2.200 POGZ Arina Puzriakova Classified gene: POGZ as Amber List (moderate evidence)
Severe microcephaly v2.200 POGZ Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Microcephaly is a variable feature (reported in at least 14/31 individuals) but severity is not stated in most cases. However, this can be a presenting feature of the disorder and there are sufficient cases from unrelated families to warrant a Green rating on this panel.
Severe microcephaly v2.200 POGZ Arina Puzriakova Gene: pogz has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1110 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from INTELLECTUAL DISABILITY to White-Sutton syndrome, OMIM:616364
Intellectual disability v3.1109 POGZ Arina Puzriakova Publications for gene: POGZ were set to 25533962
Severe microcephaly v2.199 POGZ Arina Puzriakova Phenotypes for gene: POGZ were changed from White-Sutton syndrome, MIM# 616364 to White-Sutton syndrome, OMIM:616364
Arthrogryposis v3.104 EBP Arina Puzriakova Phenotypes for gene: EBP were changed from Chondrodysplasia punctata, X-linked dominant, MIM# 302960 to Chondrodysplasia punctata, X-linked dominant, OMIM:302960
Arthrogryposis v3.103 EBP Arina Puzriakova Mode of inheritance for gene: EBP 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)
Arthrogryposis v3.102 EBP Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: EBP.
Arthrogryposis v3.102 EBP Arina Puzriakova Classified gene: EBP as Amber List (moderate evidence)
Arthrogryposis v3.102 EBP Arina Puzriakova Added comment: Comment on list classification: EBP will be flagged for GMS review to assess whether there is enough evidence and potential clinical value to rate as Green on this panel.

Flexion contractures may occur is a subset of patients with variants in this gene. However, as other manifestations such as skeletal malformations and skin abnormalities represent more prominent features of the disorder, it is less likely that cases would be tested under the Arthrogryposis panel. EBP is already Green on other relevant panels (Skeletal dysplasia v2.100, Palmoplantar keratodermas v1.7, etc).
Arthrogryposis v3.102 EBP Arina Puzriakova Gene: ebp has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.122 FOXG1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FOXG1.
Childhood onset dystonia, chorea or related movement disorder v1.122 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. All of the patients with FOXG1 variants reported in PMID 27029630 abnormal involuntary movements, including chorea/athetosis in 22/25 (88%) cases.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v1.122 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to 27029630
White matter disorders and cerebral calcification - narrow panel v1.143 RPIA Arina Puzriakova Publications for gene: RPIA were set to 31247379; 14988808; 31056085
Childhood onset dystonia, chorea or related movement disorder v1.121 FOXG1 Sarah Leigh Classified gene: FOXG1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.121 FOXG1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.121 FOXG1 Sarah Leigh Gene: foxg1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.142 RPIA Arina Puzriakova Tag Q2_21_rating tag was added to gene: RPIA.
White matter disorders and cerebral calcification - narrow panel v1.142 RPIA Arina Puzriakova Classified gene: RPIA as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.142 RPIA Arina Puzriakova Added comment: Comment on list classification: Cerebral white matter abnormalities identified in all cases to date (at least 4 unrelated families) - sufficient for RPIA to be rated Green on this panel
White matter disorders and cerebral calcification - narrow panel v1.142 RPIA Arina Puzriakova Gene: rpia has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.198 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. PMID 27029630 reports 85% (23/27) of patients with FOXG1 variants have microcephaly, defined as greater than 2 SDs below the mean for age, acquired postnatally in most cases.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.368 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to PMID: 21441262
Intellectual disability v3.1108 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Fetal anomalies v1.674 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Intellectual disability v3.1107 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, 613454; CONGENITAL VARIANT OF RETT SYNDROME (RTTCV) to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Early onset or syndromic epilepsy v2.367 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant to Rett syndrome, congenital variantRett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Fetal anomalies v1.673 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from CONGENITAL VARIANT OF RETT SYNDROME to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Severe microcephaly v2.198 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett syndrome, congenital variant, MIM# 613454 to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Childhood onset dystonia, chorea or related movement disorder v1.120 FOXG1 Sarah Leigh Phenotypes for gene: FOXG1 were changed from Rett Syndrome, congenital variant, 613454 to Rett Syndrome, congenital variant OMIM:613454; Rett syndrome, congenital variant MONDO:0013270
Severe microcephaly v2.197 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to 21441262; 19564653; 19578037
Severe microcephaly v2.196 FOXG1 Sarah Leigh Classified gene: FOXG1 as Amber List (moderate evidence)
Severe microcephaly v2.196 FOXG1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Severe microcephaly v2.196 FOXG1 Sarah Leigh Gene: foxg1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.195 FOXG1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FOXG1.
Childhood onset dystonia, chorea or related movement disorder v1.119 FOXG1 Sarah Leigh Publications for gene: FOXG1 were set to
Clefting v2.32 RERE Catherine Snow Classified gene: RERE as Amber List (moderate evidence)
Clefting v2.32 RERE Catherine Snow Gene: rere has been classified as Amber List (Moderate Evidence).
Clefting v2.31 RERE Catherine Snow gene: RERE was added
gene: RERE was added to Clefting. Sources: Literature
Mode of inheritance for gene: RERE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RERE were set to PMID: 33772547
Phenotypes for gene: RERE were set to clefting
Review for gene: RERE was set to AMBER
Added comment: Expansion of phenotype. RERE associated with neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH)
A pathogenic, de novo c.4313_4318dupTCCACC proband had cleft palate, incomplete penetrance as other individuals with NEDBEH and same variant (PMID: 27087320 PMID: 29330883) did not display clefting phenotype. There is functional support in mouse models as RERE-deficient embryos have cleft palate. Previously one patient (subject 7) with NEDBEH has been described to have a cleft lip (PMID: 27087320) Therefore rating as Amber
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.141 BOLA3 Ivone Leong Tag Q2_21_rating tag was added to gene: BOLA3.
White matter disorders and cerebral calcification - narrow panel v1.141 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549; 29501406; 24334290; 21944046; 30302924; 29654549
Inherited white matter disorders v1.111 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549; 29501406; 24334290; 21944046; 30302924; 29654549
Inherited white matter disorders v1.110 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549, 29501406, 24334290, 21944046
Inherited white matter disorders v1.109 BOLA3 Ivone Leong Phenotypes for gene: BOLA3 were changed from to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, OMIM:614299
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Classified gene: BOLA3 as Green List (high evidence)
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.108 BOLA3 Ivone Leong Gene: bola3 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.140 BOLA3 Ivone Leong Classified gene: BOLA3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.140 BOLA3 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.140 BOLA3 Ivone Leong Gene: bola3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.672 ZNF3 Arina Puzriakova gene: ZNF3 was added
gene: ZNF3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ZNF3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF3 were set to 32732226
Phenotypes for gene: ZNF3 were set to Hydrocephaly; Facial cleft
Review for gene: ZNF3 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrocephaly and facial cleft detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including a median cleft palate, partial maxillar agenesis, bilateral severe microphthalmia, arhinencephaly, partial thalamic fusion. A homozygous truncating variant (c.396A>G/ p.*132Trpext*69) in ZNF3 was found by exome sequencing.
Sources: Literature
Fetal anomalies v1.671 WDR91 Arina Puzriakova gene: WDR91 was added
gene: WDR91 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WDR91 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR91 were set to 32732226
Phenotypes for gene: WDR91 were set to Hygroma; Hydrocephaly
Review for gene: WDR91 was set to RED
Added comment: Novel candidate gene identified in a fetus with hygroma and hydrocephaly detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma, macrocephaly, abnormal ears, unilateral simian crease, hydrocephaly, cerebellar hypoplasia, and interventricular communication. A homozygous truncating variant was found by exome sequencing with concordant segregation among 4 affected fetus, 2 healthy sibs and both parents
Sources: Literature
Structural eye disease v1.69 WRAP73 Catherine Snow changed review comment from: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence as new gene disease association with one missense.
Sources: Literature; to: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence this is a new gene disease association with just one missense variant.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.139 BOLA3 Ivone Leong Phenotypes for gene: BOLA3 were changed from to Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, OMIM:614299
White matter disorders and cerebral calcification - narrow panel v1.138 BOLA3 Ivone Leong Publications for gene: BOLA3 were set to 29654549, 29501406, 24334290, 21944046
Structural eye disease v1.69 WRAP73 Catherine Snow Classified gene: WRAP73 as Amber List (moderate evidence)
Structural eye disease v1.69 WRAP73 Catherine Snow Gene: wrap73 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.670 SPTBN5 Arina Puzriakova gene: SPTBN5 was added
gene: SPTBN5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226
Phenotypes for gene: SPTBN5 were set to Multicystic kidney; Oligohydramnios
Review for gene: SPTBN5 was set to RED
Added comment: Novel candidate gene identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis. Compound heterozygous variants including a truncating variant were found by exome sequencing.
Sources: Literature
Structural eye disease v1.68 WRAP73 Catherine Snow gene: WRAP73 was added
gene: WRAP73 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: WRAP73 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WRAP73 were set to PMID: 33693649
Phenotypes for gene: WRAP73 were set to Microspherophakia
Review for gene: WRAP73 was set to AMBER
Added comment: Four individuals in two unrelated Indian families homozygous for missense variant c.1148C > T (p.Pro383Leu) in WRAP73 (old gene symbol WDR8) and reported to have Microspherophakia. Functional studies in Zebrafish showed knockout mutants and knockdown morphants exhibit decreased eye size. Amber rating as although functional evidence as new gene disease association with one missense.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.137 AIFM1 Ivone Leong Tag Q2_21_rating tag was added to gene: AIFM1.
White matter disorders and cerebral calcification - narrow panel v1.137 AIFM1 Ivone Leong Classified gene: AIFM1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.137 AIFM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.137 AIFM1 Ivone Leong Gene: aifm1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.136 AIFM1 Ivone Leong Added comment: Comment on publications: PMID: 33439541 - 2 additional cases
White matter disorders and cerebral calcification - narrow panel v1.136 AIFM1 Ivone Leong Publications for gene: AIFM1 were set to 28842795; 27102849
Fetal anomalies v1.669 SCN7A Arina Puzriakova gene: SCN7A was added
gene: SCN7A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Fetal anomalies v1.668 MYBPC2 Arina Puzriakova gene: MYBPC2 was added
gene: MYBPC2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MYBPC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBPC2 were set to 32732226
Phenotypes for gene: MYBPC2 were set to Fetal akinesia; Hydrops; Hygroma; Multiple pterygium
Review for gene: MYBPC2 was set to RED
Added comment: Novel candidate gene identified in a fetus with fetal akinesia detected by ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, hygroma, multiple pterygium. A homozygous variant (c.3394G>A/ p.Glu1132Lys) in MYBPC2 was found by exome sequencing with concordant segregation among one affected sib and two unaffected sibs.
Sources: Literature
Fetal anomalies v1.667 DNAH2 Arina Puzriakova changed review comment from: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found exome sequencing.
Sources: Literature; to: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found by exome sequencing.
Sources: Literature
Fetal anomalies v1.667 DNAH2 Arina Puzriakova gene: DNAH2 was added
gene: DNAH2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DNAH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH2 were set to 32732226
Phenotypes for gene: DNAH2 were set to Hydrops; Complex cardiopathy
Review for gene: DNAH2 was set to RED
Added comment: Novel candidate gene identified in a fetus with hydrops and complex cardiopathy detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hydrops, heterotaxy, complex cardiopathy, hypotrophic splenium, and common mesentery. Compound heterozygous variants including a truncating variant were found exome sequencing.
Sources: Literature
Intellectual disability v3.1106 SMARCE1 Arina Puzriakova Phenotypes for gene: SMARCE1 were changed from COFFIN SIRIS to Coffin-Siris syndrome 5, OMIM:616938
White matter disorders and cerebral calcification - narrow panel v1.135 AIFM1 Ivone Leong Phenotypes for gene: AIFM1 were changed from Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, MIM# 300232 to Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, OMIM:300232
White matter disorders and cerebral calcification - narrow panel v1.134 CNP Ivone Leong Tag watchlist tag was added to gene: CNP.
White matter disorders and cerebral calcification - narrow panel v1.134 CNP Ivone Leong Classified gene: CNP as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.134 CNP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
White matter disorders and cerebral calcification - narrow panel v1.134 CNP Ivone Leong Gene: cnp has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.133 CNP Ivone Leong Phenotypes for gene: CNP were changed from Hypomyelinating leukodystrophy to ?Leukodystrophy, hypomyelinating, 20, OMIM:619071
White matter disorders and cerebral calcification - narrow panel v1.132 GTF2H5 Ivone Leong edited their review of gene: GTF2H5: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Based on the available evidence there is not enough evidence to support a gene-disease association. This gene should be demoted to Amber/Red at the next review.; Changed rating: AMBER
White matter disorders and cerebral calcification - narrow panel v1.132 GTF2H5 Ivone Leong Tag Q2_21_expert_review tag was added to gene: GTF2H5.
White matter disorders and cerebral calcification - narrow panel v1.132 GTF2H5 Ivone Leong Tag Q2_21_rating tag was added to gene: GTF2H5.
White matter disorders and cerebral calcification - narrow panel v1.132 GTF2H5 Ivone Leong Added comment: Comment on publications: 5 unrelated cases of patients with variants in this gene. There was no mention of any white matter changes in patients described in PMID: 24986372 and 15220921. PMID: 30359777, the affected patient had delayed myelination.
White matter disorders and cerebral calcification - narrow panel v1.132 GTF2H5 Ivone Leong Publications for gene: GTF2H5 were set to 24986372
White matter disorders and cerebral calcification - narrow panel v1.131 GTF2H5 Ivone Leong Phenotypes for gene: GTF2H5 were changed from Photosensitive trichothiodystrophy 3; Trichothiodystrophy 3, photosensitive to delayed myelination
Fetal anomalies v1.666 SMARCC1 Arina Puzriakova Penetrance for gene SMARCC1 was set from to None
Hydrocephalus v2.105 SMARCC1 Arina Puzriakova Penetrance for gene SMARCC1 was set from to None
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.; to: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update - sufficient cases (>3) of congenital hydrocephaly which may conceivably be detected prenatally.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova Entity copied from Hydrocephalus v2.104
Fetal anomalies v1.665 SMARCC1 Arina Puzriakova gene: SMARCC1 was added
gene: SMARCC1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: SMARCC1.
Mode of inheritance for gene: SMARCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCC1 were set to 24170322; 29983323; 32732226; 33077954
Phenotypes for gene: SMARCC1 were set to Congenital hydrocephalus; Aqueductal stenosis; Septal agenesis; Corpus callosum abnormalities
Hydrocephalus v2.104 SMARCC1 Arina Puzriakova Phenotypes for gene: SMARCC1 were changed from Congenital hydrocephalus to Congenital hydrocephalus; Aqueductal stenosis; Septal agenesis; Corpus callosum abnormalities
Hydrocephalus v2.103 SMARCC1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SMARCC1.
Hydrocephalus v2.103 SMARCC1 Arina Puzriakova Publications for gene: SMARCC1 were set to 33077954; 24170322
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Classified gene: SMARCC1 as Amber List (moderate evidence)
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 9 unrelated families with different heterozygous variants in the SMARCC1 gene (PMID: 29983323; 32732226; 33077954). Note there is reduced penetrance as 4 variants were transmitted from an unaffected parent (3 variants occurred de novo; 1 was unphased). All affected individuals presented congenital hydrocephalus and aqueductal stenosis. Other variable features include corpus callosum abnormalities, septal agenesis, developmental delay, along with cardiac and skeletal abnormalities.
Hydrocephalus v2.102 SMARCC1 Arina Puzriakova Gene: smarcc1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1105 SMARCC1 Arina Puzriakova Mode of inheritance for gene: SMARCC1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.1104 DPH1 Arina Puzriakova Publications for gene: DPH1 were set to 29362492; 29410513; 26220823; 25558065
Intellectual disability v3.1103 DPH1 Arina Puzriakova Phenotypes for gene: DPH1 were changed from Developmental delay with short stature, dysmorphic features, and sparse hair, 616901 to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Fetal anomalies v1.664 DPH1 Arina Puzriakova Classified gene: DPH1 as Amber List (moderate evidence)
Fetal anomalies v1.664 DPH1 Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases of fetally-relevant phenotypes from unrelated families to warrant a Green rating on this panel.
Fetal anomalies v1.664 DPH1 Arina Puzriakova Gene: dph1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.663 DPH1 Arina Puzriakova gene: DPH1 was added
gene: DPH1 was added to Fetal anomalies. Sources: Literature
Q2_21_rating tags were added to gene: DPH1.
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH1 were set to 25558065; 29362492; 30877278; 32732226
Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Review for gene: DPH1 was set to GREEN
Added comment: Biallelic variants in this gene cause a neurodevelopmental disorder characterised by ID/DD, short stature, dysmorphic features, craniofacial and ectodermal anomalies. Several reports note antenatal anomalies and multiple congenital abnormalities that may conceivably be detected prenatally.

Fetal ultrasound phenotypes reported in literature include IUGR, polyhydramnios, craniostenosis, cardiac abnormalities, brain anomalies, and polydactyly (PMID: 25558065; 29362492; 30877278; 32732226)
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.130 GTF2H5 Ivone Leong Publications for gene: GTF2H5 were set to
Severe microcephaly v2.195 MCM7 Arina Puzriakova Classified gene: MCM7 as Amber List (moderate evidence)
Severe microcephaly v2.195 MCM7 Arina Puzriakova Added comment: Comment on list classification: Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (PMIDs: 33654309; 34059554). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.

As no clear phenotype correlations can be made at this time, rating as Amber in anticipation of further cases (2/3 presented severe microcephaly).
Severe microcephaly v2.195 MCM7 Arina Puzriakova Gene: mcm7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.194 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. Currently, MCM7 is not associated with any phenotype in OMIM or G2P.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.129 ISCA1 Ivone Leong Tag Q2_21_rating tag was added to gene: ISCA1.
White matter disorders and cerebral calcification - narrow panel v1.129 ISCA1 Ivone Leong Classified gene: ISCA1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.129 ISCA1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.129 ISCA1 Ivone Leong Gene: isca1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.128 ISCA1 Ivone Leong Phenotypes for gene: ISCA1 were changed from Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613 to Multiple mitochondrial dysfunctions syndrome 5, OMIM:617613
Intellectual disability v3.1102 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495
Early onset or syndromic epilepsy v2.366 SLC6A1 Arina Puzriakova Publications for gene: SLC6A1 were set to 25865495; Carvill et al (2015) Am J Hum Genet 96(5): 808-15
Intellectual disability v3.1101 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from EPILEPSY WITH MYOCLONIC-ATONIC SEIZURES to Myoclonic-atonic epilepsy, OMIM:616421
Early onset or syndromic epilepsy v2.365 SLC6A1 Arina Puzriakova Phenotypes for gene: SLC6A1 were changed from Myoclonic-atonic epilepsy, 616421 to Myoclonic-atonic epilepsy, OMIM:616421
Intellectual disability v3.1100 SMARCA5 Julia Baptista gene: SMARCA5 was added
gene: SMARCA5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SMARCA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA5 were set to 33980485
Phenotypes for gene: SMARCA5 were set to intellectual disability; postnatal microcephaly; hypotonia; failure to thrive
Penetrance for gene: SMARCA5 were set to unknown
Review for gene: SMARCA5 was set to GREEN
Added comment: The authors identified seven missense variants, one splice-altering variant that led to exon skipping and in-frame deletion, and one recurrent in-frame deletion in 12 individuals from
10 unrelated families. The variant was de novo in nine individuals. They presented a broad range of clinical features from isolated autism to syndromic intellectual disability.
Sources: Literature
Limb disorders v2.42 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to 31115189
Skeletal dysplasia v2.100 GLI3 Arina Puzriakova Publications for gene: GLI3 were set to
Limb disorders v2.41 GLI3 Arina Puzriakova reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32591344; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v2.99 GLI3 Arina Puzriakova reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32591344; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary ataxia with onset in adulthood v2.71 AMPD2 Zornitza Stark edited their review of gene: AMPD2: Changed rating: RED
Hereditary ataxia with onset in adulthood v2.71 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Hereditary ataxia - adult onset. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32367058; 33875678
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Ataxia and cerebellar anomalies - narrow panel v2.190 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Adult onset dystonia, chorea or related movement disorder v1.114 VPS41 James Polke gene: VPS41 was added
gene: VPS41 was added to Adult onset movement disorder. Sources: NHS GMS
Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS41 were set to 32808683; 33764426
Phenotypes for gene: VPS41 were set to Generalised Neurodevelopmental disorder; Ataxia; Dystonia
Review for gene: VPS41 was set to GREEN
Added comment: 32808683: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders.

PMID 33764426: Additional 9 individuals from 5 unrelated families reported.
Sources: NHS GMS
Adult onset dystonia, chorea or related movement disorder v1.114 VPS16 James Polke gene: VPS16 was added
gene: VPS16 was added to Adult onset movement disorder. Sources: NHS GMS
Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VPS16 were set to 32808683
Phenotypes for gene: VPS16 were set to Dystonia; Dystonia Associated with Lysosomal Abnormalities; Dystonia 30; OMIM #619291
Review for gene: VPS16 was set to GREEN
Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood.

Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals.
Sources: NHS GMS
Adult onset hereditary spastic paraplegia v1.23 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Green List (high evidence)
Adult onset hereditary spastic paraplegia v1.23 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Leaving the rating as green, but with a recommendation for review of this gene at the next GMS review as all cases have onset in childhood and this is an adult onset panel.
Adult onset hereditary spastic paraplegia v1.23 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Green List (High Evidence).
Adult onset hereditary spastic paraplegia v1.22 SLC1A4 Eleanor Williams Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Adult onset hereditary spastic paraplegia v1.21 SLC1A4 Eleanor Williams Tag Q2_21_expert_review was removed from gene: SLC1A4.
Tag Q2_21_phenotype tag was added to gene: SLC1A4.
Hereditary neuropathy or pain disorder v1.25 SORD James Polke reviewed gene: SORD: Rating: GREEN; Mode of pathogenicity: None; Publications: 32367058, 33875678; Phenotypes: Peripheral Neuropathy, Charcot-Marie Tooth Disease, Sorbitol dehydrogenase deficiency with peripheral neuropathy (OMIM # 618912); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult onset neurodegenerative disorder v2.174 SORL1 James Polke gene: SORL1 was added
gene: SORL1 was added to Neurodegenerative disorders - adult onset. Sources: NHS GMS
Mode of inheritance for gene: SORL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SORL1 were set to 28537274; 22472873; 28595629; 32587946
Phenotypes for gene: SORL1 were set to Alzheimer's Disease
Penetrance for gene: SORL1 were set to unknown
Review for gene: SORL1 was set to AMBER
Added comment: Proposed as an amber gene. A published risk locus for late onset Alzheimer's. Some case studies propose a cause of familial early onset AD, though insufficient cases/segregation at present.
Sources: NHS GMS
Severe microcephaly v2.193 TPRKB Eleanor Williams Phenotypes for gene: TPRKB were changed from Galloway-Mowat syndrome 5, MIM# 617731 to Galloway-Mowat syndrome 5, OMIM:617731
Severe microcephaly v2.192 TPRKB Eleanor Williams Publications for gene: TPRKB were set to 28805828; 30053862
Severe microcephaly v2.191 TPRKB Eleanor Williams Classified gene: TPRKB as Red List (low evidence)
Severe microcephaly v2.191 TPRKB Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red. 2 unrelated cases reported but the degree of microcephaly is not reported, so can't confirm it is in the severe range.
Severe microcephaly v2.191 TPRKB Eleanor Williams Gene: tprkb has been classified as Red List (Low Evidence).
Severe microcephaly v2.190 TPRKB Eleanor Williams reviewed gene: TPRKB: Rating: RED; Mode of pathogenicity: None; Publications: 28805828; Phenotypes: Galloway-Mowat syndrome 5, OMIM:617731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.190 SLC1A4 Eleanor Williams Phenotypes for gene: SLC1A4 were changed from Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, MIM# 616657 to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, OMIM:616657
Severe microcephaly v2.189 PTPN23 Eleanor Williams Phenotypes for gene: PTPN23 were changed from Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890 to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890
Glaucoma (developmental) v1.36 PAX6 Eleanor Williams Mode of inheritance for gene: PAX6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Classified gene: HSPD1 as Green List (high evidence)
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. The missense p.Leu47Val variant has a dominant negative effect.

This gene is also Amber with a recommendation to promote to Green on the White matter disorders and cerebral calcification - narrow panel (Version 1.127). With the following review from Zornitza Stark (Australian Genomics):

"Multiple families reported with bi-allelic variants in HSPD1 and hypomyelinating leukodystrophy. Supportive mouse model. In addition, two unrelated individuals reported with same de novo missense p.Leu47Val and leukodystrophy.
Zornitza Stark (Australian Genomics), 15 Sep 2020"
Inherited white matter disorders v1.107 HSPD1 Ivone Leong Gene: hspd1 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.106 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to 18571143; 28377887
White matter disorders and cerebral calcification - narrow panel v1.127 HSPD1 Ivone Leong Classified gene: HSPD1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.127 HSPD1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

The missense p.Leu47Val variant has a dominant negative effect.
White matter disorders and cerebral calcification - narrow panel v1.127 HSPD1 Ivone Leong Gene: hspd1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.39 HIKESHI Ivone Leong Tag Q2_21_rating tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - narrow panel v1.126 HIKESHI Ivone Leong Tag Q2_21_rating tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - narrow panel v1.126 HSPD1 Ivone Leong Tag Q2_21_rating tag was added to gene: HSPD1.
Inherited white matter disorders v1.105 HSPD1 Ivone Leong Mode of inheritance for gene: HSPD1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.126 HSPD1 Ivone Leong Mode of inheritance for gene: HSPD1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.364 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1100 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
White matter disorders and cerebral calcification - narrow panel v1.125 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to 18571143; 27405012; 32532876; 28377887; 27405012
Inherited white matter disorders v1.104 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280; Leukodystrophy, hypomyelinating, 4, 612233 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Inherited white matter disorders v1.103 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to
White matter disorders and cerebral calcification - narrow panel v1.124 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, OMIM:612233; Spastic paraplegia 13, autosomal dominant, OMIM:605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Severe microcephaly v2.188 TP53RK Eleanor Williams Phenotypes for gene: TP53RK were changed from Galloway-Mowat syndrome 4, MIM# 617730 to Galloway-Mowat syndrome 4, OMIM:617730
Severe microcephaly v2.187 TP53RK Eleanor Williams reviewed gene: TP53RK: Rating: RED; Mode of pathogenicity: None; Publications: 28805828, 30053862; Phenotypes: Galloway-Mowat syndrome 4, OMIM:17730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.187 TCF4 Eleanor Williams Phenotypes for gene: TCF4 were changed from Pitt-Hopkins syndrome, MIM# 610954 to Pitt-Hopkins syndrome, OMIM:610954
Severe microcephaly v2.186 TCF4 Eleanor Williams Publications for gene: TCF4 were set to 18728071; 22934316
Severe microcephaly v2.185 TCF4 Eleanor Williams reviewed gene: TCF4: Rating: AMBER; Mode of pathogenicity: None; Publications: 18728071, 21671391, 29318938; Phenotypes: Pitt-Hopkins syndrome OMIM:610954; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Ichthyosis and erythrokeratoderma v1.60 ASPRV1 Catherine Snow Tag Q2_21_rating tag was added to gene: ASPRV1.
Ichthyosis and erythrokeratoderma v1.60 ASPRV1 Catherine Snow reviewed gene: ASPRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32516568; Phenotypes: Ichthyosis, lamellar, autosomal dominant, OMIM #146750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow Tag Q2_21_NHS_review was removed from gene: TRPV3.
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow Tag Q2_21_rating tag was added to gene: TRPV3.
Tag Q2_21_NHS_review tag was added to gene: TRPV3.
Ichthyosis and erythrokeratoderma v1.60 TRPV3 Catherine Snow reviewed gene: TRPV3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset hereditary spastic paraplegia v1.21 SLC1A4 Eleanor Williams Tag Q2_21_expert_review tag was added to gene: SLC1A4.
Adult onset hereditary spastic paraplegia v1.21 SLC1A4 Eleanor Williams commented on gene: SLC1A4
White matter disorders and cerebral calcification - narrow panel v1.123 POLH Arina Puzriakova changed review comment from: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not revealed any evidence of involvement in white matter disease or intracranial calcification.; to: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not reveal any evidence of involvement in white matter disease or intracranial calcification.
White matter disorders and cerebral calcification - narrow panel v1.123 POLH Arina Puzriakova Tag Q2_21_rating tag was added to gene: POLH.
White matter disorders and cerebral calcification - narrow panel v1.123 POLH Arina Puzriakova Classified gene: POLH as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.123 POLH Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel update. Literature search did not revealed any evidence of involvement in white matter disease or intracranial calcification.
White matter disorders and cerebral calcification - narrow panel v1.123 POLH Arina Puzriakova Gene: polh has been classified as Green List (High Evidence).
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Classified gene: SLC1A4 as Amber List (moderate evidence)
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber but with a recommendation for Green review, following confirmation that progressive microcephaly is within the scope of this panel. 4 different variants reported.
Severe microcephaly v2.185 SLC1A4 Eleanor Williams Gene: slc1a4 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.184 SLC1A4 Eleanor Williams Tag founder-effect tag was added to gene: SLC1A4.
Tag Q2_21_rating tag was added to gene: SLC1A4.
Severe microcephaly v2.184 SLC1A4 Eleanor Williams reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: None; Publications: 25930971, 26138499, 26041762, 27193218, 29989513; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly OMIM:616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Classified gene: RAB11B as Green List (high evidence)
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green. At least 2 variants reported in 5 unrelated cases, of which white matter abnormalities were reported in all cases (4) for which brain imaging was available.
Inherited white matter disorders v1.102 RAB11B Arina Puzriakova Gene: rab11b has been classified as Green List (High Evidence).
Inherited white matter disorders v1.101 RAB11B Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v1.122 RAB11B Arina Puzriakova Classified gene: RAB11B as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.122 RAB11B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update
White matter disorders and cerebral calcification - narrow panel v1.122 RAB11B Arina Puzriakova Gene: rab11b has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.121 RAB11B Arina Puzriakova Tag Q2_21_rating tag was added to gene: RAB11B.
White matter disorders and cerebral calcification - narrow panel v1.121 RAB11B Arina Puzriakova reviewed gene: RAB11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29106825; Phenotypes: Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
White matter disorders and cerebral calcification - narrow panel v1.121 HSPD1 Ivone Leong Publications for gene: HSPD1 were set to
White matter disorders and cerebral calcification - narrow panel v1.120 HSPD1 Ivone Leong Phenotypes for gene: HSPD1 were changed from Leukodystrophy, hypomyelinating, 4, 612233; Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233; Spastic paraplegia 13, autosomal dominant, OMIM:605280
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Classified gene: HIKESHI as Green List (high evidence)
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on my previous review.
Hereditary spastic paraplegia v1.224 HIKESHI Ivone Leong Gene: hikeshi has been classified as Green List (High Evidence).
Severe microcephaly v2.184 HIKESHI Ivone Leong Classified gene: HIKESHI as Red List (low evidence)
Severe microcephaly v2.184 HIKESHI Ivone Leong Added comment: Comment on list classification: Downgraded from Amber to Red as microcephaly is not severe enough in the patients and also only seen in Ashkenazi Jewish families.
Severe microcephaly v2.184 HIKESHI Ivone Leong Gene: hikeshi has been classified as Red List (Low Evidence).
Optic neuropathy v2.41 HIKESHI Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association (only 2 cases with optic atrophy), therefore this gene has been given an Amber rating.
Optic neuropathy v2.41 HIKESHI Ivone Leong Tag watchlist tag was added to gene: HIKESHI.
Optic neuropathy v2.41 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Optic neuropathy v2.41 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Optic neuropathy. Sources: Expert list,Expert Review Amber
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Severe microcephaly v2.183 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Severe microcephaly v2.183 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Severe microcephaly. Sources: Expert list,Expert Review Amber
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Hereditary spastic paraplegia v1.223 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Hereditary spastic paraplegia v1.223 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Childhood onset hereditary spastic paraplegia v2.39 HIKESHI Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.119
Childhood onset hereditary spastic paraplegia v2.39 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
White matter disorders and cerebral calcification - narrow panel v1.119 HIKESHI Ivone Leong Classified gene: HIKESHI as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.119 HIKESHI Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.119 HIKESHI Ivone Leong Gene: hikeshi has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.118 HIKESHI Ivone Leong Tag watchlist was removed from gene: HIKESHI.
White matter disorders and cerebral calcification - narrow panel v1.118 HIKESHI Ivone Leong Tag watchlist tag was added to gene: HIKESHI.
White matter disorders and cerebral calcification - narrow panel v1.118 HIKESHI Ivone Leong Added comment: Comment on publications: PMID: 26545878. 3 unrelated cases (6 individuals), Ashkenazi Jewish families. p.Val54Leu. 4/4 (2 MRI was not reported) delayed myelination and periventricular white matter abnormalities on brain imaging, 5/6 feeding difficulties, 5/6 developmental delay, 5/5 progressively decreasing head circumference percentile (up to -2 SD), 6/6 spasticity, 5/6 increased muscle tone, 1/6 ataxia, 2/6 (same family) optic atrophy, 4/6 nystagmus, 1/6 heart failure, 1/6 perimyocarditis.

PMID: 28000699. Finnish case. Difference variant than what was described in PMID:26545878 (p.Cys4Ser). Diffuse hypomyelination, cystic changes of periventricular white matter, has increased muscle tone, spasticity, ataxia, mild optic atrophy, myopia nystagmus and epilepsy. No feeding difficulties or microcephaly.
White matter disorders and cerebral calcification - narrow panel v1.118 HIKESHI Ivone Leong Publications for gene: HIKESHI were set to 26545878
White matter disorders and cerebral calcification - narrow panel v1.117 NFU1 Arina Puzriakova edited their review of gene: NFU1: Changed publications to: 22077971, 25918518, 28470589, 29441221, 31516295, 32747156, 32669393
White matter disorders and cerebral calcification - narrow panel v1.117 NFU1 Arina Puzriakova Publications for gene: NFU1 were set to 22077971; 28470589; 29441221; 31516295; 32747156; 32669393
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Classified gene: NFU1 as Amber List (moderate evidence)
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (>3) supported by a NFU1 deficiency rat model which exhibited PAH.
Pulmonary arterial hypertension v2.15 NFU1 Arina Puzriakova Gene: nfu1 has been classified as Amber List (Moderate Evidence).
Pulmonary arterial hypertension v2.14 NFU1 Arina Puzriakova gene: NFU1 was added
gene: NFU1 was added to Pulmonary arterial hypertension. Sources: Literature
Q2_21_rating tags were added to gene: NFU1.
Mode of inheritance for gene: NFU1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFU1 were set to 22077971; 25918518; 28470589; 31516295; 32669393; 31461310
Phenotypes for gene: NFU1 were set to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Pulmonary hypertension in early infancy
Review for gene: NFU1 was set to GREEN
Added comment: Biallelic variants in this gene cause multiple mitochondrial dysfunctions syndrome, a severe neonatal onset disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, leukodystrophy, lactic acidosis, and early death.

More than 50% of infant patients are found to display significant PAH, which can initially be an isolated and prominent finding (PMID: 22077971; 25918518; 28470589; 31516295; 32669393). Pulmonary samples from NFU1-deficient individuals with PAH showed obstructive vasculopathy with proximal and acinar arterial involvement (PMID: 22077971).

Humanised rare model of NFU1 deficiency showed features of mitochondrial dysfunction comparable to those observed in patients and also developed PAH (PMID: 31461310)
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.116 NFU1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NFU1.
White matter disorders and cerebral calcification - narrow panel v1.116 NFU1 Arina Puzriakova Publications for gene: NFU1 were set to 21944046; 22077971; 32747156; 29441221
White matter disorders and cerebral calcification - narrow panel v1.115 NFU1 Arina Puzriakova Classified gene: NFU1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.115 NFU1 Arina Puzriakova Added comment: Comment on list classification: Overall there are sufficient unrelated cases (>3) with white matter abnormalities to rate this gene as Green on this panel.
White matter disorders and cerebral calcification - narrow panel v1.115 NFU1 Arina Puzriakova Gene: nfu1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.114 NFU1 Arina Puzriakova reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22077971, 28470589, 29441221, 31516295, 32747156, 32669393; Phenotypes: Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711, Leukoencephalopathy, HP:0002352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.114 HIKESHI Ivone Leong Phenotypes for gene: HIKESHI were changed from Leukodystrophy, hypomyelinating, 13, MIM# 616881 to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Intellectual disability v3.1100 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency, 608611; Ribose 5-phosphate isomerase deficiency, MIM 608611. to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Likely inborn error of metabolism v2.139 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); Ribose 5-phosphate isomerase deficiency, OMIM:608611
Early onset or syndromic epilepsy v2.364 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Undiagnosed metabolic disorders v1.459 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); ?Ribose 5-phosphate isomerase deficiency 608611 to Ribose-5-phosphate isomerase deficiency (Disorders of pentose metabolism); Ribose 5-phosphate isomerase deficiency, OMIM:608611
White matter disorders and cerebral calcification - narrow panel v1.113 RPIA Arina Puzriakova Phenotypes for gene: RPIA were changed from Ribose 5-phosphate isomerase deficiency, MIM# 608611 to Ribose 5-phosphate isomerase deficiency, OMIM:608611
Intellectual disability v3.1099 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807; Intellectual disability to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Early onset or syndromic epilepsy v2.363 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, 617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
Inherited white matter disorders v1.101 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, MIM#617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
White matter disorders and cerebral calcification - narrow panel v1.112 RAB11B Arina Puzriakova Phenotypes for gene: RAB11B were changed from Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, MIM#617807 to Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, OMIM:617807
White matter disorders and cerebral calcification - narrow panel v1.111 PTEN Arina Puzriakova Phenotypes for gene: PTEN were changed from Cowden syndrome 1, MIM# 158350 to Cowden syndrome 1, OMIM:158350
Hereditary ataxia with onset in adulthood v2.71 TBC1D23 Sarah Leigh commented on gene: TBC1D23
Hereditary ataxia with onset in adulthood v2.71 TBC1D23 Sarah Leigh Phenotypes for gene: TBC1D23 were changed from Pontocerebellar hypoplasia type 11, 617695 to Pontocerebellar hypoplasia type 11 OMIM:617695; pontocerebellar hypoplasia, type 11 MONDO:0054669
Hereditary ataxia with onset in adulthood v2.70 TBC1D23 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: TBC1D23.
Ataxia and cerebellar anomalies - narrow panel v2.190 SLC9A1 Sarah Leigh Tag Q2_21_rating tag was added to gene: SLC9A1.
Structural eye disease v1.67 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from XERODERMA PIGMENTOSUM, VARIANT TYPE, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Adult solid tumours cancer susceptibility v2.10 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Childhood solid tumours v2.18 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome v2.9 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Ataxia and cerebellar anomalies - narrow panel v2.190 SLC9A1 Sarah Leigh reviewed gene: SLC9A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
White matter disorders and cerebral calcification - narrow panel v1.110 POLH Arina Puzriakova Phenotypes for gene: POLH were changed from Xeroderma pigmentosum, variant type, 278750 to Xeroderma pigmentosum, variant type, OMIM:278750
Mitochondrial disorders v2.39 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Likely inborn error of metabolism v2.138 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Possible mitochondrial disorder - nuclear genes v1.45 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1, 605711 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Undiagnosed metabolic disorders v1.458 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Multiple mitochondrial dysfunctions syndrome 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Pyruvate dehydrogenase (PDH) deficiency v1.30 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1 OMIM:605711; multiple mitochondrial dysfunctions syndrome 1 MONDO:0011582 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711; Multiple mitochondrial dysfunctions syndrome 1, MONDO:0011582
Ataxia and cerebellar anomalies - narrow panel v2.190 SLC9A1 Sarah Leigh Classified gene: SLC9A1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.190 SLC9A1 Sarah Leigh Gene: slc9a1 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.70 SLC9A1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SLC9A1.
Hereditary ataxia with onset in adulthood v2.70 SLC9A1 Sarah Leigh commented on gene: SLC9A1
Hereditary ataxia with onset in adulthood v2.70 SLC9A1 Sarah Leigh Phenotypes for gene: SLC9A1 were changed from Lichtenstein-Knorr Syndrome to Lichtenstein-Knorr syndrome OMIM:616291; Lichtenstein-Knorr syndrome MONDO:0014572
Ataxia and cerebellar anomalies - narrow panel v2.189 SLC9A1 Sarah Leigh Phenotypes for gene: SLC9A1 were changed from Lichtenstein-Knorr syndrome, MIM# 616291 to Lichtenstein-Knorr syndrome OMIM:616291; Lichtenstein-Knorr syndrome MONDO:0014572
Hereditary ataxia with onset in adulthood v2.69 SLC9A1 Sarah Leigh Publications for gene: SLC9A1 were set to
Intellectual disability v3.1098 SCYL1 Sarah Leigh Tag watchlist was removed from gene: SCYL1.
Tag Q2_21_rating tag was added to gene: SCYL1.
Intellectual disability v3.1098 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
White matter disorders and cerebral calcification - narrow panel v1.109 NFU1 Arina Puzriakova Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711 to Multiple mitochondrial dysfunctions syndrome 1, OMIM:605711
Intellectual disability v3.1097 SCYL1 Sarah Leigh reviewed gene: SCYL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.188 NAXE Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Added to this panel as acute/early-onset ataxia is described in several cases as one of the first symptoms of disease and inclusion may allow for earlier detection. Other cerebellar signs such as nystagmus and dysarthria also reported.
Ataxia and cerebellar anomalies - narrow panel v2.188 NAXE Arina Puzriakova Entity copied from White matter disorders and cerebral calcification - narrow panel v1.108
Ataxia and cerebellar anomalies - narrow panel v2.188 NAXE Arina Puzriakova gene: NAXE was added
gene: NAXE was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber
Q2_21_rating tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27616477; 27122014; 27290639; 30022751; 31758406; 31745726
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Intellectual disability v3.1097 SCYL1 Sarah Leigh Publications for gene: SCYL1 were set to 26581903; 30914295
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Classified gene: NAXE as Green List (high evidence)
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green. Sufficient number of unrelated cases (>3) with white matter abnormalities to rate as Green on this panel.
Inherited white matter disorders v1.100 NAXE Arina Puzriakova Gene: naxe has been classified as Green List (High Evidence).
Intellectual disability v3.1096 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Inherited white matter disorders v1.99 NAXE Arina Puzriakova Publications for gene: NAXE were set to 27616477, 27122014
Inherited white matter disorders v1.98 NAXE Arina Puzriakova reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Phenotypes: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.187 SCYL1 Sarah Leigh Tag Q2_21_rating tag was added to gene: SCYL1.
Ataxia and cerebellar anomalies - narrow panel v2.187 SCYL1 Sarah Leigh edited their review of gene: SCYL1: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least nine variants reported in at least seven cases.; Changed rating: GREEN
White matter disorders and cerebral calcification - narrow panel v1.108 NAXE Arina Puzriakova Publications for gene: NAXE were set to 27616477, 27122014
White matter disorders and cerebral calcification - narrow panel v1.107 NAXE Arina Puzriakova edited their review of gene: NAXE: Changed publications to: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Changed phenotypes to: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186
Ataxia and cerebellar anomalies - narrow panel v2.187 SCYL1 Sarah Leigh Classified gene: SCYL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.187 SCYL1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.187 SCYL1 Sarah Leigh Gene: scyl1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.107 NAXE Arina Puzriakova Classified gene: NAXE as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.107 NAXE Arina Puzriakova Gene: naxe has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.106 NAXE Arina Puzriakova Classified gene: NAXE as Red List (low evidence)
White matter disorders and cerebral calcification - narrow panel v1.106 NAXE Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.
White matter disorders and cerebral calcification - narrow panel v1.106 NAXE Arina Puzriakova Gene: naxe has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.105 NAXE Arina Puzriakova Tag Q2_21_rating tag was added to gene: NAXE.
White matter disorders and cerebral calcification - narrow panel v1.105 NAXE Arina Puzriakova reviewed gene: NAXE: Rating: GREEN; Mode of pathogenicity: None; Publications: Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, OMIM:617186; Phenotypes: 27616477, 27122014, 27290639, 30022751, 31758406, 31745726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.68 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Ataxia and cerebellar anomalies - narrow panel v2.186 SCYL1 Sarah Leigh Phenotypes for gene: SCYL1 were changed from Spinocerebellar ataxia, autosomal recessive 21, MIM# 616719 to Spinocerebellar ataxia, autosomal recessive 21 OMIM:616719; acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome MONDO:0014744
Hereditary ataxia with onset in adulthood v2.67 SCYL1 Sarah Leigh commented on gene: SCYL1
Hereditary ataxia with onset in adulthood v2.67 SCYL1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SCYL1.
Ataxia and cerebellar anomalies - narrow panel v2.185 RORA Sarah Leigh Tag Q2_21_rating tag was added to gene: RORA.
Ataxia and cerebellar anomalies - narrow panel v2.185 RORA Sarah Leigh edited their review of gene: RORA: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least four variants reported in at least four cases with ataxia (PMID 29656859).; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.185 RORA Sarah Leigh Classified gene: RORA as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.185 RORA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.185 RORA Sarah Leigh Gene: rora has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.67 RORA Sarah Leigh Publications for gene: RORA were set to
Hereditary ataxia with onset in adulthood v2.66 RORA Sarah Leigh Tag Q2_21_phenotype tag was added to gene: RORA.
Hereditary ataxia with onset in adulthood v2.66 RORA Sarah Leigh commented on gene: RORA
Hereditary ataxia with onset in adulthood v2.66 RORA Sarah Leigh Phenotypes for gene: RORA were changed from Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, 618060 to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia OMIM:618060; intellectual developmental disorder with or without epilepsy or cerebellar ataxia MONDO:0060745
Ataxia and cerebellar anomalies - narrow panel v2.184 RORA Sarah Leigh Phenotypes for gene: RORA were changed from Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060 to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia OMIM:618060; intellectual developmental disorder with or without epilepsy or cerebellar ataxia MONDO:0060745
Hereditary ataxia with onset in adulthood v2.65 AP1S2 Sarah Leigh Phenotypes for gene: AP1S2 were changed from Mental retardation, X-linked syndromic 5, 304340; Pettigrew syndrome to Mental retardation, X-linked syndromic 5 OMIM:304340; syndromic X-linked intellectual disability 5 MONDO:0010574
Intellectual disability v3.1095 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B, 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Early onset or syndromic epilepsy v2.362 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Epilepsy, progressive myoclonic 1B 612437 to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Hereditary ataxia with onset in adulthood v2.64 PRICKLE1 Sarah Leigh Phenotypes for gene: PRICKLE1 were changed from Progressive myoclonic epilepsy 1B, 612437; Progressive Myoclonus Epilepsy with Ataxia to Progressive myoclonic epilepsy 1B OMIM:612437; epilepsy, progressive myoclonic, 1B MONDO:0012904
Hereditary ataxia with onset in adulthood v2.63 PRICKLE1 Sarah Leigh Publications for gene: PRICKLE1 were set to
Hereditary ataxia with onset in adulthood v2.62 PRICKLE1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: PRICKLE1.
Hereditary ataxia with onset in adulthood v2.62 PRICKLE1 Sarah Leigh commented on gene: PRICKLE1
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Homozygous rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh edited their review of gene: UFSP2: Added comment: The founder variant rs142500730 appears to the be causal for pediatric neurodevelopmental anomalies and epilepsy feautres in over seven Asian families form different locations.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (2 Asian and 1 white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals (Asian and white) in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Mitochondrial disorders v2.38 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Possible mitochondrial disorder - nuclear genes v1.44 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Likely inborn error of metabolism v2.137 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy 617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Inherited white matter disorders v1.98 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, MIM#617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
White matter disorders and cerebral calcification - narrow panel v1.105 NAXE Arina Puzriakova Phenotypes for gene: NAXE were changed from Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, MIM#617186 to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, OMIM:617186
Hereditary ataxia with onset in adulthood v2.62 AP1S2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AP1S2.
Hereditary ataxia with onset in adulthood v2.62 AMPD2 Sarah Leigh Phenotypes for gene: AMPD2 were changed from Pontocerebellar hyoplasia 9, 615809 to Pontocerebellar hyoplasia 9 OMIM:615809; pontocerebellar hypoplasia type 9 MONDO:0014351
Hereditary ataxia with onset in adulthood v2.61 AMPD2 Sarah Leigh Added comment: Comment on phenotypes: Spastic paraplegia 63 OMIM:615686 from homozygous frameshift reported in single family (Novarino et al, 2014).
Hereditary ataxia with onset in adulthood v2.61 AMPD2 Sarah Leigh Phenotypes for gene: AMPD2 were changed from Pontocerebellar hyoplasia 9, 615809; Pontocerebellar hypoplasia 9 (#615809); Spastic paraplegia homozygous frameshift reported in single family (Novarino et al, 2014). to Pontocerebellar hyoplasia 9, 615809
Hereditary ataxia with onset in adulthood v2.60 AMPD2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AMPD2.
Hereditary ataxia with onset in adulthood v2.60 AMPD2 Sarah Leigh commented on gene: AMPD2
Hereditary ataxia with onset in adulthood v2.60 ADGRG1 Sarah Leigh Phenotypes for gene: ADGRG1 were changed from Polymicrogyria, Frontoparietal, 606854; Polymicrogyria, perisylvian type, 615752 to Polymicrogyria, Frontoparietal OMIM:606854; bilateral frontoparietal polymicrogyria MONDO:0011738; Polymicrogyria, perisylvian type OMIM:615752; polymicrogyria, bilateral perisylvian, autosomal recessive MONDO:0014333
Hereditary ataxia with onset in adulthood v2.59 ADGRG1 Sarah Leigh commented on gene: ADGRG1
Hereditary ataxia with onset in adulthood v2.59 ADGRG1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ADGRG1.
Hereditary ataxia with onset in adulthood v2.59 ABCB7 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ABCB7.
Hereditary ataxia with onset in adulthood v2.59 ABCB7 Sarah Leigh commented on gene: ABCB7
Likely inborn error of metabolism v2.136 ABCB7 Sarah Leigh Added comment: Comment on phenotypes: Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only));congenital cerebellar hypoplasia/atrophy (PMID: 26242992).;Disorders of iron homeostasis
Likely inborn error of metabolism v2.136 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); congenital cerebellar hypoplasia/atrophy (PMID: 26242992).; Anemia, sideroblastic, with ataxia; Disorders of iron homeostasis to Anemia, sideroblastic, with ataxia OMIM:301310; X-linked sideroblastic anemia with ataxia MONDO:0010524
Hereditary ataxia with onset in adulthood v2.59 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021 to Anemia, sideroblastic, with ataxia OMIM:301310; X-linked sideroblastic anemia with ataxia MONDO:0010524
Hereditary ataxia with onset in adulthood v2.58 ABCB7 Sarah Leigh Phenotypes for gene: ABCB7 were changed from Anemia, sideroblastic, with ataxia; Anemia, sideroblast with ataxia, 300135; Sideroblastic Anemia and Ataxia to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Hereditary ataxia with onset in adulthood v2.57 EBF3 Sarah Leigh Tag Q2_21_expert_review was removed from gene: EBF3.
Hereditary ataxia with onset in adulthood v2.57 EBF3 Sarah Leigh changed review comment from: GMS review is requested in regard to Zornitza Stark's review; that the phenotype associated with EBF3 - Hypotonia, ataxia, and delayed development syndrome OMIM:617330 is not relevant to this panel as it is not an adult onset condtion.; to: The tag Q2_21_phenotype has been added to this gene, because variants in this gene are associated with childhood onset of ataxia in Hypotonia, ataxia, and delayed development syndrome OMIM:617330.
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Intellectual disability v3.1094 UFSP2 Konstantinos Varvagiannis changed review comment from: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature; to: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

**Monoallelic** (correction to previous review) UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh changed review comment from: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).; to: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although mRNA expression seems to be unaffected, protein stability maybe responsible for the reduced protein detected by immunoblotting in patients fibroblasts (PMID 33473208).
Intellectual disability v3.1094 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Hydrocephalus v2.101 ISLR2 Arina Puzriakova Publications for gene: ISLR2 were set to 30483960
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Classified gene: ISLR2 as Red List (low evidence)
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family reported in PMID: 30483960 with congenital hydrocephalus, arthrogryposis and abdominal distension and a homozygous a frameshift deletion that segregated with disease. Knockout mouse model recapitulates some features of the human phenotype, i.e. hydrocephalus (PMID: 29739947).

Rating Red, awaiting further cases.
Hydrocephalus v2.100 ISLR2 Arina Puzriakova Gene: islr2 has been classified as Red List (Low Evidence).
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Classified gene: ISLR2 as Red List (low evidence)
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Single family reported in PMID: 30483960 with congenital hydrocephalus, arthrogryposis and abdominal distension and a homozygous a frameshift deletion that segregated with disease. Knockout mouse model recapitulates some features of the human phenotype, i.e. hydrocephalus (PMID: 29739947).

Rating Red, awaiting further cases.
Arthrogryposis v3.101 ISLR2 Arina Puzriakova Gene: islr2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.361 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Intellectual disability v3.1094 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
rs142500730 has also been reported in individuals in the Genoimcs England 100K study, with epilepsy and intellectual disabilities.
Intellectual disability v3.1094 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1093 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Intellectual disability v3.1093 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Intellectual disability v3.1092 UFSP2 Sarah Leigh Tag founder-effect tag was added to gene: UFSP2.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 IPO8 Boaz Palterer gene: IPO8 was added
gene: IPO8 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IPO8 were set to 34010604
Phenotypes for gene: IPO8 were set to cardiovascular anomalies; joint hyperlaxity; dysmorphic features; developmental delay; immune dysregulation; allergy
Penetrance for gene: IPO8 were set to unknown
Review for gene: IPO8 was set to GREEN
Added comment: Ziegler et al. reported 12 individuals from 9 unrelated kindreds with bi-allelic loss-of-function variants in IPO8 presenting with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation. IPO8 is involved in the TGFbeta/SMAD signaling, which is a known pathway in Loeys-Dietz syndrome. Functional data in a zebrafish model.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.38 GLRX5 Ivone Leong Tag Q2_21_rating tag was added to gene: GLRX5.
Childhood onset hereditary spastic paraplegia v2.38 GLRX5 Ivone Leong Classified gene: GLRX5 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.38 GLRX5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
Childhood onset hereditary spastic paraplegia v2.38 GLRX5 Ivone Leong Gene: glrx5 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.37 GLRX5 Ivone Leong Phenotypes for gene: GLRX5 were changed from Spasticity, childhood-onset, with hyperglycinemia 616859 to Spasticity, childhood-onset, with hyperglycinemia, OMIM:616859
White matter disorders and cerebral calcification - narrow panel v1.104 GLRX5 Ivone Leong Tag Q2_21_rating tag was added to gene: GLRX5.
White matter disorders and cerebral calcification - narrow panel v1.104 GLRX5 Ivone Leong Classified gene: GLRX5 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.104 GLRX5 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.104 GLRX5 Ivone Leong Gene: glrx5 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.103 GLRX5 Ivone Leong Phenotypes for gene: GLRX5 were changed from Spasticity, childhood-onset, with hyperglycinemia, MIM# 616859 to Spasticity, childhood-onset, with hyperglycinemia, OMIM:616859
White matter disorders and cerebral calcification - narrow panel v1.102 GLB1 Ivone Leong Classified gene: GLB1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.102 GLB1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene is also Green on the White matter disorders - adult onset (Version 1.11). There is enough evidence to support a gene-disease assocation. GM1-gangliosidosis affect those in their infancy and juvenile stages as well. Therefore this gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.102 GLB1 Ivone Leong Gene: glb1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.101 GLB1 Ivone Leong Tag Q2_21_rating tag was added to gene: GLB1.
White matter disorders and cerebral calcification - narrow panel v1.101 GLB1 Ivone Leong Phenotypes for gene: GLB1 were changed from GM1-gangliosidosis, type I, MIM# 230500; GM1-gangliosidosis, type II, MIM# 230600 to GM1-gangliosidosis, type I, OMIM:230500; GM1-gangliosidosis, type II, OMIM:230600
Early onset or syndromic epilepsy v2.361 UFSP2 Konstantinos Varvagiannis reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33473208; Phenotypes: Abnormal muscle tone, Seizures, Global developmental delay, Delayed speech and language development, Intellectual disability, Strabismus; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1092 UFSP2 Konstantinos Varvagiannis gene: UFSP2 was added
gene: UFSP2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Abnormal muscle tone; Seizures; Global developmental delay; Delayed speech and language development; Intellectual disability; Strabismus
Penetrance for gene: UFSP2 were set to Complete
Added comment: Ni et al (2021 - PMID: 33473208) describe the phenotype of 8 children (belonging to 4 families - 2 of which consanguineous) homozygous for a UFSP2 missense variant [NM_018359.5:c.344T>A; p.(Val115Glu)].

Members of a broader consanguineous pedigree from Pakistan with 3 affected children with epilepsy and DD and ID underwent exome sequencing. All affected individuals were homozygous for the specific SNV with their parents (2 parent pairs, in both cases first cousins) being heterozygous. An unaffected sib was homozygous for the wt allele. Through genematching platforms 3 additional families with similarly affected individuals and homozygosity for the same variant were recruited. These additional families were from Pakistan (1/3) and Afganistan (2/3).

Based on ROH analysis from the broader first pedigree and an additional family the authors concluded on a single shared region of homozygosity on chr 4q. Lack of ES data did not allow verification of whether 2/4 families shared the same haplotype with the other 2.

The authors calculated the probability of the genotype-phenotype cosegragation occurring by chance (0.009) and this was lower than the recommended criterion (0.06) for strong evidence of pathogenicity.

Shared features included abnormal tone in most (hypotonia 6/8, limb hypertonia 1/8), seizures (8/8 - onset 2d - 7m), severe DD with speech delay/absent speech (8/8), ID (8/8), strabismus (6/8).

UFSP2 encodes UFM1-specific protease 2 involved in UFmylation, a post-translational protein modification. As summarized by the authors the cysteine protease encoded by this gene (as is also the case for UFSP1) cleaves UFM1 in the initial step of UFMylation. Apart from producing mature UFM1, the 2 proteases have also the ability to release UFM1 from UFMylated proteins, in the process of de-UFMylation. [several refs. provided]

UFMylation is important in brain development with mutations in genes encoding other components of the pathway reported in other NDD disorders (incl. UFM1, UBA5, UFC1).

Additional studies were carried to provide evidence for pathogenicity of this variant.

Skin biopsies from 3 individuals were carried out to establish fibroblast cultures. Immunoblotting revealed reduced UFSP2 levels relative to controls. mRNA levels measured by qRT-PCR revealed no differences compared to controls altogether suggesting normal mRNA but reduced protein stability.

The authors demonstrated increased levels of UFM1-conjugated proteins (incl. DDRGK1, or TRIP4). Ectopic expression of wt UFSP2 normalized the levels of UFMylated proteins in the fibroblasts which was not the case for the V115E variant. Further the variant was difficult to detect by immunoblotting consistent with an effect on protein destabilization.

Although disruption of UFMylation induces ER stress, this was not shown to occur in patient fibroblast lines, when assessed for ER stress markers.

Evaluation of data from the GTEx project, concerning UFSP2 as well as well as DDRGK1 or TRIP4 - an UFMylation target - revealed relevant expression in multiple regions of the human brain.

Overall the authors provide evidence for defective de-UFMylation in patient fibroblasts (presence of increased UFMylation marks). The authors stress out that the effect of the variant in UFMylation in brain is unknown, as UFSP1 or other enzymes might compensate in the presence of hypomorphic UFSP2 mutants.

Biallelic UFSP2 variants have previously been reported in 2 skeletal dysplasias [# 142669. BEUKES HIP DYSPLASIA; BHD and # 617974. SPONDYLOEPIMETAPHYSEAL DYSPLASIA, DI ROCCO TYPE; SEMDDR]. These disorders are not characterized by neurological dysfunction or epilepsy. The authors underscore the fact that variants identified in these disorders (Y290H, D526A, H428R) localize within the C-terminal catalytic (peptidase) domain [aa 278 – 461] while the variant here identified lies in the N-terminal substrate binding domain affecting protein stability/abundance.

In OMIM, only the 2 aforementioned disorders are currently associated with biallelic UFSP2 mutations. There is no associated phenotype in G2P. SysID includes UFSP2 among the primary ID genes.

You may consider inclusion in the current panel with amber/green rating.
Sources: Literature
Intellectual disability v3.1092 SIN3B Konstantinos Varvagiannis reviewed gene: SIN3B: Rating: AMBER; Mode of pathogenicity: None; Publications: 33811806; Phenotypes: Global developmental delay, Intellectual disability, Behavioral abnormality; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary ataxia with onset in adulthood v2.57 ERCC4 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERCC4.
Hereditary ataxia with onset in adulthood v2.57 ERCC4 Sarah Leigh commented on gene: ERCC4: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least nine variants reported in at least seven cases of Xeroderma pigmentosum, group F OMIM:278760, where neurodegeneration and ataxia was present (PMID 29403087; 28431612; 29892709).
Hereditary ataxia with onset in adulthood v2.57 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Cerebellar ataxia; Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215 to Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215
Hereditary ataxia with onset in adulthood v2.56 ERCC4 Sarah Leigh Classified gene: ERCC4 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.56 ERCC4 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary ataxia with onset in adulthood v2.56 ERCC4 Sarah Leigh Gene: ercc4 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.55 ERCC4 Sarah Leigh Phenotypes for gene: ERCC4 were changed from Cerebellar ataxia; Xeroderma pigmentosum, group F, MIM# 278760 to Cerebellar ataxia; Xeroderma pigmentosum, group F OMIM:278760; xeroderma pigmentosum group F MONDO:0010215
Severe microcephaly v2.182 SASS6 Eleanor Williams Classified gene: SASS6 as Amber List (moderate evidence)
Severe microcephaly v2.182 SASS6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber as now two cases reported with severe microcephaly. Pubmed search did not find further cases at this time.
Severe microcephaly v2.182 SASS6 Eleanor Williams Gene: sass6 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.181 SASS6 Eleanor Williams Phenotypes for gene: SASS6 were changed from autosomal recessive primary microcephaly (MCPH); ?Microcephaly 14, primary, autosomal recessive, 616402 to ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams edited their review of gene: SASS6: Changed phenotypes to: ?Microcephaly 14, primary, autosomal recessive, OMIM:616402
Severe microcephaly v2.180 SASS6 Eleanor Williams changed review comment from: Provisionally associated with ?Microcephaly 11, primary, autosomal recessive #615414 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.; to: Provisionally associated with ?Microcephaly 14, primary, autosomal recessive #616402 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.
Severe microcephaly v2.180 SASS6 Eleanor Williams Publications for gene: SASS6 were set to 24951542
Severe microcephaly v2.179 SASS6 Eleanor Williams reviewed gene: SASS6: Rating: AMBER; Mode of pathogenicity: None; Publications: 24951542, 30639237; Phenotypes: ?Microcephaly 11, primary, autosomal recessive, OMIM:615414; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.179 RUSC2 Eleanor Williams Classified gene: RUSC2 as Red List (low evidence)
Severe microcephaly v2.179 RUSC2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. 2 families reported with homozgyous nonsense variants in RUSC2 but the microcephaly phenotype is relatively mild although progressive.
Severe microcephaly v2.179 RUSC2 Eleanor Williams Gene: rusc2 has been classified as Red List (Low Evidence).
Severe microcephaly v2.178 RUSC2 Eleanor Williams reviewed gene: RUSC2: Rating: RED; Mode of pathogenicity: None; Publications: 27612186; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.178 PUS7 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUS7.
Severe microcephaly v2.178 PUS7 Eleanor Williams Classified gene: PUS7 as Amber List (moderate evidence)
Severe microcephaly v2.178 PUS7 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review. 4 families reported with a severe microcephaly phenotype.
Severe microcephaly v2.178 PUS7 Eleanor Williams Gene: pus7 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.177 PUS7 Eleanor Williams Phenotypes for gene: PUS7 were changed from Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM #618342 to Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342
Severe microcephaly v2.176 PUS7 Eleanor Williams reviewed gene: PUS7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30526862, 30778726, 31583274; Phenotypes: Intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, OMIM:618342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.176 PUF60 Eleanor Williams Classified gene: PUF60 as Amber List (moderate evidence)
Severe microcephaly v2.176 PUF60 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating at the next GMS review. 3 cases reported with heterozygous variants in PUF60 and a severe microcephaly phenotype.
Severe microcephaly v2.176 PUF60 Eleanor Williams Gene: puf60 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.175 PUF60 Eleanor Williams Phenotypes for gene: PUF60 were changed from Verheij syndrome, MIM# 615583 to Verheij syndrome, OMIM:615583
Severe microcephaly v2.174 PUF60 Eleanor Williams Publications for gene: PUF60 were set to 28327570
Severe microcephaly v2.173 PUF60 Eleanor Williams Tag Q2_21_rating tag was added to gene: PUF60.
Severe microcephaly v2.173 PUF60 Eleanor Williams reviewed gene: PUF60: Rating: GREEN; Mode of pathogenicity: None; Publications: 24140112, 27804958, 28327570, 28074499, 28471317, 32851780; Phenotypes: Verheij syndrome, OMIM:615583; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Classified gene: RFWD3 as Red List (low evidence)
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). To date, only a single patient has been reported in PMID: 28691929 - rating Red awaiting further cases.
Fetal anomalies v1.662 RFWD3 Arina Puzriakova Gene: rfwd3 has been classified as Red List (Low Evidence).
Fetal anomalies v1.661 RFWD3 Arina Puzriakova Publications for gene: RFWD3 were set to PMID: 2869192
Fetal anomalies v1.660 RFWD3 Arina Puzriakova Phenotypes for gene: RFWD3 were changed from Fanconi anaemia to ?Fanconi anemia, complementation group W, OMIM:617784
Fetal anomalies v1.659 FKBP8 Arina Puzriakova Mode of inheritance for gene: FKBP8 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Classified gene: FKBP8 as Amber List (moderate evidence)
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Added comment: Comment on list classification: Additional publication identified by Rhiannon Mellis (GOSH) describing a fetus with severe thoracolumbar scoliosis and caudal spinal cord agenesis and a homozygous (c.C572T:p.P191L) variant in FKBP8 (PMID: 29261186). Note the phenotype and MOI are distinct from other reports (PMID: 32969478).

FKBP8 remains a candidate gene and so maintaining Amber rating in anticipation of additional cases to corroborate pathogenicity.
Fetal anomalies v1.658 FKBP8 Arina Puzriakova Gene: fkbp8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.657 FKBP8 Arina Puzriakova Phenotypes for gene: FKBP8 were changed from spina bifida HP:0002414 to Spina bifida, HP:0002414; Vertebral segmentation defects
Fetal anomalies v1.656 FKBP8 Arina Puzriakova Publications for gene: FKBP8 were set to 32969478
Fetal anomalies v1.655 PLD1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: PLD1.
Fetal anomalies v1.655 PLD1 Arina Puzriakova Publications for gene: PLD1 were set to 33645542
Fetal anomalies v1.654 PLD1 Arina Puzriakova Classified gene: PLD1 as Amber List (moderate evidence)
Fetal anomalies v1.654 PLD1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Suzanne Drury (Congenica). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a fetally-relevant gene-disease association. This gene should be rated Green at the next review.
Fetal anomalies v1.654 PLD1 Arina Puzriakova Gene: pld1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.653 PLD1 Arina Puzriakova Phenotypes for gene: PLD1 were changed from HP:0001654; HP:0001627; HP:0001638 to Cardiac valvular defect, developmental, OMIM:212093
Fetal anomalies v1.652 CLTC Arina Puzriakova reviewed gene: CLTC: Rating: ; Mode of pathogenicity: None; Publications: 33743358; Phenotypes: Mental retardation, autosomal dominant 56, OMIM:617854; Mode of inheritance: None
Fetal anomalies v1.652 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854; Fetal akinesia; Fetal growth restriction
Intellectual disability v3.1092 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAMK2B.
Severe microcephaly v2.173 CAMK2B Arina Puzriakova Publications for gene: CAMK2B were set to 32875707
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Classified gene: CAMK2B as Amber List (moderate evidence)
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Added comment: Comment on list classification: Gene added to this panel and rated Green by Zornitza Stark. Variable degree of microcephaly has been reported in 9/13 individuals with CAMK2B variants (PMIDs: 29100089; 29560374; 30842224; 32875707). Severe microcephaly (HC ≤ -3 SD) is reported in at least 4 unrelated individuals.

Overall sufficient cases to rate as Green on this panel. Inclusion may be particularly beneficial for cases with milder degree of DD/ID for which this gene is also Green.
Severe microcephaly v2.172 CAMK2B Arina Puzriakova Gene: camk2b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.171 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from microcephaly; intellectual disability; behavioural problems to Mental retardation, autosomal dominant 54, OMIM:617799
Intellectual disability v3.1091 CAMK2B Arina Puzriakova Phenotypes for gene: CAMK2B were changed from Mental retardation, autosomal dominant 54 617799 to Mental retardation, autosomal dominant 54, OMIM:617799
Neonatal diabetes v2.34 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Neonatal diabetes v2.34 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Diabetes - neonatal onset. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Early onset or syndromic epilepsy v2.361 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Intellectual disability v3.1090 YIPF5 Arina Puzriakova Entity copied from Severe microcephaly v2.170
Intellectual disability v3.1090 YIPF5 Arina Puzriakova gene: YIPF5 was added
gene: YIPF5 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: YIPF5.
Mode of inheritance for gene: YIPF5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIPF5 were set to 33164986
Phenotypes for gene: YIPF5 were set to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: YIPF5.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Classified gene: YIPF5 as Amber List (moderate evidence)
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Added comment: Comment on list classification: New gene added and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (all affected individuals present progressive severe microcephaly, generalised tonic clonic seizures with onset at 1 - 7 months, diabetes diagnosed at 4 weeks - 15 months, and 5/6 also had severe DD) for inclusion on this panel: 6 patients from 5 families with different YIPF5 variants identified in PMID: 33164986. Functional analysis demonstrated that YIPF5 deficiency enhances ER stress and sensitises beta-cells to ER stress-induced apoptosis.

YIPF5 is also associated with a relevant phenotype in OMIM (MIM# 619278) but is not yet listed in G2P.

There is enough evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.170 YIPF5 Arina Puzriakova Gene: yipf5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.169 YIPF5 Arina Puzriakova Phenotypes for gene: YIPF5 were changed from Neonatal diabetes; microcephaly; seizures to Microcephaly, epilepsy, and diabetes syndrome 2, OMIM:619278
Severe microcephaly v2.168 RRP7A Arina Puzriakova Classified gene: RRP7A as Amber List (moderate evidence)
Severe microcephaly v2.168 RRP7A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33199730 report a homozygous missense variant (c.465G>C; p.Trp155Cys) in RRP7A that segregated with primary microcephaly in a consanguineous family with 10 affected individuals. Supported by animal model data. Rating Amber, awaiting further cases.
Severe microcephaly v2.168 RRP7A Arina Puzriakova Gene: rrp7a has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.37 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Mitochondrial disorders v2.37 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Mitochondrial disorders. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Mitochondrial DNA maintenance disorder v1.4 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Mitochondrial DNA maintenance disorder v1.4 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Mitochondrial DNA maintenance disorder. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Possible mitochondrial disorder - nuclear genes v1.43 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Possible mitochondrial disorder - nuclear genes v1.43 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Possible mitochondrial disorder - nuclear genes. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Ataxia and cerebellar anomalies - narrow panel v2.183 LIG3 Ivone Leong Tag watchlist tag was added to gene: LIG3.
Ataxia and cerebellar anomalies - narrow panel v2.183 LIG3 Ivone Leong edited their review of gene: LIG3: Added comment: As only 1 family has signs of ataxia and the knockout mouse model recapitulated this phenotype this gene has been given an Amber rating on this panel.; Changed rating: AMBER
Ataxia and cerebellar anomalies - narrow panel v2.183 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Retinal disorders v2.186 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Tag watchlist tag was added to gene: LIG3.
Retinal disorders v2.186 LIG3 Ivone Leong edited their review of gene: LIG3: Added comment: As only 2 affected families have macular degeneration this gene has been given an Amber rating until more evidence is available.; Changed rating: AMBER
Ataxia and cerebellar anomalies - narrow panel v2.183 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Ataxia and cerebellar anomalies - narrow panel v2.183 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Retinal disorders v2.186 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Retinal disorders v2.186 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Retinal disorders. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Intellectual disability v3.1089 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 25529582; 2670875126708753
Inherited white matter disorders v1.97 LIG3 Ivone Leong Classified gene: LIG3 as Green List (high evidence)
Inherited white matter disorders v1.97 LIG3 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Inherited white matter disorders v1.97 LIG3 Ivone Leong Gene: lig3 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.360 UNC80 Arina Puzriakova Publications for gene: UNC80 were set to 26545877; 26708753; 26708751
Inherited white matter disorders v1.96 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Classified gene: LIG3 as Green List (high evidence)
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Gastrointestinal neuromuscular disorders v1.14 LIG3 Ivone Leong Gene: lig3 has been classified as Green List (High Evidence).
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong Tag Q2_21_rating was removed from gene: LIG3.
Adult onset leukodystrophy v1.11 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Adult onset leukodystrophy v1.11 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to White matter disorders - adult onset. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Severe microcephaly v2.167 UNC80 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UNC80.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Classified gene: UNC80 as Amber List (moderate evidence)
Severe microcephaly v2.167 UNC80 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Variable degrees reported but there are enough unrelated cases (>3) with sufficiently severe microcephaly and distinct UNC80 variants to rate as Green on this panel.
Severe microcephaly v2.167 UNC80 Arina Puzriakova Gene: unc80 has been classified as Amber List (Moderate Evidence).
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Gastrointestinal neuromuscular disorders v1.13 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Gastrointestinal neuromuscular disorders. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
Inherited white matter disorders v1.96 LIG3 Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.100
Inherited white matter disorders v1.96 LIG3 Ivone Leong gene: LIG3 was added
gene: LIG3 was added to Inherited white matter disorders. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: LIG3.
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
White matter disorders and cerebral calcification - narrow panel v1.100 LIG3 Ivone Leong Tag Q2_21_rating tag was added to gene: LIG3.
White matter disorders and cerebral calcification - narrow panel v1.100 LIG3 Ivone Leong Phenotypes for gene: LIG3 were changed from gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion
White matter disorders and cerebral calcification - narrow panel v1.99 LIG3 Ivone Leong Classified gene: LIG3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.99 LIG3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:33855352. 3 unrelated families with 7 affected individuals. Clinical features of affected individuals resemble mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). All had severe dysmotility of the gut, leukoencephalopathy and/or progressive cortical atrophy. Cerebella atrophy was only seen in patients in family 3. Other neurological features were epilepsy, stroke-like episodes, migraine and developmental delay. 4 members from families 1 and 2 had macular degeneration, 1 member from family 3 had cataracts and hearing loss. Age of onset and disease severity differed, ranging from paediatric severe disease with premature death to adult cases. All affected members from the 3 families were compound heterozygous for different LIG3 variants.

LIG3 variants cause impared ligase activity, mtDNA depletion and mitochondrial dysfunction.

The authors also created a zebrafish model, which recapitulated the cerebellar phenotype (seen in mice) and eye defects and gut propulsion impairment (seen in patients). Knockdown of lig3 in zf also led to decrease in expression of mitochondrial markers.

Knocking out Lig3 in mice led to early embryonic lethality with mitochondrial dysfunction due to reduced mtDNA in the nervous system (PMID: 21390131); however, gut motility was not investigated in these mice.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.99 LIG3 Ivone Leong Gene: lig3 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1088 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Severe microcephaly v2.166 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 MIM#616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Early onset or syndromic epilepsy v2.359 UNC80 Arina Puzriakova Phenotypes for gene: UNC80 were changed from Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, 616801 to Hypotonia, infantile, with psychomotor retardation and characteristic facies 2, OMIM:616801
Severe microcephaly v2.165 UGP2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UGP2.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Classified gene: UGP2 as Amber List (moderate evidence)
Severe microcephaly v2.165 UGP2 Arina Puzriakova Added comment: Comment on list classification: Gene added to panel and rated Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (progressive microcephaly seen in all patients with available data) for inclusion on panel: 22 patients from 15 families all with the same variant identified in PMID:31820119. Therefore there is sufficient evidence to rate this gene as Green at the next GMS panel update.
Severe microcephaly v2.165 UGP2 Arina Puzriakova Gene: ugp2 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.118 FUCA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: FUCA1.
Childhood onset dystonia, chorea or related movement disorder v1.118 FUCA1 Sarah Leigh Classified gene: FUCA1 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.118 FUCA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.118 FUCA1 Sarah Leigh Gene: fuca1 has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.117 FUCA1 Sarah Leigh reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.164 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy; intellectual disability; microcephaly to Developmental and epileptic encephalopathy 83, OMIM:618744
Intellectual disability v3.1087 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Developmental and epileptic encephalopathy 83, OMIM:618744
Early onset or syndromic epilepsy v2.358 UGP2 Arina Puzriakova Phenotypes for gene: UGP2 were changed from Epileptic encephalopathy, early infantile, 83, 618744; seizures to Developmental and epileptic encephalopathy 83, OMIM:618744
Childhood onset dystonia, chorea or related movement disorder v1.117 FUCA1 Sarah Leigh Phenotypes for gene: FUCA1 were changed from to Fucosidosis OMIM:230000; fucosidosis MONDO:0009254
Childhood onset dystonia, chorea or related movement disorder v1.116 FUCA1 Sarah Leigh Publications for gene: FUCA1 were set to
Childhood onset dystonia, chorea or related movement disorder v1.115 FUCA1 Sarah Leigh Mode of inheritance for gene: FUCA1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.114 C9orf72 Sarah Leigh reviewed gene: C9orf72: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.114 C9orf72 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: C9orf72.
Tag Q2_21_expert_review tag was added to gene: C9orf72.
Hereditary ataxia with onset in adulthood v2.54 EBF3 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: EBF3.
Tag Q2_21_expert_review tag was added to gene: EBF3.
Hereditary ataxia with onset in adulthood v2.54 EBF3 Sarah Leigh reviewed gene: EBF3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia with onset in adulthood v2.54 EBF3 Sarah Leigh Publications for gene: EBF3 were set to
Intellectual disability v3.1086 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 0
Intellectual disability v3.1085 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Hereditary ataxia with onset in adulthood v2.53 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia 5, 610204; Pontocerebellar hypoplasia 4, 225753; Pontocerebellar hypoplasia 2A, 277470; Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar hypoplasia type 2A, 277470 to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Hereditary ataxia with onset in adulthood v2.52 ATP8A2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ATP8A2.
Tag Q2_21_expert_review tag was added to gene: ATP8A2.
Hereditary ataxia with onset in adulthood v2.52 ATP8A2 Sarah Leigh changed review comment from: Zornitza Stark has commented this gene is responsible for a congenital condition and not for an adult onset phenotype. However, table 1 in PMID 31612321 provides a review of the reported variants and their associated clinical features, where a few cases occur after adolescence. This provides justification for this gene being green on this adult onset panel.; to: Zornitza Stark has commented this gene is responsible for a congenital condition and not for an adult onset phenotype. However, table 1 in PMID 31612321 provides a review of the reported variants and their associated clinical features, where a few cases occur after adolescence. This provides some justification for this gene being green on this adult onset panel.
Early onset or syndromic epilepsy v2.357 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20956791; 7854532; 26701950; 20952379
Early onset or syndromic epilepsy v2.356 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar hypoplasia type 2A, 277470; ?Pontocerebellar hypoplasia type 5, 610204 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Fetal anomalies v1.651 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to
Fetal anomalies v1.650 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from PONTOCEREBELLAR HYPOPLASIA TYPE 2 AND TYPE 4; Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Arthrogryposis v3.100 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 4 225753 to Pontocerebellar hypoplasia type 4, OMIM:225753
Arthrogryposis v3.99 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to
Hereditary ataxia with onset in adulthood v2.52 ATP8A2 Sarah Leigh reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia v1.223 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Ataxia and cerebellar anomalies - narrow panel v2.182 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to PMID: 20956791; PMID: 18711368; PMID: 20952379; PMID: 21368912
Cerebellar hypoplasia v1.48 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 18711368; 20956791; 20952379; 20301773
Ataxia and cerebellar anomalies - narrow panel v2.181 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar Hypoplasia type 2A; Pontocerebellar hypoplasia 2A (#277470) and 4 (#225753); Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar Hypoplasia type 4; Pontocerebellar hypoplasia type 4, 225753; Pontocerebellar Hypoplasia; Pontocerebellar Hypoplasia type 5 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Classified gene: TSEN54 as Green List (high evidence)
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel review - only a single patient reported to date, with rhabdomyolysis and a homozygous TSEN54 variant.
Rhabdomyolysis and metabolic muscle disorders v1.46 TSEN54 Arina Puzriakova Gene: tsen54 has been classified as Green List (High Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.45 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from ?Pontocerebellar hypoplasia type 5 610204; Pontocerebellar hypoplasia type 2A 277470; Pontocerebellar hypoplasia type 4 225753 to Pontocerebellar hypoplasia type 2A, OMIM:277470
Rhabdomyolysis and metabolic muscle disorders v1.44 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 25929793; 18711368
Rhabdomyolysis and metabolic muscle disorders v1.43 TSEN54 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN54.
Rhabdomyolysis and metabolic muscle disorders v1.43 TSEN54 Arina Puzriakova reviewed gene: TSEN54: Rating: RED; Mode of pathogenicity: None; Publications: 23177318; Phenotypes: Pontocerebellar hypoplasia type 2A, OMIM:277470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.114 C9orf72 James Polke reviewed gene: C9orf72: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.114 CSTB Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CSTB.
Childhood onset dystonia, chorea or related movement disorder v1.114 CSTB Sarah Leigh reviewed gene: CSTB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset hereditary spastic paraplegia v2.36 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Childhood onset hereditary spastic paraplegia v2.36 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Inherited white matter disorders v1.95 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Inherited white matter disorders v1.95 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Inherited white matter disorders. Sources: Expert Review Amber,Literature
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Hereditary spastic paraplegia v1.222 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Hereditary spastic paraplegia v1.222 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Hereditary ataxia v1.222 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Hereditary ataxia v1.222 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary ataxia. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Ataxia and cerebellar anomalies - narrow panel v2.180 POLR3K Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.98
Ataxia and cerebellar anomalies - narrow panel v2.180 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Cerebellar hypoplasia v1.47 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to PMID: 21368912; PMID: 18711368; PMID: 20956791; PMID: 20952379;
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN54.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Classified gene: TSEN54 as Amber List (moderate evidence)
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Progressive microcephaly is a feature associated with PCH types 2 and 4. Sufficient number of unrelated cases (>3) to rate this gene as Green at the next GMS panel review.
Severe microcephaly v2.163 TSEN54 Arina Puzriakova Gene: tsen54 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.162 TSEN54 Arina Puzriakova Publications for gene: TSEN54 were set to 20952379; 20301773
White matter disorders and cerebral calcification - narrow panel v1.98 POLR3K Ivone Leong Tag watchlist tag was added to gene: POLR3K.
Tag founder-effect tag was added to gene: POLR3K.
White matter disorders and cerebral calcification - narrow panel v1.98 POLR3K Ivone Leong Classified gene: POLR3K as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.98 POLR3K Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 30584594. 2 affected individuals from 2 consanguineous families from same area in Algeria. Affected indviduals had global developmental delay with loss of motor, speech and cognitive milestones. Individuals also showed signs of nystagmus, ataxia, dystonia and spasticity. Both individuals had feeding difficulties and were tube fed, growth failure and microcephaly (-3 SD), and cryptorchidism. 1 patient had optic atrophy and hypodontia and the other patient had hypogonadotropic hypogonadism. Both individuals have the same variant (may be founder effect).

As other members of the same gene family are linked to similar phenotypes this gene has been given an Amber rating.
White matter disorders and cerebral calcification - narrow panel v1.98 POLR3K Ivone Leong Gene: polr3k has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.35 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v3.1084 AFG3L2 Sarah Leigh commented on gene: AFG3L2: Disease causing variants are both monoallelic and biallelic
Intellectual disability v3.1084 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Childhood onset hereditary spastic paraplegia v2.35 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Intellectual disability v3.1083 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Intellectual disability v3.1083 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary spastic paraplegia v1.221 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary spastic paraplegia v1.220 AFG3L2 Sarah Leigh Mode of inheritance for gene: AFG3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebellar hypoplasia v1.46 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar Hypoplasia type 5; Pontocerebellar Hypoplasia type 2A; Pontocerebellar Hypoplasia type 4; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia type 2A, 277470; Pontocerebellar hypoplasia type 4, 225753 to ?Pontocerebellar hypoplasia type 5, OMIM:610204; Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
Severe microcephaly v2.161 TSEN54 Arina Puzriakova Phenotypes for gene: TSEN54 were changed from Pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753) to Pontocerebellar hypoplasia type 2A, OMIM:277470; Pontocerebellar hypoplasia type 4, OMIM:225753
White matter disorders and cerebral calcification - narrow panel v1.97 POLR3K Ivone Leong Phenotypes for gene: POLR3K were changed from Hypomyelinating leukodystrophy-21, MIM#619310 to Leukodystrophy, hypomyelinating, 21, OMIM:619310
White matter disorders and cerebral calcification - narrow panel v1.96 LSM7 Ivone Leong Classified gene: LSM7 as Red List (low evidence)
White matter disorders and cerebral calcification - narrow panel v1.96 LSM7 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Currently there is not enough evidence to support a gene-disease association. Until there are more cases this gene has been given a Red rating.
White matter disorders and cerebral calcification - narrow panel v1.96 LSM7 Ivone Leong Gene: lsm7 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.95 LSM7 Ivone Leong Phenotypes for gene: LSM7 were changed from Leukodystrophy; fetal death to Leukodystrophy, MONDO:0019046
Adult onset hereditary spastic paraplegia v1.21 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive; Ataxia, spastic, 5, autosomal recessive; Spinocerebellar ataxia 28, autosomal dominant, 610246 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Hereditary ataxia with onset in adulthood v2.52 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Spinocerebellar ataxia 28, 610246; Ataxia, spastic, 5, autosomal recessive; spastic ataxia 5, 614487; Spinocerebellar ataxia 28; Spinocerebellar Ataxia, Dominant to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Mitochondrial disorders v2.36 AFG3L2 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity
Mitochondrial disorders v2.36 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Disorders of mitochondrial DNA maintenance and integrity; Spinocerebellar ataxia 28, 610246; Ataxia, spastic, 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Added comment: Comment on phenotypes: Ataxia, spastic, 5, autosomal recessive, 614487;Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only));Spinocerebellar ataxia 28, 610246;Disorders of mitochondrial DNA maintenance and integrity
Likely inborn error of metabolism v2.135 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive, 614487; Miscellaneous disorders/unknown function (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Spinocerebellar ataxia 28, 610246; Disorders of mitochondrial DNA maintenance and integrity to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Childhood onset hereditary spastic paraplegia v2.35 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Childhood onset dystonia, chorea or related movement disorder v1.114 AFG3L2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AFG3L2.
Adult onset hereditary spastic paraplegia v1.20 AFG3L2 Sarah Leigh commented on gene: AFG3L2
Adult onset hereditary spastic paraplegia v1.20 AFG3L2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: AFG3L2.
Adult onset hereditary spastic paraplegia v1.20 AFG3L2 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: AFG3L2.
Childhood onset dystonia, chorea or related movement disorder v1.114 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 16541453; 32219868
Childhood onset dystonia, chorea or related movement disorder v1.113 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 1654145; 332219868
Childhood onset dystonia, chorea or related movement disorder v1.112 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to 22964162; 1654145332219868
Childhood onset dystonia, chorea or related movement disorder v1.111 AFG3L2 Sarah Leigh Publications for gene: AFG3L2 were set to
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber - PMID:27392077 report on 2 families with PCH and biallelic variants in this gene (brain MRI was not available in third family). Additional cases required prior to inclusion as diagnostic-grade.
Cerebellar hypoplasia v1.45 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.179 TSEN15 Arina Puzriakova Tag watchlist tag was added to gene: TSEN15.
Ataxia and cerebellar anomalies - narrow panel v2.179 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.179 TSEN15 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber - PMID:27392077 report on 2 families with PCH and biallelic variants in this gene (brain MRI was not available in third family). Additional cases required prior to inclusion as diagnostic-grade (added watchlist tag)
Ataxia and cerebellar anomalies - narrow panel v2.179 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.51 TSEN15 Arina Puzriakova Publications for gene: TSEN15 were set to
Hereditary ataxia with onset in adulthood v2.50 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Green List (high evidence)
Hereditary ataxia with onset in adulthood v2.50 TSEN15 Arina Puzriakova Added comment: Comment on list classification: This gene should be demoted from Green to Red at the next GMS panel review
Hereditary ataxia with onset in adulthood v2.50 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Green List (High Evidence).
Hereditary ataxia with onset in adulthood v2.49 TSEN15 Arina Puzriakova reviewed gene: TSEN15: Rating: RED; Mode of pathogenicity: None; Publications: 27392077; Phenotypes: Pontocerebellar hypoplasia, type 2F, OMIM:617026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.49 TSEN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN15.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TSEN15.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Classified gene: TSEN15 as Amber List (moderate evidence)
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Added comment: Comment on list classification: TSEN15 was added and rated Green by Zornitza Stark based on PMID:27392077 (Breuss et al, 2016) who report three homozygous TSEN15 variants in four individuals from three families. All affected individuals developed progressive microcephaly of relevant severity, which represented an early and main feature of the disease presentation.

There is sufficient evidence to promote this gene to Green at the next GMS panel update.
Severe microcephaly v2.160 TSEN15 Arina Puzriakova Gene: tsen15 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.159 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F MIM#617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Childhood onset dystonia, chorea or related movement disorder v1.110 C9orf72_GGGGCC Sarah Leigh Deleted their review
Adult onset dystonia, chorea or related movement disorder v1.114 C9orf72_GGGGCC Sarah Leigh Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Childhood onset dystonia, chorea or related movement disorder v1.110 C9orf72_GGGGCC Sarah Leigh Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Childhood onset dystonia, chorea or related movement disorder v1.109 C9orf72 Sarah Leigh Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Childhood onset dystonia, chorea or related movement disorder v1.108 C9orf72 Sarah Leigh Publications for gene: C9orf72 were set to
Childhood onset dystonia, chorea or related movement disorder v1.107 C9orf72_GGGGCC Sarah Leigh Tag Q2_21_rating tag was added to STR: C9orf72_GGGGCC.
Childhood onset dystonia, chorea or related movement disorder v1.107 C9orf72_GGGGCC Sarah Leigh Classified STR: C9orf72_GGGGCC as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.107 C9orf72_GGGGCC Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.107 C9orf72_GGGGCC Sarah Leigh Str: c9orf72_ggggcc has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.106 C9orf72_GGGGCC Sarah Leigh Entity copied from Adult onset movement disorder v1.113
Childhood onset dystonia, chorea or related movement disorder v1.106 C9orf72_GGGGCC Sarah Leigh STR: C9orf72_GGGGCC was added
STR: C9orf72_GGGGCC was added to Childhood onset dystonia or chorea or related movement disorder. Sources: NHS GMS,Expert Review Green,London North GLH,Expert list
STR tags were added to STR: C9orf72_GGGGCC.
Mode of inheritance for STR: C9orf72_GGGGCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: C9orf72_GGGGCC were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Childhood onset hereditary spastic paraplegia v2.34 HPDL Sarah Leigh Publications for gene: HPDL were set to 32707086; 33188300
Hereditary ataxia with onset in adulthood v2.49 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia 2F, 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Intellectual disability v3.1083 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from delayed developmental milestones; Pontocerebellar hypoplasia, type 2F, 617026; Intellectual disability to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Early onset or syndromic epilepsy v2.355 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F, 617026; seizures to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Cerebellar hypoplasia v1.44 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Ataxia and cerebellar anomalies - narrow panel v2.178 TSEN15 Arina Puzriakova Phenotypes for gene: TSEN15 were changed from Pontocerebellar hypoplasia, type 2F 617026 to Pontocerebellar hypoplasia, type 2F, OMIM:617026
Ataxia and cerebellar anomalies - narrow panel v2.177 TSEN15 Arina Puzriakova reviewed gene: TSEN15: Rating: ; Mode of pathogenicity: None; Publications: 27392077; Phenotypes: Pontocerebellar hypoplasia, type 2F, OMIM:617026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Classified gene: LTBP1 as Amber List (moderate evidence)
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal dysplasia v2.99 LTBP1 Sarah Leigh Gene: ltbp1 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.98 LTBP1 Sarah Leigh gene: LTBP1 was added
gene: LTBP1 was added to Skeletal dysplasia. Sources: Literature
Q2_21_rating tags were added to gene: LTBP1.
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to inherited cutis laxa MONDO:0100237
Review for gene: LTBP1 was set to GREEN
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (as of 18/05/20210). At least four terminating variants were reported in unrelated cases. Supportive in vitro and in vivo studies demonstrate the role of LTBP1 in skin and bone ECM assembly and homeostasis, in human and zebrafish (PMID 33991472).
Sources: Literature
Intellectual disability v3.1082 TRIO Arina Puzriakova Publications for gene: TRIO were set to 0
Severe microcephaly v2.158 TRIO Arina Puzriakova Classified gene: TRIO as Amber List (moderate evidence)
Severe microcephaly v2.158 TRIO Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green status at the next GMS panel update - microcephaly of relevant severity to this panel is observed in at least 12 unrelated families with TRIO variants. Pathogenicity is supported by functional data and animal model.
Severe microcephaly v2.158 TRIO Arina Puzriakova Gene: trio has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.157 TRIO Arina Puzriakova Publications for gene: TRIO were set to 26721934; 32109419
Severe microcephaly v2.156 TRIO Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRIO.
Severe microcephaly v2.156 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from Mental retardation, autosomal dominant 44, MIM# 617061 to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061
Intellectual disability v3.1081 TRIO Arina Puzriakova Phenotypes for gene: TRIO were changed from INTELLECTUAL DISABILITY to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061; Intellectual developmental disorder, autosomal dominant 63, with macrocephaly, OMIM:618825
Ataxia and cerebellar anomalies - narrow panel v2.177 VRK1 Arina Puzriakova Phenotypes for gene: VRK1 were changed from Pontocerebellar Hypoplasia type 1A; Pontocerebellar Hypoplasia with infantile SMA; Pontocerebellar Hypoplasia with anterior horn cell disease; Pontocerebellar Hypoplasia; Pontocerebellar hypoplasia 1A (#607596); Pontocerebellar hypoplasia type 1A,607596 to Pontocerebellar hypoplasia type 1A, OMIM:607596
Ataxia and cerebellar anomalies - narrow panel v2.176 SPTBN2 Arina Puzriakova Phenotypes for gene: SPTBN2 were changed from Spinocerebellar ataxia 5 (AD); Spinocerebellar ataxia, autosomal recessive 14; SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 14; Spinocerebellar Ataxia, Dominant; Spinocerebellar ataxia, autosomal recessive 14 (AR); Spinocerebellar ataxia 5; SPINOCEREBELLAR ATAXIA 5 (autosomal dominant) to Spinocerebellar ataxia 5, OMIM:600224; Spinocerebellar ataxia, autosomal recessive 14, OMIM:615386
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Classified gene: FANCM as Green List (high evidence)
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence for this gene to be rated Green.
Primary ovarian insufficiency v1.43 FANCM Ivone Leong Gene: fancm has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.42 FANCM Ivone Leong Phenotypes for gene: FANCM were changed from Premature ovarian failure to ?Premature ovarian failure 15, OMIM:618096
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Tag watchlist tag was added to gene: EIF4ENIF1.
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Classified gene: EIF4ENIF1 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Added comment: Comment on list classification: Gene is not assiciated with a phenotype in OMIM or Gene2Phenotype. Gene will be kept as Amber until more evidence is available.
Primary ovarian insufficiency v1.41 EIF4ENIF1 Ivone Leong Gene: eif4enif1 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.40 EIF4ENIF1 Ivone Leong Deleted their review
Primary ovarian insufficiency v1.40 NANOS3 Ivone Leong Added comment: Comment on publications: Added new publication.
Primary ovarian insufficiency v1.40 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668; 25054146; 28076512
Primary ovarian insufficiency v1.39 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668; 25054146
Primary ovarian insufficiency v1.38 NANOS3 Ivone Leong Publications for gene: NANOS3 were set to 24091668
Primary ovarian insufficiency v1.37 MSH4 Ivone Leong Classified gene: MSH4 as Green List (high evidence)
Primary ovarian insufficiency v1.37 MSH4 Ivone Leong Gene: msh4 has been classified as Green List (High Evidence).
Primary ovarian insufficiency v1.36 MSH4 Ivone Leong gene: MSH4 was added
gene: MSH4 was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: MSH4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MSH4 were set to 28541421; 10809667; 33437391; 33448284
Phenotypes for gene: MSH4 were set to Primary ovarian insufficiency; primary ovarian failure, MONDO:0005387; non-obstructive azoospermia
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:28541421. 1 family affected by POI (NM_002440.3: c.2355+1G>A). Parents are heterozygous for the variant and 2 daughters (3 daughters and 2 sons in total) are homozygous for variant and diagnosed with POI. Variant causes exon skipping.

PMID:10809667. Msh4 knockout mouse model. Mice were viable except for low testicular weight. -/- males were infertile. -/- females, most oocytes were lost from ovaries shortly after birth.

PMID:33437391. Han Chinese patient with non-obstructive azoospermia (NOA) from a consanguineous family. Patient had homozygous variant in MSH4 (c.1552C>T:p.Q518X) and parents are heterozygous carriers.

PMID:33448284. Consanguineous family with 14 children. 2 women have been diagnosed with POI, 3 men with NOA and 1 man with oligozoospermia. All affected individuals are homozygous for variant in MSH4 (S754L).

There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Sources: Literature
Clefting v2.30 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to 20004764
Intellectual disability v3.1080 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to
Severe microcephaly v2.155 TRAPPC9 Arina Puzriakova Publications for gene: TRAPPC9 were set to 22549410; 20004765; 20004763; 30853973
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC9.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Classified gene: TRAPPC9 as Amber List (moderate evidence)
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 32 affected individuals from 9 families have been reported worldwide. Variable degrees of microcephaly are reported in almost all subjects and there are enough unrelated cases with sufficiently severe microcephaly to include as diagnostic-grade on this panel.
Severe microcephaly v2.154 TRAPPC9 Arina Puzriakova Gene: trappc9 has been classified as Amber List (Moderate Evidence).
Adult onset neurodegenerative disorder v2.174 FIG4 Ian Berry reviewed gene: FIG4: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 19118816; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ectodermal dysplasia v1.19 SNRPE Gavin Ryan reviewed gene: SNRPE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Severe microcephaly v2.153 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, MIM# 613192 to Mental retardation, autosomal recessive 13, OMIM:613192
Intellectual disability v3.1079 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from Mental retardation, autosomal recessive 13, 613192; Mental Retardation, Recessive; MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 13 (MRT13) to Mental retardation, autosomal recessive 13, OMIM:613192
Clefting v2.29 TRAPPC9 Arina Puzriakova Phenotypes for gene: TRAPPC9 were changed from MENTAL RETARDATION, AUTOSOMAL RECESSIVE 13; MRT13 to Mental retardation, autosomal recessive 13, OMIM:613192
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRAPPC6B.
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Intellectual disability v3.1078 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Early onset or syndromic epilepsy v2.354 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Early onset or syndromic epilepsy v2.353 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838; DOI 10.1055/s-0039-1693664
Intellectual disability v3.1077 TRAPPC6B Arina Puzriakova Publications for gene: TRAPPC6B were set to 28626029; 28397838
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Classified gene: TRAPPC6B as Amber List (moderate evidence)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 9 individuals from 5 families have been reported, all harbouring loss-of-function variants in homozygous state. Progressive microcephaly of relevant severity to this panel (HC ≤ -3 SD) was reported in 7/7 cases (clinical details limited for one family).

TRAPPC6B is associated with a relevant phenotype in OMIM (MIM# 617862)
Severe microcephaly v2.151 TRAPPC6B Arina Puzriakova Gene: trappc6b has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Tag watchlist tag was added to gene: MSH5.
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Classified gene: MSH5 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.35 MSH5 Ivone Leong Gene: msh5 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.34 MSH5 Ivone Leong Phenotypes for gene: MSH5 were changed from ?Premature ovarian failure 13 617442 to ?Premature ovarian failure 13, OMIM:617442
Primary ovarian insufficiency v1.33 MSH5 Ivone Leong Publications for gene: MSH5 were set to 28175301
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Classified gene: EIF4ENIF1 as Green List (high evidence)
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is 3 unrelated cases associated with this gene, therefore there is enough evidence to support a gene-disease association.
Primary ovarian insufficiency v1.32 EIF4ENIF1 Ivone Leong Gene: eif4enif1 has been classified as Green List (High Evidence).
Clefting v2.28 SEPT9 Zornitza Stark reviewed gene: SEPT9: Rating: AMBER; Mode of pathogenicity: None; Publications: 18492087; Phenotypes: Amyotrophy, hereditary neuralgic, MIM# 162100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh changed review comment from: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300; to: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300

Comment from Zornitza Stark for FXN:
Primarily an ataxia, and also commonly caused by a GAA trinucleotide repeat expansion in intron 1 of the FXN gene.
Primary ovarian insufficiency v1.31 EIF4ENIF1 Ivone Leong Publications for gene: EIF4ENIF1 were set to 23902945
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Classified gene: DIAPH2 as Red List (low evidence)
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert review.
Primary ovarian insufficiency v1.30 DIAPH2 Ivone Leong Gene: diaph2 has been classified as Red List (Low Evidence).
Primary ovarian insufficiency v1.29 DIAPH2 Ivone Leong Phenotypes for gene: DIAPH2 were changed from Premature ovarian failure,300511 to ?Premature ovarian failure 2A, OMIM:300511
Primary ovarian insufficiency v1.28 DIAPH2 Ivone Leong Publications for gene: DIAPH2 were set to 9497258
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Classified gene: HSF2BP as Red List (low evidence)
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support gene-disease association. This gene has been given a Red rating.
Primary ovarian insufficiency v1.27 HSF2BP Ivone Leong Gene: hsf2bp has been classified as Red List (Low Evidence).
Primary ovarian insufficiency v1.26 HSF2BP Ivone Leong Phenotypes for gene: HSF2BP were changed from Premature ovarian failure, OMIM#619245 to Premature ovarian failure 19, OMIM:619245
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Classified gene: C14orf39 as Amber List (moderate evidence)
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.25 C14orf39 Ivone Leong Gene: c14orf39 has been classified as Amber List (Moderate Evidence).
Primary ovarian insufficiency v1.24 C14orf39 Ivone Leong Phenotypes for gene: C14orf39 were changed from Premature ovarian insufficiency to ?Premature ovarian failure 18, OMIM:619203
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Classified gene: BUB1B as Amber List (moderate evidence)
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary ovarian insufficiency v1.23 BUB1B Ivone Leong Gene: bub1b has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Classified gene: PKD2 as Red List (low evidence)
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert reviews. This gene is also Red on the Thoracic aortic aneurysm and dissection (Version 1.7) panel.
Thoracic aortic aneurysm or dissection v1.114 PKD2 Ivone Leong Gene: pkd2 has been classified as Red List (Low Evidence).
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Classified gene: PKD1 as Red List (low evidence)
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Added comment: Comment on list classification: Demoted from Amber to Red based on expert reviews. This gene is also Red on the Thoracic aortic aneurysm and dissection (Version 1.7) panel.
Thoracic aortic aneurysm or dissection v1.113 PKD1 Ivone Leong Gene: pkd1 has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.94 ACER3 Ivone Leong Classified gene: ACER3 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.94 ACER3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
White matter disorders and cerebral calcification - narrow panel v1.94 ACER3 Ivone Leong Gene: acer3 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.93 ACER3 Ivone Leong Tag watchlist tag was added to gene: ACER3.
White matter disorders and cerebral calcification - narrow panel v1.93 ACER3 Ivone Leong Phenotypes for gene: ACER3 were changed from Leukodystrophy to ?Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh Tag Q2_21_rating tag was added to STR: FXN_GAA.
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh edited their review of STR: FXN_GAA: Added comment: The FXN expansion has a well recognized association with Friedreich ataxia OMIM:229300; Changed rating: GREEN; Changed publications to: 10399865, 8596916, 33670433
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh Classified STR: FXN_GAA as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.105 FXN_GAA Sarah Leigh Str: fxn_gaa has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.104 FXN_GAA Sarah Leigh Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.175
Childhood onset dystonia, chorea or related movement disorder v1.104 FXN_GAA Sarah Leigh STR: FXN_GAA was added
STR: FXN_GAA was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list,Expert Review Green
STR tags were added to STR: FXN_GAA.
Mode of inheritance for STR: FXN_GAA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for STR: FXN_GAA were set to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Severe microcephaly v2.150 PTPN23 Eleanor Williams changed review comment from: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly confirmed in 2 cases, a further 3 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.; to: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly (OFC > 3 SD below mean) confirmed in 1 case, a further 4 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.
Severe microcephaly v2.150 PTPN23 Eleanor Williams reviewed gene: PTPN23: Rating: AMBER; Mode of pathogenicity: None; Publications: 31395947, 29899372, 29090338, 27848944, 25558065; Phenotypes: Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, OMIM:618890; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.175 MTCL1 Arina Puzriakova Classified gene: MTCL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.175 MTCL1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - two unrelated individuals with different LoF variants in this gene. Ataxia with cerebellar atrophy was the predominant presentation in both cases (PMIDs: 30548255; 32961396). Knockout animal model recapitulates human phenotypes and provides functional support.
Ataxia and cerebellar anomalies - narrow panel v2.175 MTCL1 Arina Puzriakova Gene: mtcl1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.174 MTCL1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MTCL1.
Ataxia and cerebellar anomalies - narrow panel v2.174 MTCL1 Arina Puzriakova reviewed gene: MTCL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30548255, 32961396; Phenotypes: Cerebellar ataxia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ehlers Danlos syndrome with a likely monogenic cause v2.57 LTBP2 Andžela Lazdāne changed review comment from: Based on the literature several individuals were suspected of marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature; to: Based on the literature several individuals were suspected of Marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature
Ehlers Danlos syndrome with a likely monogenic cause v2.57 LTBP2 Andžela Lazdāne gene: LTBP2 was added
gene: LTBP2 was added to Ehlers Danlos syndromes. Sources: Literature
Mode of inheritance for gene: LTBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP2 were set to PMID: 20179738; PMID: 20617341
Phenotypes for gene: LTBP2 were set to Inreased arm-span-to-height ratio; Decreased upper-to-lower body ratio; Lens dislocation; Pectus excavatum; Myopia
Penetrance for gene: LTBP2 were set to Complete
Review for gene: LTBP2 was set to AMBER
Added comment: Based on the literature several individuals were suspected of marfan syndrome. Not only due to eye changes, but also due to stature, increased arm span and decreased upper-to-lower body ratio.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.92 KIAA1161 Ivone Leong Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047; 33958240, 30649222
White matter disorders and cerebral calcification - narrow panel v1.91 KIAA1161 Ivone Leong Publications for gene: KIAA1161 were set to 30656188; 30649222; 30460687; 29910000; 31951047
White matter disorders and cerebral calcification - narrow panel v1.90 ZFYVE26 Ivone Leong Classified gene: ZFYVE26 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.90 ZFYVE26 Ivone Leong Added comment: Comment on list classification: Promoted Red to Amber. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene is Green on the White matter disorders - adult onset (Version 1.10) panel. The age of onset can be in childhood. This gene should be Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.90 ZFYVE26 Ivone Leong Gene: zfyve26 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.89 ZFYVE26 Ivone Leong Tag Q2_21_rating tag was added to gene: ZFYVE26.
White matter disorders and cerebral calcification - narrow panel v1.89 KIAA1161 Ivone Leong Phenotypes for gene: KIAA1161 were changed from to Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM:618317
White matter disorders and cerebral calcification - narrow panel v1.88 KIAA1161 Ivone Leong commented on gene: KIAA1161
White matter disorders and cerebral calcification - narrow panel v1.88 KIAA1161 Ivone Leong Tag new-gene-name tag was added to gene: KIAA1161.
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Classified gene: SPEG as Green List (high evidence)
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as per my previous review.
Dilated Cardiomyopathy and conduction defects v1.70 SPEG Ivone Leong Gene: speg has been classified as Green List (High Evidence).
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong Tag Q2_21_rating was removed from gene: SPEG.
Dilated and arrhythmogenic cardiomyopathy v1.25 SPEG Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.42
Dilated and arrhythmogenic cardiomyopathy v1.25 SPEG Ivone Leong gene: SPEG was added
gene: SPEG was added to Dilated cardiomyopathy - adult and teen. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: SPEG.
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647; 33926407
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong Entity copied from Cardiomyopathies - including childhood onset v1.42
Dilated Cardiomyopathy and conduction defects v1.69 SPEG Ivone Leong gene: SPEG was added
gene: SPEG was added to Dilated Cardiomyopathy and conduction defects. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: SPEG.
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647; 33926407
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Tag Q2_21_rating tag was added to gene: SPEG.
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Classified gene: SPEG as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. DCM is are reported in some of the reported cases (>3 cases). This gene has enough evidence to support a gene-disease association. This gene should be Green at the next review.
Paediatric or syndromic cardiomyopathy v1.42 SPEG Ivone Leong Gene: speg has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.41 SPEG Ivone Leong Publications for gene: SPEG were set to 32925938; 33794647
Paediatric or syndromic cardiomyopathy v1.40 SPEG Ivone Leong Phenotypes for gene: SPEG were changed from Dilated cardiomyopathy; centronuclear myopathy to Dilated cardiomyopathy, MONDO:0005021; Centronuclear myopathy 5, OMIM:615959
Severe microcephaly v2.150 PPP1R15B Eleanor Williams changed review comment from: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.; to: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly (2 severe), but two have the same variant reported.
Severe microcephaly v2.150 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Severe microcephaly v2.150 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Early onset or syndromic epilepsy v2.352 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Intellectual disability v3.1076 MINPP1 Arina Puzriakova Entity copied from Ataxia and cerebellar anomalies - narrow panel v2.174
Intellectual disability v3.1076 MINPP1 Arina Puzriakova gene: MINPP1 was added
gene: MINPP1 was added to Intellectual disability. Sources: Literature,Expert Review Amber
Q2_21_rating tags were added to gene: MINPP1.
Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MINPP1 were set to 33257696; 33168985
Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - narrow panel v2.174 MINPP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MINPP1.
Ataxia and cerebellar anomalies - narrow panel v2.174 MINPP1 Arina Puzriakova Publications for gene: MINPP1 were set to 33257696
Ataxia and cerebellar anomalies - narrow panel v2.173 MINPP1 Arina Puzriakova Classified gene: MINPP1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.173 MINPP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green status at the next GMS panel update.

To date, at least 16 individuals from 10 unrelated families reported, all with different biallelic variants in MINPP1 (5 truncating, 6 missense). Main clinical characteristics included mild to severe PCH on brain MRI (16/16), moderate to severe DD/ID (16/16), microcephaly (14/16), and seizures (12/16). Supported by some functional data (PMIDs: 33257696; 33168985)
Ataxia and cerebellar anomalies - narrow panel v2.173 MINPP1 Arina Puzriakova Gene: minpp1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Tag Q2_21_rating tag was added to gene: CERS1.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh edited their review of gene: CERS1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least two missense variants reported in two unrelated cases, together with supportive functional evidence.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Classified gene: CERS1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.351 CERS1 Sarah Leigh Gene: cers1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.350 CERS1 Sarah Leigh Phenotypes for gene: CERS1 were changed from ?Epilepsy, progressive myoclonic, 8, 616230 to ?Epilepsy, progressive myoclonic, 8 OMIM:616230; progressive myoclonic epilepsy type 8 MONDO:0014545
Early onset or syndromic epilepsy v2.349 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Early onset or syndromic epilepsy v2.348 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074; 30800706; 21625621
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Added comment: Comment on publications: Previous publication entry:
26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C);26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.149 PPP1R15B Eleanor Williams Publications for gene: PPP1R15B were set to 26307080: In a Canadian sister and brother, born of second-cousin parents, with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination, and intellectual disability, Kernohan et al. (2015) identified homozygosity for a c.1972C-T mutation in PPP1R15B (R658C); 26159176: In a brother and sister from a consanguineous Algerian family with microcephaly, short stature, intellectual disability, and diabetes (MSSGM2, 616817), Abdulkarim et al. (2015) identified homozygosity for the R658C substitution.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Classified gene: PPP1R15B as Amber List (moderate evidence)
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. 3 unrelated cases with microcephaly, but two have the same variant reported.
Severe microcephaly v2.148 PPP1R15B Eleanor Williams Gene: ppp1r15b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.147 PPP1R15B Eleanor Williams changed review comment from: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (ethnicity not stated) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.; to: Associated with Microcephaly, short stature, and impaired glucose metabolism 2 #616817 in OMIM.

PubMed: 27640355 - Mohammad et al 2016 - report WES of 2 siblings who presented with cirrhosis and required liver transplantation at age 7 and 22 months. Compound heterozygous mutations in PPP1R15B were identified. Microcephaly was also noted in both siblings. One sibling at age 4 years had head circumference at the third percentile, the other had holoprosencephaly and head circumference was below the 3rd percentile for gestational age at birth. Compound het variants in PPP1R15B; c.63G>A (p.W21*), inherited from the father, and c.674delC (p.P225LfsX10), inherited from the mother.

PubMed: 26159176 - Abdulkarim et al 2015 - report a homozygous c.1972C>T, p.R658C variant in PPP1R15B in two siblings from a consanguineous family of Algerian origin with young-onset diabetes, microcephaly, and short stature. First sibling had adult cranial perimeter: 46 cm, −4.0 SD. The sister had a similar presentation but was not available for detailed evaluation.

PubMed: 26307080 - Kernohan et al 2015 - report a consanguineous family (enrolled in Canada) with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings and a homozygous c.1972G>A; p.R658C variant in PPP1R15B. First sibling had head circumference of 28.5 cm (−5.0 SD) at birth, second sibling had a head circumference of head circumference of 37 cm (−6 to −7 SD) at 15 months.
Severe microcephaly v2.147 PPP1R15B Eleanor Williams Phenotypes for gene: PPP1R15B were changed from Microcephaly, short stature, and impaired glucose metabolism 2, 616817; MSSGM2 to Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817
Severe microcephaly v2.146 PPP1R15B Eleanor Williams reviewed gene: PPP1R15B: Rating: AMBER; Mode of pathogenicity: None; Publications: 27640355, 26159176, 26307080; Phenotypes: Microcephaly, short stature, and impaired glucose metabolism 2, OMIM:616817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.347 CERS1 Sarah Leigh Publications for gene: CERS1 were set to 19243074
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Classified gene: NSF as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.346 NSF Sarah Leigh Gene: nsf has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1075 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v2.345 NSF Sarah Leigh reviewed gene: NSF: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Tag Q2_21_rating tag was added to gene: PMPCB.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene for Neurodegeneration in Early Childhood. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh edited their review of gene: PMPCB: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least five variants reported in three unrelated cases, together with supportive functional studies (PMID 29576218).; Changed rating: GREEN
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.345 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh Classified gene: PMPCB as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.172 PMPCB Sarah Leigh Gene: pmpcb has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.48 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Mitochondrial disorders v2.35 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Intellectual disability v3.1075 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Early onset or syndromic epilepsy v2.344 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Likely inborn error of metabolism v2.134 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Possible mitochondrial disorder - nuclear genes v1.42 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Ataxia and cerebellar anomalies - narrow panel v2.171 PMPCB Sarah Leigh Phenotypes for gene: PMPCB were changed from Multiple mitochondrial dysfunctions syndrome 6, MIM# 617954 to Multiple mitochondrial dysfunctions syndrome 6 OMIM:617954; multiple mitochondrial dysfunctions syndrome 6 MONDO:0054785
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh Tag Q2_21_rating tag was added to gene: GLRB.
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh edited their review of gene: GLRB: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in three unrelated cases.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh Classified gene: GLRB as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh Gene: glrb has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.47 GLRB Sarah Leigh Publications for gene: GLRB were set to 23238346; 11929858; 21391991
White matter disorders and cerebral calcification - narrow panel v1.88 ERCC5 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC5.
White matter disorders and cerebral calcification - narrow panel v1.88 ERCC5 Eleanor Williams Classified gene: ERCC5 as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.88 ERCC5 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green but with a recommendation for amber or red rating following GMS review. As Expert reviewer reports there is no specific white matter abnormalities/leukodystrphy reported in the cases to date.
White matter disorders and cerebral calcification - narrow panel v1.88 ERCC5 Eleanor Williams Gene: ercc5 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.87 ERCC5 Eleanor Williams Phenotypes for gene: ERCC5 were changed from Xeroderma pigmentosum, group G, 278780; Xeroderma pigmentosum, group G/Cockayne syndrome, 278780 to Cerebrooculofacioskeletal syndrome 3 OMIM:616570; Xeroderma pigmentosum, group G/Cockayne syndrome OMIM:278780
White matter disorders and cerebral calcification - narrow panel v1.86 ERCC5 Eleanor Williams Publications for gene: ERCC5 were set to
White matter disorders and cerebral calcification - narrow panel v1.85 ERCC5 Eleanor Williams reviewed gene: ERCC5: Rating: AMBER; Mode of pathogenicity: None; Publications: 8818951, 9096355, 24700531, 11228268, 8317483; Phenotypes: Cerebrooculofacioskeletal syndrome 3 OMIM:616570, Xeroderma pigmentosum, group G/Cockayne syndrome OMIM:278780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.46 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Paroxysmal central nervous system disorders v1.12 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Paroxysmal central nervous system disorders v1.11 GLRB Sarah Leigh Publications for gene: GLRB were set to 23238346; 11929858; 21391991
Childhood onset dystonia, chorea or related movement disorder v1.102 GLRB Sarah Leigh Publications for gene: GLRB were set to 21391991; 23238346; 11929858
Childhood onset dystonia, chorea or related movement disorder v1.101 GLRB Sarah Leigh Phenotypes for gene: GLRB were changed from Hyperekplexia 2, 614619 to Hyperekplexia 2 OMIM:614619; hyperekplexia 2 MONDO:0013828
Likely inborn error of metabolism v2.133 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Intellectual disability v3.1074 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - narrow panel v2.170 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hypertrophic cardiomyopathy v2.21 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia v1.221 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - narrow panel v2.169 FXN_GAA Sarah Leigh Phenotypes for STR: FXN_GAA were changed from Friedreich ataxia 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia with onset in adulthood v2.45 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia, 229300; Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Likely inborn error of metabolism v2.132 FXN Sarah Leigh Added comment: Comment on phenotypes: Friedreich ataxia, 229300;Friedreich ataxia with retained reflexes, 229300;Hereditary ataxia;Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Likely inborn error of metabolism v2.132 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300; Friedreich ataxia with retained reflexes, 229300; Hereditary ataxia; Defective Fe-S/lipoic acid biosynthesis (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary neuropathy v1.385 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Hereditary Neuropathies; Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Adult onset hereditary spastic paraplegia v1.20 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Childhood onset hereditary spastic paraplegia v2.33 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Hereditary ataxia v1.220 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
Ataxia and cerebellar anomalies - narrow panel v2.168 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreichataxia,229300Friedreichataxiawithretainedreflexes,229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
White matter disorders and cerebral calcification - narrow panel v1.85 ERCC4 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC4.
White matter disorders and cerebral calcification - narrow panel v1.85 ERCC4 Eleanor Williams Phenotypes for gene: ERCC4 were changed from Xeroderma pigmentosum, type F/Cockayne syndrome, 278760; Xeroderma pigmentosum, group F, 278760 to Xeroderma pigmentosum, type F/Cockayne syndrome, OMIM:278760; XFE progeroid syndrome, OMIM:610965
White matter disorders and cerebral calcification - narrow panel v1.84 ERCC4 Eleanor Williams Publications for gene: ERCC4 were set to
White matter disorders and cerebral calcification - narrow panel v1.83 ERCC4 Eleanor Williams Classified gene: ERCC4 as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.83 ERCC4 Eleanor Williams Added comment: Comment on list classification: Leaving as green for now, but with a recommendation for an amber rating following GMS review. One case where white matter lesions are reported as part of a broader phenotype and 2 cases with milder phenotypes related to white matter.
White matter disorders and cerebral calcification - narrow panel v1.83 ERCC4 Eleanor Williams Gene: ercc4 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.167 CAD Arina Puzriakova Publications for gene: CAD were set to 32820246
Ataxia and cerebellar anomalies - narrow panel v2.166 CAD Arina Puzriakova Classified gene: CAD as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.166 CAD Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There are sufficient cases with ataxia and biallelic variants in this gene to rate as Green on this panel, but note that not all cases present this feature (ataxia reported in 8/18 individuals to date - PMID: 32820246)
Ataxia and cerebellar anomalies - narrow panel v2.166 CAD Arina Puzriakova Gene: cad has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.82 ERCC4 Eleanor Williams reviewed gene: ERCC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 23623389, 29105242; Phenotypes: Xeroderma pigmentosum, type F/Cockayne syndrome, OMIM:278760, XFE progeroid syndrome, OMIM:610965; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.165 CAD Arina Puzriakova Tag Q2_21_rating tag was added to gene: CAD.
White matter disorders and cerebral calcification - narrow panel v1.82 ERCC3 Eleanor Williams Phenotypes for gene: ERCC3 were changed from Xeroderma pigmentosum, group B, 610651; Trichothiodystrophy, 601675 to Trichothiodystrophy 2, photosensitive, OMIM:616390; Xeroderma pigmentosum, group B, OMIM:610651
White matter disorders and cerebral calcification - narrow panel v1.81 ERCC3 Eleanor Williams Publications for gene: ERCC3 were set to
White matter disorders and cerebral calcification - narrow panel v1.80 ERCC3 Eleanor Williams Classified gene: ERCC3 as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.80 ERCC3 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green, but with recommendation for red rating following GMS review. No evidence that variants in this gene is associated with white matter disease.
White matter disorders and cerebral calcification - narrow panel v1.80 ERCC3 Eleanor Williams Gene: ercc3 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.79 ERCC3 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC3.
White matter disorders and cerebral calcification - narrow panel v1.79 ERCC3 Eleanor Williams reviewed gene: ERCC3: Rating: RED; Mode of pathogenicity: None; Publications: 9012405, 2167179, 16947863, 8408834, 8304337; Phenotypes: Trichothiodystrophy 2, photosensitive, OMIM:616390, Xeroderma pigmentosum, group B, OMIM:610651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.165 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50; OMIM # 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.343 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Intellectual disability v3.1073 CAD Arina Puzriakova Phenotypes for gene: CAD were changed from Epileptic encephalopathy, early infantile, 50 - MIM 616457 to Developmental and epileptic encephalopathy 50, OMIM:616457
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Intellectual disability v3.1072 TMEM222 Sarah Leigh Tag Q2_21_rating tag was added to gene: TMEM222.
Intellectual disability v3.1072 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Moderate to severe intellectual disability was evident in all families.; Changed rating: GREEN
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh edited their review of gene: TMEM222: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (TMEM222 not listed on OMIM 11/05/2021). At least ten variants reported in at least nine unrelated families. Seizures were evident in six individuals from six families.; Changed rating: GREEN
Intellectual disability v3.1072 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Intellectual disability v3.1072 TMEM222 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Intellectual disability v3.1072 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Classified gene: TMEM222 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Early onset or syndromic epilepsy v2.342 TMEM222 Sarah Leigh Gene: tmem222 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.341 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Intellectual disability v3.1071 TMEM222 Sarah Leigh Publications for gene: TMEM222 were set to 33824500
Pulmonary arterial hypertension v2.13 KDR Stefan Graf reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33320693, 31980491; Phenotypes: pulmonary arterial hypertension, significantly reduced diffusing coefficient for carbon monoxide, late disease onset; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Parkinson Disease and Complex Parkinsonism v1.70 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from ?{Parkinson disease 5, susceptibility to} to {?Parkinson disease 5, susceptibility to}, OMIM:613643
Adult onset hereditary spastic paraplegia v1.19 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491, AR to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Adult onset hereditary spastic paraplegia v1.18 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 29735986; 28007905; 23359680
Adult onset hereditary spastic paraplegia v1.17 UCHL1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: UCHL1.
Adult onset hereditary spastic paraplegia v1.17 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.44 UCHL1 Arina Puzriakova changed review comment from: Tagged for GMS expert review (Q2_21) to seek opinion on whether this gene rating needs to be changed. Ten individuals from four families have been reported with a childhood-onset neurodegenerative disorder and different biallelic variants in this gene. Age of onset ranges from 2 to 10 years, however visual loss appears to be one of the first presenting features in most cases and ataxia becomes apparent later in the clinical course (PMIDs: 23359680; 28007905; 29735986; 32656641); to: Tagged for GMS expert review (Q2_21) to seek opinion on whether this gene rating needs to be changed. Ten individuals from four families have been reported with a childhood-onset neurodegenerative disorder and different biallelic variants in this gene. Age of onset ranges from 2 to 10 years, however visual loss appears to be one of the first presenting features in most cases and ataxia becomes apparent later in the clinical course (PMIDs: 23359680; 28007905; 29735986; 32656641). Inclusion may be justified to ensure that edge cases may be identified.
Childhood onset hereditary spastic paraplegia v2.32 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491, AR to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Childhood onset hereditary spastic paraplegia v2.31 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 29735986; 28007905; 23359680
Hereditary ataxia with onset in adulthood v2.44 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy; Autosomal recessive spastic paraplegia 79, 615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary ataxia with onset in adulthood v2.43 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to 23359680
Hereditary ataxia with onset in adulthood v2.42 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary ataxia with onset in adulthood v2.42 UCHL1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: UCHL1.
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Classified gene: UCHL1 as Green List (high evidence)
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Green - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with different biallelic variants, supported by functional and animal model data.
Hereditary ataxia v1.219 UCHL1 Arina Puzriakova Gene: uchl1 has been classified as Green List (High Evidence).
Hereditary ataxia v1.218 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Hereditary ataxia v1.217 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to PMID: 23359680
Hereditary ataxia v1.216 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641, 11555633, 33159930; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.164 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Early onset ataxia and optic neuropathy to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Ataxia and cerebellar anomalies - narrow panel v2.163 UCHL1 Arina Puzriakova Publications for gene: UCHL1 were set to PMID: 23359680
Ataxia and cerebellar anomalies - narrow panel v2.162 UCHL1 Arina Puzriakova Classified gene: UCHL1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.162 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with biallelic variants, supported by functional and animal model data.
Ataxia and cerebellar anomalies - narrow panel v2.162 UCHL1 Arina Puzriakova Gene: uchl1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.161 UCHL1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: UCHL1.
Ataxia and cerebellar anomalies - narrow panel v2.161 UCHL1 Arina Puzriakova reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 28007905, 29735986, 32656641, 11555633, 33159930; Phenotypes: Spastic paraplegia 79, autosomal recessive, OMIM:615491; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1070 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Intellectual disability v3.1070 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intellectual disability. Sources: Literature,Expert Review Red
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Familial pulmonary fibrosis v1.16 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Familial pulmonary fibrosis v1.16 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Familial pulmonary fibrosis. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Intracerebral calcification disorders v1.28 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Intracerebral calcification disorders v1.28 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Intracerebral calcification disorders. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
Cholestasis v1.84 FARSA Ivone Leong Entity copied from White matter disorders and cerebral calcification - narrow panel v1.79
Cholestasis v1.84 FARSA Ivone Leong gene: FARSA was added
gene: FARSA was added to Cholestasis. Sources: Expert Review Red,Literature
Mode of inheritance for gene: FARSA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARSA were set to 31355908
Phenotypes for gene: FARSA were set to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - narrow panel v1.79 FARSA Ivone Leong Classified gene: FARSA as Red List (low evidence)
White matter disorders and cerebral calcification - narrow panel v1.79 FARSA Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is currently not enough evidence to support a gene-disease association. This gene has been given a Red rating.
White matter disorders and cerebral calcification - narrow panel v1.79 FARSA Ivone Leong Gene: farsa has been classified as Red List (Low Evidence).
White matter disorders and cerebral calcification - narrow panel v1.78 FARSA Ivone Leong Phenotypes for gene: FARSA were changed from Rajab interstitial lung disease with brain calcifications 2, OMIM:619013 to ?Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - narrow panel v1.77 FARSA Ivone Leong Phenotypes for gene: FARSA were changed from Rajab interstitial lung disease with brain calcifications 2, MIM# 619013 to Rajab interstitial lung disease with brain calcifications 2, OMIM:619013
White matter disorders and cerebral calcification - narrow panel v1.76 ZFYVE26 Ivone Leong Phenotypes for gene: ZFYVE26 were changed from Spastic paraplegia 15, autosomal recessive, MIM#270700 to Spastic paraplegia 15, autosomal recessive, OMIM:270700
White matter disorders and cerebral calcification - narrow panel v1.75 ZFYVE26 Ivone Leong Publications for gene: ZFYVE26 were set to
White matter disorders and cerebral calcification - narrow panel v1.74 WARS2 Ivone Leong Tag Q2_21_rating tag was added to gene: WARS2.
White matter disorders and cerebral calcification - narrow panel v1.74 WARS2 Ivone Leong Classified gene: WARS2 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.74 WARS2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.74 WARS2 Ivone Leong Gene: wars2 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.73 WARS2 Ivone Leong Phenotypes for gene: WARS2 were changed from Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, MIM# 617710 to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, OMIM:617710
Lipodystrophy - childhood onset v2.15 OTULIN Ivone Leong Classified gene: OTULIN as Amber List (moderate evidence)
Lipodystrophy - childhood onset v2.15 OTULIN Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Lipodystrophy - childhood onset v2.15 OTULIN Ivone Leong Gene: otulin has been classified as Amber List (Moderate Evidence).
Lipodystrophy - childhood onset v2.14 OTULIN Ivone Leong Tag Q2_21_rating tag was added to gene: OTULIN.
Lipodystrophy - childhood onset v2.14 KCNJ6 Ivone Leong Classified gene: KCNJ6 as Amber List (moderate evidence)
Lipodystrophy - childhood onset v2.14 KCNJ6 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Lipodystrophy - childhood onset v2.14 KCNJ6 Ivone Leong Gene: kcnj6 has been classified as Amber List (Moderate Evidence).
Lipodystrophy - childhood onset v2.13 KCNJ6 Ivone Leong Tag Q2_21_rating tag was added to gene: KCNJ6.
Lipodystrophy - childhood onset v2.13 FBN1 Ivone Leong Classified gene: FBN1 as Amber List (moderate evidence)
Lipodystrophy - childhood onset v2.13 FBN1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Lipodystrophy - childhood onset v2.13 FBN1 Ivone Leong Gene: fbn1 has been classified as Amber List (Moderate Evidence).
Lipodystrophy - childhood onset v2.12 FBN1 Ivone Leong Tag Q2_21_rating tag was added to gene: FBN1.
Intellectual disability v3.1069 CAPN15 Zornitza Stark gene: CAPN15 was added
gene: CAPN15 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CAPN15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN15 were set to 33410501; 32885237
Phenotypes for gene: CAPN15 were set to Oculogastrointestinal neurodevelopmental syndrome, MIM# 619318
Review for gene: CAPN15 was set to GREEN
gene: CAPN15 was marked as current diagnostic
Added comment: 5 families reported, including DD/ID in 3. Profound in one family with bi-allelic LoF variant, PMID 33410501.
Sources: Literature
Intellectual disability v3.1069 CHD5 Zornitza Stark gene: CHD5 was added
gene: CHD5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CHD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD5 were set to 33944996
Phenotypes for gene: CHD5 were set to Intellectual disability; Epilepsy
Review for gene: CHD5 was set to GREEN
gene: CHD5 was marked as current diagnostic
Added comment: 16 unrelated individuals reported with language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%).
Sources: Literature
Intellectual disability v3.1069 FBXO31 Zornitza Stark edited their review of gene: FBXO31: Added comment: PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.

AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.; Changed rating: GREEN; Changed publications to: 24623383, 33675180, 32989326
Paediatric or syndromic cardiomyopathy v1.39 SPEG Zornitza Stark gene: SPEG was added
gene: SPEG was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: SPEG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEG were set to 32925938; 33794647
Phenotypes for gene: SPEG were set to Dilated cardiomyopathy; centronuclear myopathy
Review for gene: SPEG was set to GREEN
Added comment: Reports of early onset isolated DCM, as well as cardiomyopathy in the context of skeletal myopathy.
Sources: Literature
Proteinuric renal disease v2.50 RCAN1 Zornitza Stark gene: RCAN1 was added
gene: RCAN1 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: RCAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RCAN1 were set to 33863784
Phenotypes for gene: RCAN1 were set to FSGS; proteinuria
Review for gene: RCAN1 was set to AMBER
Added comment: Two families reported, some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 ZNFX1 Zornitza Stark reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33872655, 33876776; Phenotypes: Multisystem inflammation, susceptibility to viral infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 STXBP3 Zornitza Stark reviewed gene: STXBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33891011; Phenotypes: Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss, Immune Dysregulation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v2.97 NEPRO Zornitza Stark gene: NEPRO was added
gene: NEPRO was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant. PMID 31250547: 1 family with homozygous novel missense All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.72 LSM7 Zornitza Stark gene: LSM7 was added
gene: LSM7 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to https://doi.org/10.1016/j.xhgg.2021.100034
Phenotypes for gene: LSM7 were set to Leukodystrophy; fetal death
Review for gene: LSM7 was set to RED
Added comment: Homozygous variant (p.Asp41Asn) identified in a child with leukodystrophy and a homozygous variant (p.Arg69Pro) identified in an individual that died in utero. In vitro and in vivo (zebrafish) assays supporting pathogenicity of the 2 variants.
Sources: Literature
Intellectual disability v3.1069 PTPN4 Zornitza Stark gene: PTPN4 was added
gene: PTPN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Phenotypes for gene: PTPN4 were set to Intellectual disability
Review for gene: PTPN4 was set to GREEN
gene: PTPN4 was marked as current diagnostic
Added comment: >3 unrelated probands and supportive mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.72 POLR3K Zornitza Stark gene: POLR3K was added
gene: POLR3K was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Hypomyelinating leukodystrophy-21, MIM#619310
Review for gene: POLR3K was set to AMBER
Added comment: Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes.

Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Literature
Congenital muscular dystrophy v2.8 JAG2 Zornitza Stark gene: JAG2 was added
gene: JAG2 was added to Congenital muscular dystrophy. Sources: Literature
Mode of inheritance for gene: JAG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAG2 were set to 33861953
Phenotypes for gene: JAG2 were set to muscular dystrophy
Review for gene: JAG2 was set to GREEN
gene: JAG2 was marked as current diagnostic
Added comment: Whole-exome sequencing identified 13 families with rare homozygous or compound heterozygous JAG2 variants. Bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy.
Sources: Literature
Intellectual disability v3.1069 ANKRD17 Zornitza Stark gene: ANKRD17 was added
gene: ANKRD17 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ANKRD17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD17 were set to 33909992
Phenotypes for gene: ANKRD17 were set to Intellectual disability, speech delay, and dysmorphism
Review for gene: ANKRD17 was set to GREEN
gene: ANKRD17 was marked as current diagnostic
Added comment: 34 predominantly LoF variants reported - 29 de novo, 1 inherited from an affected parent, 1 inherited from a suspected mosaic parent. Main phenotypes were dev delay/ID, motor delay, and speech delay.
Sources: Literature
Intellectual disability v3.1069 SIN3B Zornitza Stark gene: SIN3B was added
gene: SIN3B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIN3B were set to 33811806
Phenotypes for gene: SIN3B were set to Syndromic intellectual disability
Review for gene: SIN3B was set to GREEN
gene: SIN3B was marked as current diagnostic
Added comment: PMID: 33811806
- 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs)
- syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth.
Sources: Literature
Intellectual disability v3.1069 DPYSL5 Zornitza Stark gene: DPYSL5 was added
gene: DPYSL5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL5 were set to 33894126
Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
Review for gene: DPYSL5 was set to GREEN
gene: DPYSL5 was marked as current diagnostic
Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.100 VPS41 Zornitza Stark edited their review of gene: VPS41: Added comment: PMID 33764426: Additional 9 individuals from 5 unrelated families reported.; Changed rating: GREEN; Changed publications to: 32808683, 33764426; Set current diagnostic: yes
Renal ciliopathies v1.41 XPNPEP3 Zornitza Stark reviewed gene: XPNPEP3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32660933, 20179356; Phenotypes: Nephronophthisis-like nephropathy 1, OMIM #613159; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ehlers Danlos syndrome with a likely monogenic cause v2.57 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Set current diagnostic: yes
Ehlers Danlos syndrome with a likely monogenic cause v2.57 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Added comment: PMID 33807164: third unrelated family reported, single affected individual with bi-alllelic LoF variant, cutis laxa and multiple herniations.; Changed rating: GREEN; Changed publications to: 32006683, 31792352, 33807164
White matter disorders and cerebral calcification - narrow panel v1.72 LIG3 Zornitza Stark gene: LIG3 was added
gene: LIG3 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG3 were set to 33855352
Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Review for gene: LIG3 was set to GREEN
Added comment: Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Sources: Literature
Proteinuric renal disease v2.50 PRDM15 Zornitza Stark gene: PRDM15 was added
gene: PRDM15 was added to Proteinuric renal disease. Sources: Literature
Mode of inheritance for gene: PRDM15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM15 were set to 31950080
Phenotypes for gene: PRDM15 were set to Steroid resistant nephrotic syndrome; Holoprosencephaly
Review for gene: PRDM15 was set to AMBER
Added comment: Four consanguineous families reported with same homozygous variant, C844Y, shown to be LoF. Syndromic SRNS including HPE, brain malformations, polydactyly, congenital heart disease. Mouse model, extensive functional data focused on the brain phenotype. Two additional homozygous missense identified with isolated SRNS.
Sources: Literature
Rare anaemia v1.21 SLC19A1 Zornitza Stark gene: SLC19A1 was added
gene: SLC19A1 was added to Rare anaemia. Sources: Literature
Mode of inheritance for gene: SLC19A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A1 were set to 32276275
Phenotypes for gene: SLC19A1 were set to Megaloblastic anemia, folate-responsive, MIM# 601775
Review for gene: SLC19A1 was set to RED
Added comment: Single individual reported with in-frame deletion, some functional data.
Sources: Literature
Monogenic hearing loss v2.162 GREB1L Zornitza Stark gene: GREB1L was added
gene: GREB1L was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to 29955957; 32585897
Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80, MIM# 619274
Review for gene: GREB1L was set to GREEN
gene: GREB1L was marked as current diagnostic
Added comment: DFNA80 is characterized by nonsyndromic congenital deafness associated with absent or malformed cochleae and eighth cranial nerves.

Four unrelated families reported, no comment on a renal phenotype. Note variants in this gene are also associated with renal agenesis.
Sources: Literature
Intellectual disability v3.1069 EMC10 Zornitza Stark edited their review of gene: EMC10: Added comment: PMID 33531666: Additional 12 individuals from 7 Middle Eastern families reported. Same variant in all, suggestive of founder effect (but different to the previously reported family).; Changed rating: GREEN; Changed publications to: 32869858, 33531666; Changed phenotypes to: Neurodevelopmental disorder with dysmorphic facies and variable seizures, MIM# 619264
Early onset or syndromic epilepsy v2.340 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to AMBER
Added comment: Seizures have been reported in 7 individuals (from 6 families). Consider inclusion with amber/green rating. From the ID panel :

Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Intellectual disability v3.1069 TMEM222 Konstantinos Varvagiannis gene: TMEM222 was added
gene: TMEM222 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMEM222 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM222 were set to 33824500
Phenotypes for gene: TMEM222 were set to Motor delay; Delayed speech and language development; Intellectual disability; Generalized hypotonia; Broad-based gait; Abnormality of nervous system morphology; Seizures; Microcephaly; Behavioral abnormality
Penetrance for gene: TMEM222 were set to Complete
Review for gene: TMEM222 was set to GREEN
Added comment: Polla et al (2021 - PMID: 33824500) report 17 individuals from 9 unrelated families, with biallelic TMEM222 pathogenic variants.

The phenotype included motor, speech delay and moderate to severe ID (as universal features). Other manifestations included hypotonia (10/15), broad gait (5/12), seizures (7/17 - belonging to 6/9 families), MRI abnormalities (5/8). Variable behavioral abnormalities were observed (aggressive behavior, shy character, stereotypic movements etc). Abnormal OFC was a feature in several with microcephaly in 7 subjects from 4 families (measurements not available for all 17). Nonspecific facial features were reported in 10/17. Rare features incl. body tremors, decreased lower extremity muscle mass or disorder of motor neurons.

TMEM222 variants were identified following exome sequencing. Previous investigations incl. metabolic studies, FMR1, chromosomes by standard karyotype or CMA, SMA, CMT1A were reported to be normal (available for some individuals).

TMEM222 variants missense and pLoF ones mostly found in homozygosity (7/9 families were consanguineous, compound heterozygosity reported in a single case from the 9 families). Sanger sequencing was used for confirmation of variants, parental carrier state as well as testing of sibs (unaffected sibs tested in 4 families).

Few individuals had additional genetic findings in other genes, though classified as VUS (3 families).

The gene encodes transmembrane protein 222 (208 residues) which however has unknown function. The protein comprises 3 transmembrane domains and a domain of unknown function. TMEMs are a group of transmembrane proteins spanning membranes with - most commonly - unclear function.

The authors measured expression by qPCR mRNA analysis, demonstrating highest fetal and adult brain expression (incl. parietal and occipital cortex). Expression levels from GTEx data also support a role in neurodevelopment.

Immunocytochemistry revealed highest levels in mature human iPSC-derived glutaminergic cortical neurons and moderate in immature ones. Additional studies supported that the gene is highly expressed in dendrites and might play a role in postsynaptic vesicles (colocalization with postsynaptic and early endosomal markers).

A previous study by Riazuddin et al (2017 - PMID: 27457812) had identified TMEM222 as a candidate gene for ID. This family (PKMR213) however appears to be included as family 2 in the aforementioned publication (same pedigree, variant and phenotype in both articles).

In OMIM there is currently no associated phenotype.

The gene is listed among the primary ID genes in SysID.

Please consider inclusion in the ID panel with green (or amber) rating. This gene may also be included in other panels e.g. for epilepsy, microcephaly, etc.
Sources: Literature
Fetal anomalies v1.649 CLTC Arina Puzriakova Publications for gene: CLTC were set to
Intellectual disability v3.1069 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability, Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Early onset or syndromic epilepsy v2.340 CLTC Arina Puzriakova Phenotypes for gene: CLTC were changed from Mental retardation, autosomal dominant 56, 617854; Autosomal dominant non-syndromic intellectual disability; Epilepsy and intellectual disability to Mental retardation, autosomal dominant 56, OMIM:617854
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Tag Q2_21_rating tag was added to gene: SASH3.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Classified gene: SASH3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 4 unrelated individuals presenting combined immunodeficiency in association with variants in this gene. Supported by functional data and animal model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.421 SASH3 Arina Puzriakova Gene: sash3 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.648 RFWD3 Rhiannon Mellis gene: RFWD3 was added
gene: RFWD3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RFWD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFWD3 were set to PMID: 2869192
Phenotypes for gene: RFWD3 were set to Fanconi anaemia
Review for gene: RFWD3 was set to RED
Added comment: Fetally relevant phenotype but only one case reported in literature so far so await further cases.

(In the single reported case, the child had: intrauterine growth retardation, duodenal atresia, radial ray malformations, bilateral absent thumbs, small midface, ventriculomegaly, hypoplastic left kidney, and polysplenia. Brain MRI showed rarefied periventricular white matter, narrow corpus callosum, abnormal pituitary, and Chiari malformation type I)
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.420 SASH3 Arina Puzriakova Publications for gene: SASH3 were set to
White matter disorders and cerebral calcification - narrow panel v1.72 ERCC2 Eleanor Williams Classified gene: ERCC2 as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.72 ERCC2 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green, but with a recommendation of an amber rating following GMS review. Only one case reported with a white matter abnormality.
White matter disorders and cerebral calcification - narrow panel v1.72 ERCC2 Eleanor Williams Gene: ercc2 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.71 ERCC2 Eleanor Williams Phenotypes for gene: ERCC2 were changed from Xeroderma pigmentosum, group D, 278730; Trichothiodystrophy, 601675 to Trichothiodystrophy 1, photosensitive, OMIM:601675
White matter disorders and cerebral calcification - narrow panel v1.70 ERCC2 Eleanor Williams Publications for gene: ERCC2 were set to MIM#601675
White matter disorders and cerebral calcification - narrow panel v1.69 ERCC2 Eleanor Williams Tag Q2_21_rating tag was added to gene: ERCC2.
White matter disorders and cerebral calcification - narrow panel v1.69 ERCC2 Eleanor Williams commented on gene: ERCC2
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 SPI1 Boaz Palterer gene: SPI1 was added
gene: SPI1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SPI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPI1 were set to 33951726
Phenotypes for gene: SPI1 were set to agammaglobulinemia
Penetrance for gene: SPI1 were set to unknown
Review for gene: SPI1 was set to GREEN
Added comment: Carole le Coz et al. described 6 unrelated patients with agammaglobulinemia harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1.
The phenotype was functionally replicated by transfection of mutant PU.1
(https://rupress.org/jem/article-abstract/218/7/e20201750/212070/Constrained-chromatin-accessibility-in-PU-1?redirectedFrom=fulltext)
Sources: Literature
Intellectual disability v3.1068 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF 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 v3.1067 UBTF Arina Puzriakova Publications for gene: UBTF were set to 26350204; 28777933
Childhood onset dystonia, chorea or related movement disorder v1.100 UBTF Arina Puzriakova Classified gene: UBTF as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.100 UBTF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green status at the next GMS panel update
Childhood onset dystonia, chorea or related movement disorder v1.100 UBTF Arina Puzriakova Gene: ubtf has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.99 UBTF Arina Puzriakova Publications for gene: UBTF were set to 28777933; 29300972
Childhood onset dystonia, chorea or related movement disorder v1.98 UBTF Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBTF.
Childhood onset dystonia, chorea or related movement disorder v1.98 UBTF Arina Puzriakova edited their review of gene: UBTF: 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
Childhood onset dystonia, chorea or related movement disorder v1.98 UBTF Arina Puzriakova reviewed gene: UBTF: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777933, 29300972, 30517966, 31931739, 33026538; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ataxia and cerebellar anomalies - narrow panel v2.161 UBTF Arina Puzriakova Publications for gene: UBTF were set to 29300972
Ataxia and cerebellar anomalies - narrow panel v2.160 UBTF Arina Puzriakova Mode of pathogenicity for gene: UBTF 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
Ataxia and cerebellar anomalies - narrow panel v2.159 UBTF Arina Puzriakova Classified gene: UBTF as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.159 UBTF Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 9 unrelated individuals from different ethnic backgrounds in literature with neuroregression including ataxia as an early feature due to a recurrent variant in this gene (PMIDs: 28777933; 29300972; 30517966; 31931739)
Ataxia and cerebellar anomalies - narrow panel v2.159 UBTF Arina Puzriakova Gene: ubtf has been classified as Amber List (Moderate Evidence).
Inherited white matter disorders v1.94 VPS11 Ivone Leong Classified gene: VPS11 as Green List (high evidence)
Inherited white matter disorders v1.94 VPS11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. This gene is also rated Green on the Genetic epilepsy syndromes (Version 2.339).

It is also on the White matter disorders and cerebral calcification - narrow panel (Version 1.69) as an Amber gene with a recommendation to be promoted to Green. The following review is present:

"Recurrent homozygous variant, p.Cys846Gly identified in more than 10 families of Ashkenazi Jewish descent. One other variant reported in another family in PMID 27473128. Functional data.
Zornitza Stark (Australian Genomics), 16 Sep 2020"

There is enough evidence to support a gene-disease association.
Inherited white matter disorders v1.94 VPS11 Ivone Leong Gene: vps11 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.93 VPS11 Ivone Leong Phenotypes for gene: VPS11 were changed from Leukodystrophy, hypomyelinating, 12, MIM#616683 to Leukodystrophy, hypomyelinating, 12, OMIM:616683
Inherited white matter disorders v1.92 VPS11 Ivone Leong Publications for gene: VPS11 were set to 26307567, 27120463
Ataxia and cerebellar anomalies - narrow panel v2.158 UBTF Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBTF.
Ataxia and cerebellar anomalies - narrow panel v2.158 UBTF Arina Puzriakova reviewed gene: UBTF: 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: 28777933, 29300972, 30517966, 31931739; Phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1066 VPS11 Ivone Leong commented on gene: VPS11
Intellectual disability v3.1066 VPS11 Ivone Leong Tag watchlist was removed from gene: VPS11.
Tag Q2_21_rating tag was added to gene: VPS11.
White matter disorders and cerebral calcification - narrow panel v1.69 VPS11 Ivone Leong Tag Q2_21_rating tag was added to gene: VPS11.
White matter disorders and cerebral calcification - narrow panel v1.69 VPS11 Ivone Leong Classified gene: VPS11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.69 VPS11 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.69 VPS11 Ivone Leong Gene: vps11 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.68 VPS11 Ivone Leong Phenotypes for gene: VPS11 were changed from Leukodystrophy, hypomyelinating, 12, MIM#616683 to Leukodystrophy, hypomyelinating, 12, OMIM:616683
White matter disorders and cerebral calcification - narrow panel v1.67 VPS11 Ivone Leong Publications for gene: VPS11 were set to 26307567, 27120463
White matter disorders and cerebral calcification - narrow panel v1.66 UFM1 Ivone Leong Tag Q2_21_rating tag was added to gene: UFM1.
White matter disorders and cerebral calcification - narrow panel v1.66 UFM1 Ivone Leong Classified gene: UFM1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.66 UFM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be made Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.66 UFM1 Ivone Leong Gene: ufm1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.65 UFM1 Ivone Leong Phenotypes for gene: UFM1 were changed from Leukodystrophy, hypomyelinating, 14, MIM# 617899 to Leukodystrophy, hypomyelinating, 14, OMIM:617899
White matter disorders and cerebral calcification - narrow panel v1.64 TUFM Ivone Leong commented on gene: TUFM: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.64 TUFM Ivone Leong Tag Q2_21_rating tag was added to gene: TUFM.
White matter disorders and cerebral calcification - narrow panel v1.64 TUFM Ivone Leong Phenotypes for gene: TUFM were changed from Mitochondrial Leukoencephalopathy to Mitochondrial Leukoencephalopathy; Combined oxidative phosphorylation deficiency 4, OMIM:610678
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 CHD7 Helen Lord gene: CHD7 was added
gene: CHD7 was added to Craniosynostosis. Sources: Expert Review
Mode of inheritance for gene: CHD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHD7 were set to 33844462; 30498854; 33288889
Phenotypes for gene: CHD7 were set to craniosynostosis
Review for gene: CHD7 was set to AMBER
Added comment: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053*) - NGS in proband, sanger sequencing used to exclude variant from the parents.
Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted.
In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected:
Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036*) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures.
Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis.

Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia.
Zebrafish model of CHARGE - flattening of the head is observed.
Sources: Expert Review
White matter disorders and cerebral calcification - narrow panel v1.63 TUFM Ivone Leong Added comment: Comment on publications: 25735936 - summarises the findings of exome analysis in 109 patients. 16 out of 42 patients with a high suspicion of a mitochondrial disorder were reported as having a disease causing mutation found in the mitochondrial gene panel - of which TUFM was one of the genes with the biochemical diagnosis of combined OXPHOS enzyme deficiency.;25655951;17160893 (case report)
White matter disorders and cerebral calcification - narrow panel v1.63 TUFM Ivone Leong Publications for gene: TUFM were set to 25735936 - summarises the findings of exome analysis in 109 patients. 16 out of 42 patients with a high suspicion of a mitochondrial disorder were reported as having a disease causing mutation found in the mitochondrial gene panel - of which TUFM was one of the genes with the biochemical diagnosis of combined OXPHOS enzyme deficiency.; 25655951; 17160893 (case report)
White matter disorders and cerebral calcification - narrow panel v1.62 TMEM63A Ivone Leong Tag Q2_21_rating tag was added to gene: TMEM63A.
White matter disorders and cerebral calcification - narrow panel v1.62 TMEM63A Ivone Leong Publications for gene: TMEM63A were set to 31587869
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Classified gene: TMEM63A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 33597727. 2 additional cases.

PMID: 33785861. 1 additional case.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Gene: tmem63a has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Classified gene: TMEM63A as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 33597727. 2 additional cases.

PMID: 33785861. 1 additional case.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.61 TMEM63A Ivone Leong Gene: tmem63a has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.98 FXN Sarah Leigh Phenotypes for gene: FXN were changed from Friedreich ataxia; Friedreich ataxia with retained reflexes, 229300 to Friedreich ataxia OMIM:229300; Friedreich ataxia with retained reflexes OMIM:229300; Friedreich ataxia 1 MONDO:0100340
White matter disorders and cerebral calcification - narrow panel v1.60 TMEM63A Ivone Leong Phenotypes for gene: TMEM63A were changed from Leukodystrophy, hypomyelinating, 19, transient infantile, MIM# 618688 to Leukodystrophy, hypomyelinating, 19, transient infantile, OMIM:618688
Paediatric disorders - additional genes v1.93 CTU2 Ivone Leong Entity copied from Severe microcephaly v2.146
Paediatric disorders - additional genes v1.93 CTU2 Ivone Leong gene: CTU2 was added
gene: CTU2 was added to Paediatric disorders - additional genes. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: CTU2.
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546; 27480277; 31301155
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Differences in sex development v2.47 CTU2 Ivone Leong Entity copied from Severe microcephaly v2.146
Differences in sex development v2.47 CTU2 Ivone Leong gene: CTU2 was added
gene: CTU2 was added to Disorders of sex development. Sources: Expert Review Amber,Expert list
Q2_21_rating tags were added to gene: CTU2.
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 26633546; 27480277; 31301155
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Intellectual disability v3.1066 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from developmental regression; motor and language regression; developmental delay; Neurodegeneration, childhood-onset, with brain atrophy, 617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Ataxia and cerebellar anomalies - narrow panel v2.158 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy MIM#617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Childhood onset dystonia, chorea or related movement disorder v1.97 UBTF Arina Puzriakova Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy MIM#617672 to Neurodegeneration, childhood-onset, with brain atrophy, OMIM:617672
Intellectual disability v3.1065 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Abnormality of nervous system morphology; Abnormality of head or neck; Microcephaly; Intellectual disability to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Severe microcephaly v2.146 CTU2 Ivone Leong Tag Q2_21_rating tag was added to gene: CTU2.
Severe microcephaly v2.146 CTU2 Ivone Leong Classified gene: CTU2 as Amber List (moderate evidence)
Severe microcephaly v2.146 CTU2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID:26633546. Affected members of all 3 families have microcephaly, facial dysmorphia and unilateral renal agenesis. 2/3 families have ambiguous genitalia; however, only 1 family had karyotyping done, which showed normal male karyotype (46 XY). 2/3 had congenital heart disease.

PMID: 27480277. Same variant as PMID:26633546. Affected individuals in this extended family have similar phenotype as PMID:26633546. Patient 1: in addition to microcephaly also has renal anomalies (small kidneys) and possible ambiguous genitalia with normal XY karyotype. Patient 2: cousin of patient 1. In addition to microcephaly did not have renal anomalies and nor ambiguous genitalia. Both patients have congenital heart disease.

PMID: 31301155. 5 new cases, all with microcephaly. 4/5 with renal anomalies, 2/5 with ambiguous genitalia, 4/5 congenital heart disease.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.146 CTU2 Ivone Leong Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.145 DYNC1I2 Arina Puzriakova Phenotypes for gene: DYNC1I2 were changed from Neurodevelopmental disorder with microcephaly and structural brain anomalies , MIM#618492 to Neurodevelopmental disorder with microcephaly and structural brain anomalies, OMIM:618492
Cerebral vascular malformations v2.51 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from Seckel syndrome 8 615807 to Seckel syndrome 8, OMIM:615807
Intellectual disability v3.1064 DNA2 Arina Puzriakova reviewed gene: DNA2: Rating: RED; Mode of pathogenicity: None; Publications: 24389050, 31045292; Phenotypes: Seckel syndrome 8, OMIM:615807; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v2.144 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050; 31045292
Intellectual disability v3.1064 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 23352259; 24389050
Intellectual disability v3.1063 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from PRIMORDIAL DWARFISM SECKEL SYNDROME 8; SCKL8 to Seckel syndrome 8, OMIM:615807
Severe microcephaly v2.143 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from Seckel syndrome 8, OMIM:615807 to Seckel syndrome 8, OMIM:615807; Microcephalic primordial dwarfism, MONDO:0017950
Severe microcephaly v2.142 DNA2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DNA2.
Severe microcephaly v2.142 DNA2 Arina Puzriakova Classified gene: DNA2 as Amber List (moderate evidence)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 different homozygous variants identified in at least 5 unrelated families with microcephalic primordial dwarfism (PMIDs: 24389050; 31045292)
Severe microcephaly v2.142 DNA2 Arina Puzriakova Gene: dna2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.131 WFS1 Eleanor Williams Added comment: Comment on phenotypes: Previous phenotypes were: Diabetes with additional phenotypes suggestive of a monogenic aetiology;Inherited optic neuropathies;Wolfram syndrome 1, 222300;Mitochondrial respiratory chain disorders caused by nuclear variants only;Hereditary ataxia;Familial diabetes;Congenital hearing impairment (profound/severe)
Likely inborn error of metabolism v2.131 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Diabetes with additional phenotypes suggestive of a monogenic aetiology; Inherited optic neuropathies; Wolfram syndrome 1, 222300; Mitochondrial respiratory chain disorders caused by nuclear variants only; Hereditary ataxia; Familial diabetes; Congenital hearing impairment (profound/severe) to Wolfram syndrome 1, OMIM:222300; Wolfram-like syndrome, autosomal dominant, OMIM:614296; Diabetes mellitus, noninsulin-dependent, association with, OMIM:125853
Likely inborn error of metabolism v2.130 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27604308; 30171196
Likely inborn error of metabolism v2.129 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Added comment: Comment on phenotypes: Original phenotypes were: Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies.
Undiagnosed metabolic disorders v1.457 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome 1 (Mitochondrial respiratory chain disorders (caused by nuclear variants only)); Congenital hearing impairment (profound/severe); Diabetes with additional phenotypes suggestive of a monogenic aetiology; Familial diabetes; Hereditary ataxia; Inherited optic neuropathies to Wolfram syndrome 1, OMIM:222300
Undiagnosed metabolic disorders v1.456 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.157 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome 1, 222300 to Wolfram syndrome 1, OMIM:222300
Ataxia and cerebellar anomalies - narrow panel v2.156 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.141 DNA2 Arina Puzriakova Publications for gene: DNA2 were set to 24389050
Severe microcephaly v2.140 DNA2 Arina Puzriakova Phenotypes for gene: DNA2 were changed from ?Seckel syndrome 8, 615807; SCKL8 to Seckel syndrome 8, OMIM:615807
Severe microcephaly v2.139 CTU2 Ivone Leong Publications for gene: CTU2 were set to 26633546
Severe microcephaly v2.138 CTU2 Ivone Leong Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MIM#618142) to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, OMIM:618142
Severe microcephaly v2.137 CTCF Ivone Leong Classified gene: CTCF as Amber List (moderate evidence)
Severe microcephaly v2.137 CTCF Ivone Leong Gene: ctcf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.136 CTCF Ivone Leong gene: CTCF was added
gene: CTCF was added to Severe microcephaly. Sources: Expert list
Q2_21_rating tags were added to gene: CTCF.
Mode of inheritance for gene: CTCF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTCF were set to 23746550; 30893510; 28619046
Phenotypes for gene: CTCF were set to Mental retardation, autosomal dominant 21, OMIM:615502
Review for gene: CTCF was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. New gene added by Zornitza Stark (however, it was added under the gene symbol CTSF but should be CTCF) with the following review:

"Recommended gene rating: Green
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
Created: 4 Sep 2020, 10:18 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation, autosomal dominant 21 (MIM#615502)

Publications

23746550
30893510
28619046

Variants in this GENE are reported as part of current diagnostic practice
Created: 4 Sep 2020, 10:18 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Expert list
Severe microcephaly v2.135 CTSF Ivone Leong edited their review of gene: CTSF: Added comment: This gene has been tagged with "curated_removed" as it should be CTCF not CTSF gene added to this panel.; Changed rating: RED
Severe microcephaly v2.135 CTSF Ivone Leong Tag curated_removed tag was added to gene: CTSF.
Severe microcephaly v2.135 CTSF Ivone Leong changed review comment from: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.; to: Comment on phenotypes: CTSF is not associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Added comment: Comment on phenotypes: CTSF is no longer associated with Mental retardation, autosomal dominant 21, OMIM:615502 on OMIM.
Severe microcephaly v2.135 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21, OMIM:615502 to Ceroid lipofuscinosis, neuronal, 13, Kufs type, OMIM:615362
Severe microcephaly v2.134 CTSF Ivone Leong Phenotypes for gene: CTSF were changed from Mental retardation, autosomal dominant 21 (MIM#615502) to Mental retardation, autosomal dominant 21, OMIM:615502
Optic neuropathy v2.40 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome to Wolfram syndrome 1, OMIM:222300
Optic neuropathy v2.39 WFS1 Eleanor Williams Publications for gene: WFS1 were set to
Optic neuropathy v2.38 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Monogenic diabetes v2.42 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Monogenic diabetes v2.41 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Familial diabetes v1.61 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome, 222300 to Wolfram syndrome, OMIM:222300
Familial diabetes v1.60 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Familial diabetes v1.59 WFS1 Eleanor Williams reviewed gene: WFS1: Rating: ; Mode of pathogenicity: None; Publications: 33693650; Phenotypes: ; Mode of inheritance: None
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.62 WFS1 Eleanor Williams Phenotypes for gene: WFS1 were changed from Wolfram syndrome, 222300; Deafness, autosomal dominant 6/14/38, 600965; Wolfram-like syndrome, autosomal dominant, 614296; {Diabetes mellitus, noninsulin-dependent, association with}, 125853; ?Cataract 41,116400; Deafness,autosomal dominant 6/14/38, 600965; Wolfram syndrome, 222300; {Diabetes mellitus, noninsulin-dependent,association with}; diabetes insipidus or optic atrophy to Wolfram syndrome, OMIM:222300; Deafness, autosomal dominant 6/14/38, OMIM:600965; Wolfram-like syndrome, autosomal dominant, OMIM:614296; {Diabetes mellitus, noninsulin-dependent, association with}, OMIM:125853; ?Cataract 41, OMIM:116400; diabetes insipidus or optic atrophy
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.61 WFS1 Eleanor Williams Publications for gene: WFS1 were set to 27217304; 27185633
Diabetes with additional phenotypes suggestive of a monogenic aetiology v1.60 WFS1 Eleanor Williams commented on gene: WFS1
Adult onset neurodegenerative disorder v2.174 SNCB Eleanor Williams reviewed gene: SNCB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33760043, 15365127, 12641375; Phenotypes: Dementia, Lewy body, OMIM:127750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset dementia (encompassing fronto-temporal dementia and prion disease) v1.48 SNCB Eleanor Williams reviewed gene: SNCB: Rating: AMBER; Mode of pathogenicity: None; Publications: 33760043, 15365127, 12641375; Phenotypes: Dementia, Lewy body, OMIM:127750; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Lipodystrophy - childhood onset v2.12 OTULIN Ivone Leong Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099 to Autoinflammation, panniculitis, and dermatosis syndrome, OMIM:617099
Lipodystrophy - childhood onset v2.11 FBN1 Ivone Leong Phenotypes for gene: FBN1 were changed from Marfan lipodystrophy syndrome, MIM# 616914 to Marfan lipodystrophy syndrome, OMIM:616914
Lipodystrophy - childhood onset v2.10 KCNJ6 Ivone Leong Phenotypes for gene: KCNJ6 were changed from Keppen-Lubinsky syndrome, MIM# 614098; MONDO:0013572 to Keppen-Lubinsky syndrome, OMIM:614098; Keppen-Lubinsky syndrome, MONDO:0013572
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Tag watchlist tag was added to gene: ZCCHC8.
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Classified gene: ZCCHC8 as Amber List (moderate evidence)
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Familial pulmonary fibrosis v1.15 ZCCHC8 Ivone Leong Gene: zcchc8 has been classified as Amber List (Moderate Evidence).
Familial pulmonary fibrosis v1.14 ZCCHC8 Ivone Leong Phenotypes for gene: ZCCHC8 were changed from Pulmonary fibrosis to ?Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5, OMIM:618674
Primary lymphoedema v2.12 ARAP3 Ivone Leong Classified gene: ARAP3 as Amber List (moderate evidence)
Primary lymphoedema v2.12 ARAP3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Primary lymphoedema v2.12 ARAP3 Ivone Leong Gene: arap3 has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v2.11 ARAP3 Ivone Leong Tag watchlist tag was added to gene: ARAP3.
Primary lymphoedema v2.11 RORC Ivone Leong Classified gene: RORC as Amber List (moderate evidence)
Primary lymphoedema v2.11 RORC Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been rated Amber.
Primary lymphoedema v2.11 RORC Ivone Leong Gene: rorc has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v2.10 RORC Ivone Leong Tag watchlist tag was added to gene: RORC.
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Classified gene: CSNK2A1 as Amber List (moderate evidence)
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.133 CSNK2A1 Ivone Leong Gene: csnk2a1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Tag Q2_21_rating tag was added to gene: CSNK2A1.
Severe microcephaly v2.132 CSNK2A1 Ivone Leong Phenotypes for gene: CSNK2A1 were changed from Okur-Chung neurodevelopmental syndrome MIM#617062 to Okur-Chung neurodevelopmental syndrome, OMIM:617062
Severe microcephaly v2.131 CHAMP1 Ivone Leong Classified gene: CHAMP1 as Amber List (moderate evidence)
Severe microcephaly v2.131 CHAMP1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.131 CHAMP1 Ivone Leong Gene: champ1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.130 CHAMP1 Ivone Leong Tag Q2_21_rating tag was added to gene: CHAMP1.
Severe microcephaly v2.130 CHAMP1 Ivone Leong Added comment: Comment on publications: PMID: 26751395 additional paper
Severe microcephaly v2.130 CHAMP1 Ivone Leong Publications for gene: CHAMP1 were set to 27148580; 26340335
Severe microcephaly v2.129 CHAMP1 Ivone Leong Phenotypes for gene: CHAMP1 were changed from Mental retardation, autosomal dominant 40 (MIM#616579) to Mental retardation, autosomal dominant 40, OMIM:616579
Severe microcephaly v2.128 CEP63 Ivone Leong commented on gene: CEP63
Severe microcephaly v2.128 CEP63 Ivone Leong Tag Q2_21_expert_review tag was added to gene: CEP63.
Severe microcephaly v2.128 CEP57 Ivone Leong Classified gene: CEP57 as Amber List (moderate evidence)
Severe microcephaly v2.128 CEP57 Ivone Leong Gene: cep57 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.127 CEP57 Ivone Leong gene: CEP57 was added
gene: CEP57 was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: CEP57.
Mode of inheritance for gene: CEP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP57 were set to 24259107; 30010053; 21552266
Phenotypes for gene: CEP57 were set to Mosaic variegated aneuploidy syndrome 2, OMIM:614114
Review for gene: CEP57 was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There are 7 reported cases (9 affected individuals) with homozygous/compound heterzygous variants in this gene (4 variants - c.520_521delGA, c.915_925dup11, c241C>T, c.697delA). Microcephaly is reported in 5/9 individuals (4 families - in 1 family with 2 affected sibs only 1 sib had microcephaly). Those with microcephaly are either compound heterozygous or homozygous for c.915_925dup11 (Mexican, Caucasian, Moroccan origin). There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Severe microcephaly v2.126 TRIP13 Ivone Leong Classified gene: TRIP13 as Amber List (moderate evidence)
Severe microcephaly v2.126 TRIP13 Ivone Leong Gene: trip13 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.125 TRIP13 Ivone Leong gene: TRIP13 was added
gene: TRIP13 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: TRIP13.
Mode of inheritance for gene: TRIP13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIP13 were set to 28553959
Phenotypes for gene: TRIP13 were set to Mosaic variegated aneuploidy syndrome 3, OMIM:617598
Review for gene: TRIP13 was set to AMBER
Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 28553959 describes 6 probands with variants in this gene. 3/6 probands had microcephaly (2 of these probands have the same homozygous variant and may be due to a founder effect). Therefore, there is currently not enough evidence to support a gene-disease association. This gene has been rated Amber for now.
Sources: Literature
Severe microcephaly v2.124 BUB1B Ivone Leong Classified gene: BUB1B as Amber List (moderate evidence)
Severe microcephaly v2.124 BUB1B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.124 BUB1B Ivone Leong Gene: bub1b has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.123 BUB1B Ivone Leong Tag Q2_21_rating tag was added to gene: BUB1B.
Severe microcephaly v2.123 BUB1B Ivone Leong Phenotypes for gene: BUB1B were changed from Mosaic variegated aneuploidy syndrome 1 (MIM#257300) to Mosaic variegated aneuploidy syndrome 1, OMIM:257300
Severe microcephaly v2.122 BPTF Ivone Leong Classified gene: BPTF as Amber List (moderate evidence)
Severe microcephaly v2.122 BPTF Ivone Leong Added comment: Comment on list classification: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-diseas association. This gene should be rated Green at the next review.
Severe microcephaly v2.122 BPTF Ivone Leong Gene: bptf has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.121 BPTF Ivone Leong Tag Q2_21_rating tag was added to gene: BPTF.
Severe microcephaly v2.121 BPTF Ivone Leong Added comment: Comment on publications: PMID:33522091 additonal paper describing 12/20 unrelated cases with microcephaly
Severe microcephaly v2.121 BPTF Ivone Leong Publications for gene: BPTF were set to 28942966
Severe microcephaly v2.120 BPTF Ivone Leong Phenotypes for gene: BPTF were changed from Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755 to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755
White matter disorders and cerebral calcification - narrow panel v1.59 AARS Ivone Leong commented on gene: AARS: Added new-gene-name tag, new approved HGNC gene symbol for AARS is AARS1
White matter disorders and cerebral calcification - narrow panel v1.59 AARS Ivone Leong Tag new-gene-name tag was added to gene: AARS.
Severe microcephaly v2.119 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
White matter disorders and cerebral calcification - narrow panel v1.59 AARS Ivone Leong Classified gene: AARS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.59 AARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
White matter disorders and cerebral calcification - narrow panel v1.59 AARS Ivone Leong Gene: aars has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.58 AARS Ivone Leong Tag Q2_21_rating tag was added to gene: AARS.
Severe microcephaly v2.119 AARS Ivone Leong Classified gene: AARS as Amber List (moderate evidence)
Severe microcephaly v2.119 AARS Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant disorder in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.119 AARS Ivone Leong Gene: aars has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.118 AARS Ivone Leong commented on gene: AARS
Severe microcephaly v2.118 AARS Ivone Leong Tag new-gene-name tag was added to gene: AARS.
Intellectual disability v3.1062 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1062 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from Primordial dwarfism; motor and speech delay; intellectual disability; global developmental delay. to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Intellectual disability v3.1061 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Intellectual disability v3.1061 WDR4 Ivone Leong Publications for gene: WDR4 were set to 29597095; 26416026
Severe microcephaly v2.118 WDR4 Ivone Leong reviewed gene: WDR4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Severe microcephaly v2.118 WDR4 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR4.
Severe microcephaly v2.118 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095; 30079490; 29597095
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 IL6ST Eleanor Williams reviewed gene: IL6ST: Rating: ; Mode of pathogenicity: None; Publications: 33517393; Phenotypes: ; Mode of inheritance: None
Unexplained young onset end-stage renal disease v1.18 OCRL Eleanor Williams Publications for gene: OCRL were set to 21249396; 17384968
Unexplained young onset end-stage renal disease v1.17 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from LOWE OCULOCEREBRORENAL SYNDROME #309000; Dent disease 2 #300555 to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555
Unexplained young onset end-stage renal disease v1.16 OCRL Eleanor Williams edited their review of gene: OCRL: Added comment: Genotype/Phenotype information: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explain symptom heterogeneity and may help stratify patients; Changed publications: 33517444
Undiagnosed metabolic disorders v1.456 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Dent disease 2 300555; Lowe syndrome 309000 to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Undiagnosed metabolic disorders v1.455 OCRL Eleanor Williams Publications for gene: OCRL were set to 27604308; 8504307; 9632163; 9632163; 15627218; 27625797
Undiagnosed metabolic disorders v1.454 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v2.129 OCRL Eleanor Williams Publications for gene: OCRL were set to 27604308; 8504307; 9632163; 9632163; 15627218; 27625797
Likely inborn error of metabolism v2.128 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Dent disease 2 300555; Lowe syndrome 309000 to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Likely inborn error of metabolism v2.127 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.648 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from DENT DISEASE TYPE 2; LOWE OCULOCEREBRORENAL SYNDROME to Dent disease 2, OMIM:300555; Lowe syndrome, OMIM:309000
Fetal anomalies v1.647 OCRL Eleanor Williams Publications for gene: OCRL were set to
Fetal anomalies v1.646 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1060 OCRL Eleanor Williams Publications for gene: OCRL were set to
Intellectual disability v3.1059 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Proteinuric renal disease v2.50 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from LOWE OCULOCEREBRORENAL SYNDROME #309000; Dent disease 2 #300555 to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555
Childhood onset dystonia, chorea or related movement disorder v1.96 FITM2 Sarah Leigh edited their review of gene: FITM2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in at least three unrelated cases. Supportive drosophila model.; Changed rating: GREEN
Proteinuric renal disease v2.49 OCRL Eleanor Williams commented on gene: OCRL: Genotype/Phenotype information: PMID: 33517444 - Ramadesikan et al 2021 - studied the cellular effect of 7 OCRL1 (OCRL) variants identified in Lowe Syndrome patients in kidney epithelial cells. Differences in cell spreading, ciliogenesis, protein localization and degree of Golgi apparatus fragmentation were observed. The results help provide a framework to explains symptom heterogeneity and may help stratify patients.
Adult onset leukodystrophy v1.10 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000 to Lowe syndrome, OMIM:309000
Adult onset leukodystrophy v1.9 OCRL Eleanor Williams Publications for gene: OCRL were set to 27159321; 25527826; 28334938; 20301621; 24357685
Adult onset leukodystrophy v1.8 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.74 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome; Confirmed DD gene for LOWE OCULOCEREBRORENAL SYNDROME to Lowe syndrome, OMIM:309000; Confirmed DD gene for LOWE OCULOCEREBRORENAL SYNDROME
Childhood onset dystonia, chorea or related movement disorder v1.96 FITM2 Sarah Leigh Tag Q2_21_rating tag was added to gene: FITM2.
Childhood onset dystonia, chorea or related movement disorder v1.96 FITM2 Sarah Leigh Classified gene: FITM2 as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.96 FITM2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.96 FITM2 Sarah Leigh Gene: fitm2 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.73 OCRL Eleanor Williams Publications for gene: OCRL were set to
Bilateral congenital or childhood onset cataracts v2.72 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Nephrocalcinosis or nephrolithiasis v2.18 OCRL Eleanor Williams Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000; Dent disease 2, 300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome to Lowe syndrome, OMIM:309000; Dent disease 2, OMIM:300555; As for CLCN5 (Nephrocalcinosis with low molecular weight proteinuria and pregressive CKD) but may include intellectual disability and other features of Lowe syndrome
Nephrocalcinosis or nephrolithiasis v2.17 OCRL Eleanor Williams Publications for gene: OCRL were set to
Nephrocalcinosis or nephrolithiasis v2.16 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Glaucoma (developmental) v1.35 OCRL Eleanor Williams Publications for gene: OCRL were set to 19168822
Glaucoma (developmental) v1.34 OCRL Eleanor Williams reviewed gene: OCRL: Rating: ; Mode of pathogenicity: None; Publications: 33517444; Phenotypes: ; Mode of inheritance: None
Childhood onset dystonia, chorea or related movement disorder v1.95 FITM2 Sarah Leigh Phenotypes for gene: FITM2 were changed from Siddiqi syndrome MIM#618635; dystonia; deafness to Siddiqi syndrome OMIM:618635; siddiqi syndrome MONDO:0032842
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh Tag Q2_21_phenotype tag was added to gene: SCN1A.
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh edited their review of gene: SCN1A: Added comment: A non-Dravet syndrome epileptic encephalopathy phenotype associated with SCN1A variants. Eight cases carriers of p.Thr226Met shared this non-typical phenotype. This phenotype is not represented in OMIM, but they have been notified of the reporting publication (PMID 28794249), additional phenotype may be added to OMIM in the future.; Changed rating: GREEN
Primary lymphoedema v2.10 RORC Ivone Leong Phenotypes for gene: RORC were changed from Lymphoedema to Lymphoedema, MONDO:0019297
Primary lymphoedema v2.9 ARAP3 Ivone Leong Phenotypes for gene: ARAP3 were changed from Lymphoedema to Lymphoedema, MONDO:0019297
Retinal disorders v2.185 FAM57B Ivone Leong Classified gene: FAM57B as Amber List (moderate evidence)
Retinal disorders v2.185 FAM57B Ivone Leong Added comment: Comment on list classification: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Retinal disorders v2.185 FAM57B Ivone Leong Gene: fam57b has been classified as Amber List (Moderate Evidence).
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh Classified gene: SCN1A as Amber List (moderate evidence)
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh Gene: scn1a has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.184 FAM57B Ivone Leong Tag Q2_21_rating tag was added to gene: FAM57B.
Childhood onset dystonia, chorea or related movement disorder v1.93 SCN1A Sarah Leigh Publications for gene: SCN1A were set to 19332696; 16054936
Intellectual disability v3.1059 CDH11 Arina Puzriakova Phenotypes for gene: CDH11 were changed from Elsahy-Waters syndrome to Elsahy-Waters syndrome, OMIM:211380; Teebi hypertelorism syndrome
Intellectual disability v3.1058 CDH11 Arina Puzriakova Publications for gene: CDH11 were set to 27431290; 29271567
Ataxia and cerebellar anomalies - narrow panel v2.156 SCN1A Sarah Leigh edited their review of gene: SCN1A: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 9 variants reported in unrelated cases.; Changed rating: GREEN
Intellectual disability v3.1057 CDH11 Arina Puzriakova Added comment: Comment on mode of inheritance: Association with biallelic variants well-established, with ID reported in all cases to date. On the other hand, DD/ID is variable in individuals with monoallelic variants (PMID: 33811546) - 7/19 cases (4 families) presented a developmental phenotype including very mild speech delays in 5/7, mild-moderate DD in 1/7, and global delay in 1/7 individuals.

Overall, given the mostly mild degree of cognitive delay, as well as intra- and interfamilial reduced penetrance of this feature, there is currently not enough evidence to rate as Green on this panel for the monoallelic disease.
Intellectual disability v3.1057 CDH11 Arina Puzriakova Mode of inheritance for gene: CDH11 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.156 SCN1A Sarah Leigh Tag Q2_21_rating tag was added to gene: SCN1A.
Ataxia and cerebellar anomalies - narrow panel v2.156 SCN1A Sarah Leigh Publications for gene: SCN1A were set to 27264139; 27817982; 28732259
Ataxia and cerebellar anomalies - narrow panel v2.155 SCN1A Sarah Leigh Classified gene: SCN1A as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.155 SCN1A Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.155 SCN1A Sarah Leigh Gene: scn1a has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.117 WDR4 Ivone Leong Publications for gene: WDR4 were set to 26416026; 29597095
Severe microcephaly v2.116 WDR4 Ivone Leong Phenotypes for gene: WDR4 were changed from MPD; microcephalic primordial dwarfism to Galloway-Mowat syndrome 6, OMIM:61834; Microcephaly, growth deficiency, seizures, and brain malformations, OMIM:618347
Severe microcephaly v2.115 WDR37 Ivone Leong Classified gene: WDR37 as Amber List (moderate evidence)
Severe microcephaly v2.115 WDR37 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support this gene-disease association. This gene should be rated Green at the next review.
Severe microcephaly v2.115 WDR37 Ivone Leong Gene: wdr37 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.114 WDR37 Ivone Leong Tag Q2_21_rating tag was added to gene: WDR37.
Ataxia and cerebellar anomalies - narrow panel v2.154 SCN1A Sarah Leigh Phenotypes for gene: SCN1A were changed from Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208 to Dravet syndrome OMIM:607208; developmental and epileptic encephalopathy, 6 MONDO:0100079
Severe microcephaly v2.114 WDR37 Ivone Leong Phenotypes for gene: WDR37 were changed from Neurooculocardiogenitourinary syndrome MIM#618652 to Neurooculocardiogenitourinary syndrome, OMIM:618652
Proteinuric renal disease v2.49 APOL1 Eleanor Williams Publications for gene: APOL1 were set to 20647424; 23766536
Proteinuric renal disease v2.48 APOL1 Eleanor Williams edited their review of gene: APOL1: Added comment: PMID: 33517446 - Ge et al 2021 - demonstrate a mouse model to study APOL1 risk variants associated susceptibility to NFAT-mediated FSGS. They provide evidence that APOL1 G1 induced glomerular lipid accumulation correlates with loss of renal function and confirm that APOL1 G1/G2 risk variant is associated with mitochondrial dysfunction.; Changed publications: 33517446
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.339 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Tag Q2_21_rating was removed from gene: UFSP2.
Tag founder-effect tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.338 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208; 28892125; 26428751; 32755715
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Classified gene: UFSP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Added comment: Comment on list classification: A founder variant (rs142500730) reported in four South Asian families (haplotype analysis available for two of the families proves relatedness). Functional studies suggest that although expression seems to be unaffected, immunoblotting indicates that protein stability maybe affected (PMID 33473208).
Early onset or syndromic epilepsy v2.337 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Green List (High Evidence).
Intellectual disability v3.1056 HTT Eleanor Williams changed review comment from: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.; to: PMID: 33432339 - Jung et al 2021 - further characterisation of the family previously reported in PMID: 27329733 (Rodan et al 2016) - using WGS they confirm they are the most likely cause of the LOMARS phenotype and clarify their locations as NM_002111.8(HTT): c.8157T>A (p.Phe2719Leu) and NM_002111.8(HTT)c.4469+1G>A (Note there are incorrect Clinvar entries). Functional studies show them each to be a hypomorphic mutation, resulting in severe deficiency of huntingtin in compound heterozygotes.

Still only 2 cases reported to date (PMID: 27329733/33432339 and 26740508) with biallelic LOF variants in HTT associated with the LOMARS phenotype although this study add further weight with some functional data.
Intellectual disability v3.1056 HTT Eleanor Williams reviewed gene: HTT: Rating: ; Mode of pathogenicity: None; Publications: 33432339; Phenotypes: Lopes-Maciel-Rodan syndrome OMIM:617435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection v1.112 PKD1 Dmitrijs Rots reviewed gene: PKD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: No OMIM reference for the pediatric neurodevelopmental anomalies and epilepsy feautres. Monoallelic variants have previously been associated with skeletal dysplasias (PMIDs 28892125;26428751;32755715), but there does not appear to be any phenotypic overlap between these and the phenotype seen for the biallelic rs142500730.
Early onset or syndromic epilepsy v2.336 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Thoracic aortic aneurysm or dissection v1.112 PKD2 Dmitrijs Rots reviewed gene: PKD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v2.30 FAR1 Arina Puzriakova Classified gene: FAR1 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v2.30 FAR1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update
Childhood onset hereditary spastic paraplegia v2.30 FAR1 Arina Puzriakova Gene: far1 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v2.29 FAR1 Arina Puzriakova gene: FAR1 was added
gene: FAR1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: FAR1.
Mode of inheritance for gene: FAR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FAR1 were set to 25439727; 30561787; 33239752
Phenotypes for gene: FAR1 were set to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Review for gene: FAR1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants (PMID: 33239752). Paediatric onset.
Sources: Literature
Skeletal dysplasia v2.97 UFSP2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974). Supportive functional studies presented for one of the variants (PMID 26428751).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974), within the UFSP2 C-terminal C78 peptidase domain, which is required for its catalytic activity. Supportive functional studies presented for one of the variants (PMID 26428751) .
Ataxia and cerebellar anomalies - narrow panel v2.153 TGM6 Ivone Leong commented on gene: TGM6
Ataxia and cerebellar anomalies - narrow panel v2.153 TGM6 Ivone Leong Tag Q2_21_rating tag was added to gene: TGM6.
Ataxia and cerebellar anomalies - narrow panel v2.153 TGM6 Ivone Leong Tag Q2_21_expert_review tag was added to gene: TGM6.
Ataxia and cerebellar anomalies - narrow panel v2.153 TGM6 Ivone Leong Phenotypes for gene: TGM6 were changed from Spinocerebellar ataxia 35, 613908 to Spinocerebellar ataxia 35, OMIM:613908
Ataxia and cerebellar anomalies - narrow panel v2.152 TGM6 Ivone Leong Publications for gene: TGM6 were set to 32426513; 30670339
Ataxia and cerebellar anomalies - narrow panel v2.151 TGM6 Ivone Leong Publications for gene: TGM6 were set to
Ataxia and cerebellar anomalies - narrow panel v2.150 TDP2 Ivone Leong Tag Q2_21_rating tag was added to gene: TDP2.
Ataxia and cerebellar anomalies - narrow panel v2.150 TDP2 Ivone Leong Classified gene: TDP2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.150 TDP2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.150 TDP2 Ivone Leong Gene: tdp2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Early onset or syndromic epilepsy v2.335 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 33473208
Skeletal dysplasia v2.97 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 28892125; 26428751; 32755715
Skeletal dysplasia v2.96 UFSP2 Sarah Leigh Added comment: Comment on phenotypes: A biallelic variant rs142500730 has been associated with pediatric neurodevelopmental anomalies and epilepsy (PMID 33473208).
Skeletal dysplasia v2.96 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702 to ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Classified gene: UFSP2 as Amber List (moderate evidence)
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Skeletal dysplasia v2.95 UFSP2 Sarah Leigh Gene: ufsp2 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh Tag Q2_21_rating tag was added to gene: UFSP2.
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh reviewed gene: UFSP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

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

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Classified gene: FAR1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update
Bilateral congenital or childhood onset cataracts v2.72 FAR1 Arina Puzriakova Gene: far1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.71 FAR1 Arina Puzriakova gene: FAR1 was added
gene: FAR1 was added to Cataracts. Sources: Literature
Q2_21_rating tags were added to gene: FAR1.
Mode of inheritance for gene: FAR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FAR1 were set to 25439727; 30561787; 33239752
Phenotypes for gene: FAR1 were set to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Review for gene: FAR1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease. Congenital/juvenile cataracts are reported in 4/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and in 12/12 patients with heterozygous de novo variants (PMID: 33239752)
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.149 SPG7 Ivone Leong Tag Q2_21_expert_review tag was added to gene: SPG7.
Ataxia and cerebellar anomalies - narrow panel v2.149 SPG7 Ivone Leong edited their review of gene: SPG7: Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID:33774748. Age of onset reported ranged from 12-61 yo (mean age = 39.1). 25 unrelated families of Irish descent.
PMID:32161564. Age of onset 25 - 45 yo.
PMID:31068484. Age of onset 35.5 +/- 14.3 years (mean age = 50.4). 241 patients were part of the study.
PMID:23065789. Age of onset 10 - 45 yo. 137 patients were part of the study.

As the age of onset is quite a wide range this gene will remain Green to ensure edge cases are identified. This gene has been tagged for GMS expert review on whether this gene's rating needs to be changed.; Changed publications: 33774748, 32161564, 31068484, 23065789
Dilated and arrhythmogenic cardiomyopathy v1.24 RHBDF1 Ivone Leong Classified gene: RHBDF1 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.24 RHBDF1 Ivone Leong Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.23 RHBDF1 Ivone Leong gene: RHBDF1 was added
gene: RHBDF1 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
watchlist tags were added to gene: RHBDF1.
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Review for gene: RHBDF1 was set to AMBER
Added comment: This gene is rated Amber on the Cardiomyopathies - including childhood onset (Version 1.39) panel with the following reviews:

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 20 Apr 2021"

"Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant. Sources: Literature
Zornitza Stark (Australian Genomics), 16 Apr 2021"
Sources: Literature
Intellectual disability v3.1056 FAR1 Arina Puzriakova Publications for gene: FAR1 were set to 25439727
Intellectual disability v3.1055 FAR1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: FAR1.
Tag Q2_21_MOI tag was added to gene: FAR1.
Intellectual disability v3.1055 FAR1 Arina Puzriakova reviewed gene: FAR1: Rating: ; Mode of pathogenicity: None; Publications: 25439727, 30561787, 33239752; Phenotypes: ; Mode of inheritance: None
Paediatric or syndromic cardiomyopathy v1.39 NRAP Ivone Leong Classified gene: NRAP as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.39 NRAP Ivone Leong Gene: nrap has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.38 NRAP Ivone Leong gene: NRAP was added
gene: NRAP was added to Cardiomyopathies - including childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: NRAP.
Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474; 32870709
Phenotypes for gene: NRAP were set to Dilated cardiomyopathy, MONDO:0005021 Edit
Review for gene: NRAP was set to GREEN
Added comment: This gene is Green on the Dilated cardiomyopathy - adult and teen (Version 1.22) with the following reviews:

"This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases of patients with variants in this gene and having DCM. https://doi.org/10.1101/2020.10.12.20211474 also describes a CRISPR knockout zebrafish which had a cardiac phenotype. Therefore, there is enough evidence to support a gene-disease association and this gene is recommended to be promoted Green at the next panel review. Sources: Literature
Ivone Leong (Genomics England Curator), 25 Feb 2021"

"Twenty unrelated families reported with childhood onset DCM. May be more appropriate for the paediatric cardiomyopathy panel."

As affected individuals have childhood onset DCM it was deemed appropriate to add this gene to this panel as well.
Sources: Literature
Skeletal dysplasia v2.94 UFSP2 Sarah Leigh Mode of inheritance for gene: UFSP2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v1.92 ADAMTS19 Ivone Leong Classified gene: ADAMTS19 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.92 ADAMTS19 Ivone Leong Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.91 ADAMTS19 Ivone Leong gene: ADAMTS19 was added
gene: ADAMTS19 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_rating, Q2_21_phenotype tags were added to gene: ADAMTS19.
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 31844321; 32323311
Phenotypes for gene: ADAMTS19 were set to Non-syndromic heart valve disease; heart valve disease, MONDO:0002869
Review for gene: ADAMTS19 was set to AMBER
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. It is a Green gene on the Familial non syndromic congenital heart disease (Version 1.60) panel with the following reviews:

"New 2020 paper reports 3 additional consanguineous families (2 affected sibs in each) with anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. All 3 families had homozygous LoF variants in ADAMTS19, which segregated with disease. No functional studies. Previously reported 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Zornitza Stark (Australian Genomics), 1 Jul 2020"

"PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype Sources: Literature
Zornitza Stark (Australian Genomics), 1 May 2020"

After consulting the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to GMS specialist review panel to consider whether the isolated phenotype is appropriate for inclusion. If appropriate then this gene should be promoted to Green status.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 PLG Matthew Buckland gene: PLG was added
gene: PLG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PLG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLG were set to PMID: 28795768
Phenotypes for gene: PLG were set to Non-C1 Hereditary Angioedema
Penetrance for gene: PLG were set to unknown
Review for gene: PLG was set to GREEN
Added comment: Bork et al. identified the exon9 mutation in PLG in four index families with normal-C1 hereditary angioedema and a further 9 families studied, with shared clinical features.
Sufficient information to ascribe causality.
Sources: Literature
Skeletal dysplasia v2.93 UFSP2 Sarah Leigh Phenotypes for gene: UFSP2 were changed from Beukes Hip Dysplasia 142669, Spondyloepimetaphyseal dysplasia, Di Rocco type 617974 to ?Beukes Hip Dysplasia OMIM:142669; hip dysplasia, Beukes type MONDO:0007726; ?Spondyloepimetaphyseal dysplasia, Di Rocco type OMIM:617974; spondyloepimetaphyseal dysplasia, di rocco type MONDO:0060702
Skeletal dysplasia v2.92 UFSP2 Sarah Leigh Publications for gene: UFSP2 were set to 28892125; 26428751
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Classified gene: BRWD1 as Red List (low evidence)
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. As only 1 case has situs inversus this gene has been added to this panel as a Red gene.

After discussion with the Genomics England Clinical Team it was decided that this gene would be better suited for the Respiratory ciliopathies including non-CF bronchiectasis (Version 1.45). This gene has been added as an Amber gene with a recommendation for Green status on that panel.
Laterality disorders and isomerism v1.45 BRWD1 Ivone Leong Gene: brwd1 has been classified as Red List (Low Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.45 BRWD1 Ivone Leong Classified gene: BRWD1 as Amber List (moderate evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.45 BRWD1 Ivone Leong Gene: brwd1 has been classified as Amber List (Moderate Evidence).
Respiratory ciliopathies including non-CF bronchiectasis v1.44 BRWD1 Ivone Leong gene: BRWD1 was added
gene: BRWD1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Q2_21_rating tags were added to gene: BRWD1.
Mode of inheritance for gene: BRWD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRWD1 were set to 33389130
Phenotypes for gene: BRWD1 were set to Primary ciliary dyskinesia, asthenoteratozoospermia
Review for gene: BRWD1 was set to GREEN
Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene was added to the Laterality disorders and isomerism (Version 1.44) panel by Zornitza Stark with the following review:

"Biallelic missense variants reported in 3 unrelated individuals. Apart from asthenoteratozoospermia, all 3 had PCD or "PCD-like" symptoms of reccurring airway infections, bronchiectasis, and rhinosinusitis. One individual had situs inversus. Studies on cells from one indivdidual showed abnormal respiratory cilia structure. BRWD1 staining was absent from respiratory cilia in this individual (present in controls). Sources: Literature
Zornitza Stark (Australian Genomics), 7 Feb 2021"

After discussion with the Genomics England Clinical Team it was decided that this gene was better suited to this panel.
Sources: Literature
Laterality disorders and isomerism v1.44 NODAL Ivone Leong commented on gene: NODAL
Laterality disorders and isomerism v1.44 NODAL Ivone Leong Tag Q2_21_expert_review tag was added to gene: NODAL.
Laterality disorders and isomerism v1.44 NKX2-5 Ivone Leong Publications for gene: NKX2-5 were set to 25742962; 26805889
Laterality disorders and isomerism v1.43 NKX2-5 Ivone Leong edited their review of gene: NKX2-5: Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype.

PMID: 12414819 describes 2 unrelated families. Family 1: 4 family members with variant in NKX2-5 had atrial septum defect. One of these family members was also diagnosed with polyspenia, midline symmetrical liver, ascending colon and caecum were shifted to the midline and forwards with the small intestine on the left. Family 2: 3 affected family members had atrial septum defect.

PMID: 25118008 describes a proband with a frameshift variant in NKX2-5 with the following phenotypes: double outlet right ventricle, common AV canal, total anomalous pulmonary venous connection, asplenia, failure to thrive and short stature. The proband also had distorted organ position and liver was centrally located and spleen was not identied at 1 week of age. Also had intestinal malformation and underwent Ladd procedure and gastrostomy tube placement at 3 weeks. The authors in this paper notes that NKX2-5 variants are associated with cardiac malformations that are commonly seen in patients with heterotaxy (i.e. transposition of great artieries and double outlet right ventricle) and also with asplenia in some patients.

After discussion with the Genomics England Clinical Team it was decided that this gene should remain Amber on this panel.; Changed rating: AMBER; Changed publications: 12414819, 25118008
Cholestasis v1.83 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Cholestasis v1.83 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Cholestasis v1.82 AP1S1 Ivone Leong gene: AP1S1 was added
gene: AP1S1 was added to Cholestasis. Sources: Literature
Q2_21_rating tags were added to gene: AP1S1.
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098; 15668823; 19057675; 23423674; 30244301
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Review for gene: AP1S1 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.40) with the following reviews:

" Established gene-disease association with MEDNIK syndrome - PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant - AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"

"This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review."

After discussion with the Genomics England Clinical Team it was decided that this gene should also be included in this panel.
Sources: Literature
Monogenic hearing loss v2.162 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Monogenic hearing loss v2.162 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Monogenic hearing loss v2.161 AP1S1 Ivone Leong gene: AP1S1 was added
gene: AP1S1 was added to Hearing loss. Sources: Literature
Q2_21_rating tags were added to gene: AP1S1.
Mode of inheritance for gene: AP1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1S1 were set to 32306098; 15668823; 19057675; 23423674; 30244301
Phenotypes for gene: AP1S1 were set to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Review for gene: AP1S1 was set to GREEN
Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.40) with the following reviews:

" Established gene-disease association with MEDNIK syndrome - PMID: 32306098 propose a clinical and genetic expansion for AP1S1-associated disease - 2 consanguineous families, each carrying a homozygous missense AP1S1 variant - AP1S1 knockout cell line demonstrated tight-junction and polarity abnormalities that were rescued by WT AP1S1, but not the AP1S1 missense variants. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"

"This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review."

After discussion with the Genomics England Clinical Team it was decided that this gene should also be included in this panel.
Sources: Literature
Intellectual disability v3.1055 HERC2 Arina Puzriakova Publications for gene: HERC2 were set to 23065719
Intestinal failure or congenital diarrhoea v1.40 AP1S1 Ivone Leong Publications for gene: AP1S1 were set to 32306098; 15668823, 19057675, 23423674, 30244301
Intellectual disability v3.1054 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 to Mental retardation, autosomal recessive 38, OMIM:615516
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Classified gene: AP1S1 as Amber List (moderate evidence)
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype.

After discussion with the Genomics England Clinical Team it was decided that it was appropriate to consider all evidence (including the cases that have an intestinal phenotype for this gene - MEDNIK syndrome), therefore, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Intestinal failure or congenital diarrhoea v1.39 AP1S1 Ivone Leong Gene: ap1s1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.334 HERC2 Arina Puzriakova Phenotypes for gene: HERC2 were changed from Mental retardation, autosomal recessive 38 (MIM 615516) to Mental retardation, autosomal recessive 38, OMIM:615516
Intestinal failure or congenital diarrhoea v1.38 AP1S1 Ivone Leong Tag Q2_21_rating tag was added to gene: AP1S1.
Intestinal failure or congenital diarrhoea v1.38 AP1S1 Ivone Leong Phenotypes for gene: AP1S1 were changed from Non-syndromic congenital intestinal failure to Non-syndromic congenital intestinal failure; MEDNIK syndrome, OMIM:609313
Intestinal failure or congenital diarrhoea v1.37 AP1S1 Ivone Leong Publications for gene: AP1S1 were set to 32306098
VACTERL-like phenotypes v1.31 PLVAP Ivone Leong Classified gene: PLVAP as Green List (high evidence)
VACTERL-like phenotypes v1.31 PLVAP Ivone Leong Gene: plvap has been classified as Green List (High Evidence).
CAKUT v1.162 PLVAP Ivone Leong Classified gene: PLVAP as Green List (high evidence)
CAKUT v1.162 PLVAP Ivone Leong Gene: plvap has been classified as Green List (High Evidence).
VACTERL-like phenotypes v1.30 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to VACTERL-like phenotypes. Sources: Literature
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
CAKUT v1.161 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to CAKUT. Sources: Literature
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
Intellectual disability v3.1053 NUBPL Arina Puzriakova Phenotypes for gene: NUBPL were changed from MITOCHONDRIAL COMPLEX I DEFICIENCY to Mitochondrial complex I deficiency, nuclear type 21, OMIM:618242
Paediatric disorders - additional genes v1.90 PLVAP Ivone Leong Classified gene: PLVAP as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.90 PLVAP Ivone Leong Gene: plvap has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.89 PLVAP Ivone Leong gene: PLVAP was added
gene: PLVAP was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_rating tags were added to gene: PLVAP.
Mode of inheritance for gene: PLVAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLVAP were set to 29875123; 29661969; 26207260; 31215290
Phenotypes for gene: PLVAP were set to Diarrhoea 10, protein-losing enteropathy type, OMIM:618183
Review for gene: PLVAP was set to GREEN
Added comment: This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. It is currently Amber with a recommendation to promote to Green on the Intestinal failure panel (Version 1.36) with the following reviews:

"Diarrhoea-10 is a protein-losing enteropathy characterized by intractable secretory diarrhoea and massive protein loss due to leaky fenestrated capillaries. Features include early-onset anasarca, severe hypoalbuminemia, hypogammaglobulinemia, and hypertriglyceridemia, as well as electrolyte abnormalities. Some patients exhibit facial dysmorphism and cardiac and renal anomalies. Intrafamilial variability has been observed, and the disease can be severe, with death occurring in infancy in some patients. Four unrelated families reported. Sources: Expert Review
Zornitza Stark (Australian Genomics), 5 Jan 2021"

"Comment on publications: PMID: 26207260. Patient is of Afgan descent born to consanguineous parents. Presented at 8 days of life with secretory diarrhea, metabolic acidosis, lethargy, poor feeding, and severe hyponatremia causing seizures. Further examination shows patient had bilateral colobomas, undescended testes, mildly dysplastic kidneys bilaterally, low-set ears, and micrognathia. PMID: 29875123. 2 patients (first cousins) from a Muslim Arab consanguineous kindred presented with anasarca, severe hypoalbuminaemia and hypogammaglobinaemia. PMID: 29661969. Patient is of Turkish descent born to consanguineous parents. Presented with severe haematochezia and moderate anasarca. Other findings: dysmorphism, metabolic acidosis, electrolyte deficiencies, elevated GGT, choroid plexus cysts, iris cysts, ASD, VSD, dilated megaureter with dilated renal pelvis, venous thrombosis. PMID: 31215290. Patient born to consanguineous parents. As well as intestinal phenotypes, she also had dysmorphic features, renal and cardiac phenotypes.
Ivone Leong (Genomics England Curator), 12 Apr 2021"

After discussion with the Geomics England Clinical Team it was decided that this gene should also be on this panel.
Sources: Literature
Paediatric disorders - additional genes v1.88 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.88 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.87 FOXP4 Ivone Leong gene: FOXP4 was added
gene: FOXP4 was added to Paediatric disorders - additional genes. Sources: Literature
Q2_21_phenotype tags were added to gene: FOXP4.
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not in OMIM.

This gene is present as an Amber gene on the Intellectual disability panel (Version 3.1052) with the following reviews:

"This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel? Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here. Sources: Literature
Zornitza Stark (Australian Genomics), 4 Nov 2020"

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 4 Dec 2020"

After discussion with the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to review by the GMS specialist group.
Sources: Literature
Fetal anomalies v1.646 FOXP4 Ivone Leong Tag Q2_21_rating was removed from gene: FOXP4.
Fetal anomalies v1.646 FOXP4 Ivone Leong Classified gene: FOXP4 as Amber List (moderate evidence)
Fetal anomalies v1.646 FOXP4 Ivone Leong Gene: foxp4 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.645 FOXP4 Ivone Leong gene: FOXP4 was added
gene: FOXP4 was added to Fetal anomalies. Sources: Literature
Q2_21_rating, Q2_21_phenotype tags were added to gene: FOXP4.
Mode of inheritance for gene: FOXP4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FOXP4 were set to 33110267
Phenotypes for gene: FOXP4 were set to Neurodevelopmental disorder; multiple congenital abnormalities
Review for gene: FOXP4 was set to AMBER
Added comment: This gene is associated with a phenotype in Gene2Phenotype but not in OMIM.

This gene is present as an Amber gene on the Intellectual disability panel (Version 3.1052) with the following reviews:

"This gene is a little bit difficult to place, may be Green on Fetal Anomalies panel? Eight unrelated individuals reported, seven de novo missense, and one individual with a truncating variant. Detailed phenotypic information available on 6. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia (2/6), cervical spine abnormalities, and ptosis. Intellectual disability described as mild in 2, some had normal intellect despite the early speech and language delays, hence Amber rating here. Sources: Literature
Zornitza Stark (Australian Genomics), 4 Nov 2020"

"Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). As ID is not present in the majority of affected patients, and the affected individuals only show mild ID, this gene has been given an Amber rating.
Ivone Leong (Genomics England Curator), 4 Dec 2020"

After discussion with the Genomics England Clinical Team it was decided that this gene should be added to this panel as an Amber gene and subject to review by the GMS specialist group.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.28 HPDL Cristina Dias reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32707086, 33188300; Phenotypes: microcephaly, spastic paraplegia, seizures, demyelinating neuropathy, regression, developmental delay, chronic progression, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1052 INPP4A Arina Puzriakova Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures
Intellectual disability v3.1051 INPP4A Arina Puzriakova Publications for gene: INPP4A were set to 21937992
Intellectual disability v3.1050 INPP4A Arina Puzriakova Classified gene: INPP4A as Amber List (moderate evidence)
Intellectual disability v3.1050 INPP4A Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber. 2 unrelated families with severe ID and biallelic variants in this gene reported to date (PMIDs: 25338135; 31978615)
Intellectual disability v3.1050 INPP4A Arina Puzriakova Gene: inpp4a has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1049 UBE4A Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.; to: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - PMID:33420346 report 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Tag Q2_21_rating tag was added to gene: UBE4A.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Classified gene: UBE4A as Amber List (moderate evidence)
Intellectual disability v3.1049 UBE4A Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene Green at the next GMS panel update - 4 unrelated families with different homozygous LoF variants in UBE4A, supported by some functional data and animal model. Severe ID and GDD was a feature in all affected individuals (8 total).

UBE4A is not associated with any phenotype in OMIM (last edited on 17/09/2010) but has a 'probable' disease confidence rating for 'UBE4A-associated neurodevelopmental disorder' in Gene2Phenotype.
Intellectual disability v3.1049 UBE4A Arina Puzriakova Gene: ube4a has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline if this gene is upgraded to Green on this panel in the future.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Added comment: Comment on list classification: Rating Amber with monoallelic MOI, awaiting further cases with seizures (2/3 de novo cases with epilepsy - PMID: 33711248). Currently 'Red' evidence level for biallelic form.
Early onset or syndromic epilepsy v2.333 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Early onset or syndromic epilepsy v2.332 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.331 NCDN Arina Puzriakova gene: NCDN was added
gene: NCDN was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NCDN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to AMBER
Added comment: NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. All 3 sibs had generalised seizures (fever induced in 2), while 2/3 individuals with heterozygous variants developed epileptic spasms presenting several times per day prior to treatment. Supportive functional data included.
Sources: Literature
Intellectual disability v3.1048 NCDN Arina Puzriakova Tag Q2_21_rating tag was added to gene: NCDN.
Intellectual disability v3.1048 NCDN Arina Puzriakova Classified gene: NCDN as Amber List (moderate evidence)
Intellectual disability v3.1048 NCDN Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient evidence to rate this gene as Green with 'monoallelic' MOI at next GMS panel update.

- PMID: 33711248 (2021) - Six affected individuals (3 sibs with homozygous missense, and 3 unrelated patients with different de novo missense variants) with variable degrees of DD, ID, and seizures. Severity of ID in individuals with heterozygous variants is severe, moderate, and mild (but also learning disabilities), respectively. ID in the 3 sibs was determined as mild. Supportive functional data included.

NCDN is not yet associated with any phenotype in OMIM (last edited on 08/08/2012) but in Gene2Phenotype monoallelic disease has a 'probable' confidence rating while biallelic variants have a 'possible' disease confidence rating.
Intellectual disability v3.1048 NCDN Arina Puzriakova Gene: ncdn has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1047 NCDN Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
Intellectual disability v3.1047 NCDN Arina Puzriakova Mode of inheritance for gene: NCDN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.41 MAPKAPK5 Arina Puzriakova Classified gene: MAPKAPK5 as Amber List (moderate evidence)
Limb disorders v2.41 MAPKAPK5 Arina Puzriakova Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Limb disorders v2.40 MAPKAPK5 Arina Puzriakova gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 33442026
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism; Synpolydactyly
Review for gene: MAPKAPK5 was set to AMBER
Added comment: MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.

- PMID: 33442026 (2021) - 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Rating Amber, awaiting further cases.
Sources: Literature
Intellectual disability v3.1046 MAPKAPK5 Arina Puzriakova Tag watchlist tag was added to gene: MAPKAPK5.
Intellectual disability v3.1046 MAPKAPK5 Arina Puzriakova Publications for gene: MAPKAPK5 were set to 3344202
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Classified gene: MAPKAPK5 as Amber List (moderate evidence)
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Rating Amber, awaiting further cases (added watchlist tag)

- PMID: 33442026 report on 2 unrelated families with a comparable phenotype including severe GDD, who harbour different homozygous truncating variants in MAPKAPK5. Some functional evidence indicating the variants impact expression and function of MAPKAPK5 protein.

MAPKAPK5 is not yet associated with any phenotype in OMIM (last edited on 06/04/2016) but has a 'probable' disease confidence rating for 'MAPKAPK5-associated syndrome with synpolydactyly' in Gene2Phenotype.
Intellectual disability v3.1045 MAPKAPK5 Arina Puzriakova Gene: mapkapk5 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.113 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Severe microcephaly v2.113 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Severe microcephaly v2.112 COPB1 Arina Puzriakova gene: COPB1 was added
gene: COPB1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Added comment: COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. Affected patients developed cataracts, severe ID and variable microcephaly - at least 1 individual from each family with microcephaly of relevant severity to this panel (HC ≥ -3SD). Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.70 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Bilateral congenital or childhood onset cataracts v2.70 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Bilateral congenital or childhood onset cataracts v2.69 COPB1 Arina Puzriakova gene: COPB1 was added
gene: COPB1 was added to Cataracts. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Review for gene: COPB1 was set to AMBER
Added comment: COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. All affected patients developed cataracts, among other features such as severe ID and variable microcephaly. Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.92 SCN1A Dmitrijs Rots reviewed gene: SCN1A: 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: 28794249; Phenotypes: seizures, developmental delay, dystonia, choreoathetosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1044 COPB1 Arina Puzriakova Tag watchlist tag was added to gene: COPB1.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Classified gene: COPB1 as Amber List (moderate evidence)
Intellectual disability v3.1044 COPB1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. PMID:33632302 reports on six individuals from two unrelated families with different homozygous variants in this gene. All affected patients had severe ID. Rating Amber, awaiting further cases.
Intellectual disability v3.1044 COPB1 Arina Puzriakova Gene: copb1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1043 COPB1 Arina Puzriakova Phenotypes for gene: COPB1 were changed from Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts to Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly
Childhood onset dystonia, chorea or related movement disorder v1.92 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from Cutis laxa, autosomal dominant 3 616603; Cutis laxa, autosomal recessive, type IIIA 219150; Spastic paraplegia 9A, autosomal dominant 601162; Spastic paraplegia 9B, autosomal recessive 616586 to Cutis laxa, autosomal dominant 3 OMIM:616603; cutis laxa, autosomal dominant 3 MONDO:0014706; Cutis laxa, autosomal recessive, type IIIA OMIM:219150; ALDH18A1-related de Barsy syndromeMONDO:0009053; Spastic paraplegia 9A, autosomal dominant OMIM:601162; hereditary spastic paraplegia 9A MONDO:0011006; Spastic paraplegia 9B, autosomal recessive OMIM:616586; autosomal recessive complex spastic paraplegia type 9B MONDO:0014702
Childhood onset dystonia, chorea or related movement disorder v1.91 ALDH18A1 Sarah Leigh Tag Q2_21_phenotype tag was added to gene: ALDH18A1.
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh edited their review of gene: ANGPTL6: Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen. At least 9 variants reported in at least 11 families with Familial Intracranial Aneurysm. Expression and secretion studies have been performed for NM_031917.2. c.1378A>T, p.Lys460Ter, showing that although it is expressed it is not secreted.; Changed rating: GREEN
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh Tag Q2_21_rating tag was added to gene: ANGPTL6.
Cerebral vascular malformations v2.50 ANGPTL6 Sarah Leigh Publications for gene: ANGPTL6 were set to 29304371; 33106390
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Classified gene: ANGPTL6 as Amber List (moderate evidence)
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Cerebral vascular malformations v2.49 ANGPTL6 Sarah Leigh Gene: angptl6 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.48 ANGPTL6 Sarah Leigh Phenotypes for gene: ANGPTL6 were changed from Cerebral aneurysm to brain aneurysm MONDO:0005291
Cystic kidney disease v2.26 FLCN Eleanor Williams Classified gene: FLCN as Amber List (moderate evidence)
Cystic kidney disease v2.26 FLCN Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, with a recommendation for green rating at the next GMS review.
Cystic kidney disease v2.26 FLCN Eleanor Williams Gene: flcn has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.25 FLCN Eleanor Williams Tag Q2_21_rating tag was added to gene: FLCN.
Cystic kidney disease v2.25 FLCN Eleanor Williams commented on gene: FLCN
Cystic kidney disease v2.25 FLCN Eleanor Williams Publications for gene: FLCN were set to PMID: 19785621; 31266032
Cystic kidney disease v2.24 FLCN Eleanor Williams Phenotypes for gene: FLCN were changed from renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma to Birt-Hogg-Dube syndrome, OMIM:135150; renal cysts; cutaneous fibrofolliculoma; pneumothorax; pulmonary cysts; renal cell carcinoma; renal oncocytoma
White matter disorders and cerebral calcification - narrow panel v1.58 FIG4 Eleanor Williams Classified gene: FIG4 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.58 FIG4 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating at the next GMS review as there are 4 cases with variants in this gene and a leukoencephalopathy phenotype, plus a supportive mouse model.
White matter disorders and cerebral calcification - narrow panel v1.58 FIG4 Eleanor Williams Gene: fig4 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.57 FIG4 Eleanor Williams Phenotypes for gene: FIG4 were changed from Charcot-Marie-Tooth disease, type 4J 611228; Yunis-Varon syndrome 216340; leukoencephalopathy to Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Yunis-Varon syndrome, OMIM:216340; leukoencephalopathy, HP:0002352
White matter disorders and cerebral calcification - narrow panel v1.56 FIG4 Eleanor Williams Tag Q2_21_rating tag was added to gene: FIG4.
White matter disorders and cerebral calcification - narrow panel v1.56 FIG4 Eleanor Williams commented on gene: FIG4
White matter disorders and cerebral calcification - narrow panel v1.56 ERCC1 Eleanor Williams changed review comment from: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling. ; to: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child (CS20LO) was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling.
White matter disorders and cerebral calcification - narrow panel v1.56 ERCC1 Eleanor Williams Publications for gene: ERCC1 were set to 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure; 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome; 21612988
White matter disorders and cerebral calcification - narrow panel v1.55 ERCC1 Eleanor Williams edited their review of gene: ERCC1: Changed publications: 17273966, 23623389, 21612988, 33315086
White matter disorders and cerebral calcification - narrow panel v1.55 ERCC1 Eleanor Williams changed review comment from: 3 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - can't access paper. Not in PubMed but review by Gregg et al 2011 (PMID: 21612988) report that it describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.; to: 4 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. And in the 4th family liver dysfunction was reported from a young age. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - conference abstract - can't access. Review by Gregg et al 2011 (PMID: 21612988) report that this abstract describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.

PMID: 33315086 - Apelt et al 2020 - describe 2 siblings with bi-allelic ERCC1 mutations (a missense and a deletion of exon 4) and a unique phenotype of short stature, photosensitivity, progressive cholestatic liver disease, and renal tubulopathy. Mild intellectual disability is reported. Brain magnetic resonance imaging (MRI) at 10 and 12 years for the respective siblings showed mild cerebral atrophy with moderate cerebellar atrophy, and mild brainstem atrophy in one sibling.
Segmental overgrowth disorders - Deep sequencing v2.13 NLRP2 Sarah Leigh Classified gene: NLRP2 as Amber List (moderate evidence)
Segmental overgrowth disorders - Deep sequencing v2.13 NLRP2 Sarah Leigh Gene: nlrp2 has been classified as Amber List (Moderate Evidence).
Segmental overgrowth disorders - Deep sequencing v2.12 NLRP2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Maternal NLRP2 variants result in epigenitic disturbance at sites in trans, eg: IC2 in imprinting region at 11p15.5 (PMID 19300480).
Segmental overgrowth disorders - Deep sequencing v2.12 NLRP2 Sarah Leigh Mode of pathogenicity for gene: NLRP2 was changed from Other to Other
Segmental overgrowth disorders - Deep sequencing v2.11 NLRP2 Sarah Leigh gene: NLRP2 was added
gene: NLRP2 was added to Segmental overgrowth disorders. Sources: Literature
Mode of inheritance for gene: NLRP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NLRP2 were set to 26323243; 29574422; 19300480; 30877238; 33090377
Phenotypes for gene: NLRP2 were set to Beckwith-Wiedemann syndrome due to imprinting defect of 11p15 MONDO:0016475
Mode of pathogenicity for gene: NLRP2 was set to Other
Review for gene: NLRP2 was set to AMBER
Added comment: Maternal bialliec variants may result in epigentic distubance of IC2 in imprinting region at 11p15.5 in trans, resulting in Beckwith-Wiedemann syndrome (PMID 19300480) and early embryonic arest, (causing infertility)(PMID 30877238). These findings are supported by a mouse knock out model (PMID 33090377). At least 9 human NLRP2 variants have been identified in families with the above clinical features.
Sources: Literature
White matter disorders and cerebral calcification - narrow panel v1.55 ERCC1 Eleanor Williams Classified gene: ERCC1 as Green List (high evidence)
White matter disorders and cerebral calcification - narrow panel v1.55 ERCC1 Eleanor Williams Added comment: Comment on list classification: Leaving rating as green for now, but with recommendation for amber or red rating at the next GMS review. There does not appear to be evidence that this is a white matter disorder.
White matter disorders and cerebral calcification - narrow panel v1.55 ERCC1 Eleanor Williams Gene: ercc1 has been classified as Green List (High Evidence).
White matter disorders and cerebral calcification - narrow panel v1.54 ERCC1 Eleanor Williams Publications for gene: ERCC1 were set to 17273966 - ERCC1 deficiency in a patient with cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure; 23623389 - homozygous missense variant reported in a patient with Cockayne syndrome
White matter disorders and cerebral calcification - narrow panel v1.53 ERCC1 Eleanor Williams edited their review of gene: ERCC1: Added comment: 3 patients reported with biallelic variants in ERCC1. In two cases there were developmental symptoms from birth. In the third neurodegenerative symptoms became apparent at age 15. No specific mention of white matter abnormalities.

PMID: 17273966 - Jaspers et al 2007 - report a child (165TOR) with cerebro-oculo-facio-skeletal syndrome showing relatively mild impairment of Nucleotide excision repair (NER) but very severe developmental symptoms and death in early infancy. Compound heterozygous variants in ERCC1 were found (one nonsense and and one missense) each inherited from one parent. NMR showed simplified gyral pattern and cerebellar hypoplasia. NO specific white matter abnormalites are reported.

PMID: 23623389 - Kashiyama et al 2013 - through targeted sequencing of ERCC1 and ERCC4 they report 1 patient with a homozygous missense variant. The child was diagnosed with Cockayne syndrome type II. Brain MRI at birth indicated a possible polymicrogyria; a NMR scan at 4 months of age showed large bilateral subdurals but no major visible malformations; at 9 months an abnormal electroencephalogram was recorded.

Imoto K, Boyle J, Oh K, Khan S, Ueda T, Nadem C, Slor H, Orgal S, Gadoth N, Busch D, Jaspers NG, Tamura D, JJ DiGiovanna, Kraemer KH. Patients with defects in the interacting nucleotide excision repair proteins ERCC1 or XPF show xeroderma pigmentosum with late onset severe neurological degeneration. J Invest Dermatol. 2007;127 Supp. 92 - can't access paper. Not in PubMed but review by Gregg et al 2011 (PMID: 21612988) report that it describes a patient with compound het variants in ERCC1 (nonsense mutation and a splicing mutation). The patient showed progressive neurodegeneration from age 15 resulting in dementia and cortical atrophy.; Changed rating: AMBER; Changed publications: 17273966, 23623389, 21612988; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.53 ERCC1 Eleanor Williams Added comment: Comment on phenotypes: Only associated with Cerebrooculofacioskeletal syndrome 4 in OMIM and Gene2Phenotype so removing Xeroderma pigmentosum as a phenotype.
White matter disorders and cerebral calcification - narrow panel v1.53 ERCC1 Eleanor Williams Phenotypes for gene: ERCC1 were changed from Xeroderma Pigmentosum to Cerebrooculofacioskeletal syndrome 4, OMIM:610758
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Classified gene: SETD5 as Red List (low evidence)
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Added comment: Comment on list classification: Associated with Mental retardation, autosomal dominant 23 OMIM:615761 in OMIM and as confirmed Gen2Phen gene. At least one de novo variant has been reported a case of Moyamoya disease MONDO:0016820, who also had features of OMIM:615761.
Cerebral vascular malformations v2.47 SETD5 Sarah Leigh Gene: setd5 has been classified as Red List (Low Evidence).
Cerebral vascular malformations v2.46 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from MoyaMoya; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336 to Moyamoya disease MONDO:0016820; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Cerebral vascular malformations v2.45 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946 to Moyamoya disease MONDO:0016820; Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.44 CHD4 Sarah Leigh changed review comment from: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene / condition association. Moya Moya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.; to: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moyamoya disease MONDO:0016820, this is a new gene / condition association. Moyamoya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moyamoya.
Cerebral vascular malformations v2.44 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864 to Moyamoya disease MONDO:0016820; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Cerebral vascular malformations v2.43 CNOT3 Sarah Leigh changed review comment from: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), who also had some of the features of OMIM:618672.; to: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya disease MONDO:0016820, who also had some of the features of OMIM:618672.
White matter disorders and cerebral calcification - narrow panel v1.52 EPRS Eleanor Williams Classified gene: EPRS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.52 EPRS Eleanor Williams Gene: eprs has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.51 EPRS Eleanor Williams Tag Q2_21_rating tag was added to gene: EPRS.
White matter disorders and cerebral calcification - narrow panel v1.51 EPRS Eleanor Williams Classified gene: EPRS as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.51 EPRS Eleanor Williams Added comment: Comment on list classification: promoting from grey to amber but with recommendation for green rating following GMS review. 4 unrelated cases, presentation before age of 18.
White matter disorders and cerebral calcification - narrow panel v1.51 EPRS Eleanor Williams Gene: eprs has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.43 SETD5 Sarah Leigh Phenotypes for gene: SETD5 were changed from Moya Moya; Mental retardation, autosomal dominant 23, MIM# 615761 to MoyaMoya; Mental retardation, autosomal dominant 23 OMIM:615761; intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency MONDO:0014336
Early onset or syndromic epilepsy v2.330 UFSP2 Tracy Lester gene: UFSP2 was added
gene: UFSP2 was added to Genetic epilepsy syndromes. Sources: NHS GMS
Mode of inheritance for gene: UFSP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UFSP2 were set to 33473208
Phenotypes for gene: UFSP2 were set to Poor weight gain; microcephaly; epilepsy; developmental delay; lack of speech; intellectual disability
Penetrance for gene: UFSP2 were set to Complete
Mode of pathogenicity for gene: UFSP2 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: UFSP2 was set to GREEN
Added comment: This is a founder variant that has been reported homozygously in several individuals with an epileptic encephalopathy like phenotype. Three additional cases have been identified in the GEL 100K database by the MSK GeCIP. Recessive LOF variants in this gene cause a skeletal dysplasia phenotype. Functional studies support a gain of function for this variant.
Sources: NHS GMS
White matter disorders and cerebral calcification - narrow panel v1.50 EPRS Eleanor Williams edited their review of gene: EPRS: Added comment: As reported by the expert reviewer PMID: 29576217 (Mendes et al 2018) reports 4 unrelated affected individuals with hypomyelination and biallelic (homozygous or compound het) pathogenic variants in EPRS. 5 variants in total identified (1 nonsense, 1 frameshift, 3 missense). Variants segregated with the disease in all 4 families. All 4 presented initially before the age of 18 and in all brain MRI showed a hypomyelinating leukodystrophy with thinning of the corpus callosum. In 3 cases the variant was identified by WES, in one by direct sequencing of EPRS1.

PMID: 33805425 - Sawaguchi et al 2021 - using a mouse model they show that EPRS1 variant Arg339-to-Ter (R339X) (found in one of the patients in Mendes et al in heterozgyous state with another variant) localizes EPRS1 proteins as polymeric aggregates into Rab7-positive vesicle structures in mouse oligodendroglial FBD-102b cells. Wild-type proteins are distributed throughout the cell bodies. This seems to inhibit cell morphological differentiation.; Changed rating: GREEN; Changed publications: 29576217, 33805425; Changed phenotypes: Leukodystrophy, hypomyelinating, 15, OMIM:617951; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh changed review comment from: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672 in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), in addition to some of the features of OMIM:618672.; to: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (OMIM:618672) in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), who also had some of the features of OMIM:618672.
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Classified gene: CNOT3 as Amber List (moderate evidence)
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Added comment: Comment on list classification: Associated with Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672 in OMIM and as confirmed Gen2Phen gene for CNOT3 syndrome. At least two de novo variants have been reported in two cases with Moyamoya angiopathy (MMA), in addition to some of the features of OMIM:618672.
Cerebral vascular malformations v2.42 CNOT3 Sarah Leigh Gene: cnot3 has been classified as Amber List (Moderate Evidence).
Cerebral vascular malformations v2.41 CNOT3 Sarah Leigh Phenotypes for gene: CNOT3 were changed from Moya Moya; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM# 618672 to Intellectual developmental disorder with speech delay, autism, and dysmorphic facies OMIM:618672; intellectual developmental disorder with speech delay, autism, and dysmorphic facies MONDO:0032864
Adult onset leukodystrophy v1.8 EPRS Eleanor Williams commented on gene: EPRS
Adult onset leukodystrophy v1.8 EPRS Eleanor Williams Tag new-gene-name tag was added to gene: EPRS.
White matter disorders and cerebral calcification - narrow panel v1.50 EPRS Eleanor Williams commented on gene: EPRS
White matter disorders and cerebral calcification - narrow panel v1.50 EPRS Eleanor Williams Tag new-gene-name tag was added to gene: EPRS.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh changed review comment from: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene condition association. Moya Moya is relevant to this panel -Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.; to: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene / condition association. Moya Moya is relevant to this panel - Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Classified gene: CHD4 as Red List (low evidence)
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Added comment: Comment on list classification: PMID 31474762 reports variants in CHD4 cases of Moya Moya, this is a new gene condition association. Moya Moya is relevant to this panel -Cerebral vascular malformations. So far there is not enough evidence for this gene to be amber or green for Moya Moya.
Cerebral vascular malformations v2.40 CHD4 Sarah Leigh Gene: chd4 has been classified as Red List (Low Evidence).
Cerebral vascular malformations v2.39 CHD4 Sarah Leigh Publications for gene: CHD4 were set to 31474762; 27616479
Cerebral vascular malformations v2.38 CHD4 Sarah Leigh Publications for gene: CHD4 were set to 31474762
Fetal anomalies v1.644 CHD4 Sarah Leigh Added comment: Comment on phenotypes: Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease
Fetal anomalies v1.644 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Syndromic INTELLECTUAL DISABILITY with or without congenital heart disease to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Intellectual disability v3.1042 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Sifrim-Hitz-Weiss syndrome 617159 to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Cerebral vascular malformations v2.37 CHD4 Sarah Leigh Phenotypes for gene: CHD4 were changed from Moya Moya; Sifrim-Hitz-Weiss syndrome, MIM# 617159 to Sifrim-Hitz-Weiss syndrome OMIM:617159; Sifrim-Hitz-Weiss syndrome MONDO:0014946
Arthrogryposis v3.98 ERBB3 Sarah Leigh edited their review of gene: ERBB3: Added comment: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Lethal congenital contractural syndrome 2 OMIM:607598 and as a confirmed gene for Hirschprung disease with intestinal pseudo-obstruction. At least 7 variants reported in at least 4 unrelated cases.; Changed rating: GREEN
Arthrogryposis v3.98 ERBB3 Sarah Leigh Tag Q2_21_rating tag was added to gene: ERBB3.
Arthrogryposis v3.98 ERBB3 Sarah Leigh Classified gene: ERBB3 as Amber List (moderate evidence)
Arthrogryposis v3.98 ERBB3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Arthrogryposis v3.98 ERBB3 Sarah Leigh Gene: erbb3 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v3.97 ERBB3 Sarah Leigh Publications for gene: ERBB3 were set to 17701904; 12519750
Arthrogryposis v3.96 ERBB3 Sarah Leigh Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2 607598 to ?Lethal congenital contractural syndrome 2 OMIM:607598; lethal congenital contracture syndrome 2 MONDO:0011868
Skeletal dysplasia v2.91 FBN2 Sarah Leigh Deleted their comment
Skeletal dysplasia v2.91 FBN2 Sarah Leigh commented on gene: FBN2: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.
DDG2P v2.27 FBN2 Sarah Leigh commented on gene: FBN2: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.
DDG2P v2.27 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.643 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.91 FBN2 Sarah Leigh edited their review of gene: FBN2: Added comment: It would appear from PMIDs 33571691, 25558065 & 28383543 that biallelic variants should be considered for this gene and as such the MOI should be changed to BOTH monallelic and biallelic, autosomal or pseudoautosomal.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v2.91 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
DDG2P v2.27 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from CONGENITAL CONTRACTURAL ARACHNODACTYLY 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Fetal anomalies v1.643 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from CONGENITAL CONTRACTURAL ARACHNODACTYLY to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Skeletal dysplasia v2.90 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Skeletal dysplasia v2.89 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032; 33571691; 25558065; 28383543
DDG2P v2.26 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 10797416; 11281275; 9199560; 8900230; 9737771; 20799338; 9106527
DDG2P v2.25 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Fetal anomalies v1.642 FBN2 Sarah Leigh Publications for gene: FBN2 were set to
Skeletal dysplasia v2.88 FBN2 Sarah Leigh Publications for gene: FBN2 were set to
Fetal anomalies v1.641 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Skeletal dysplasia v2.87 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Arthrogryposis v3.95 FBN2 Sarah Leigh reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Arthrogryposis v3.95 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032; 33571691
Arthrogryposis v3.94 FBN2 Sarah Leigh Tag Q2_21_MOI tag was added to gene: FBN2.
Arthrogryposis v3.94 FBN2 Sarah Leigh Phenotypes for gene: FBN2 were changed from Contractural arachnodactyly, congenital 121050 to Contractural arachnodactyly, congenital OMIM:121050; congenital contractural arachnodactyly MONDO:0007363
Arthrogryposis v3.93 FBN2 Sarah Leigh Publications for gene: FBN2 were set to 7493032
Likely inborn error of metabolism v2.127 OPA1 Sarah Leigh Added comment: Comment on phenotypes: Optic atrophy plus syndrome, 125250;{Glaucoma, normal tension, susceptibility to}, 606657;Disorders of mitochondrial DNA maintenance and integrity;Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions;Optic atrophy 1, 165500;Mitochondrial DNA Depletion Syndrome;Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Likely inborn error of metabolism v2.127 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to}, 606657; Disorders of mitochondrial DNA maintenance and integrity; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Mitochondrial disorders v2.34 OPA1 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity;{Glaucoma, normal tension, susceptibility to}, 606657
Mitochondrial disorders v2.34 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Disorders of mitochondrial DNA maintenance and integrity; Optic atrophy 1, 165500; {Glaucoma, normal tension, susceptibility to}, 606657; Optic atrophy plus syndrome, 125250; Mitochondrial DNA Depletion Syndrome; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500 to ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Ataxia and cerebellar anomalies - narrow panel v2.149 OPA1 Sarah Leigh edited their review of gene: OPA1: Added comment: Associated with relevant phenotypes in OMIM and as confirmed Gen2Phen gene for Optic atrophy plus syndrome OMIM:125250 and a probable gene for Behr syndrome OMIM:210000. At least biallelic 11 variants reported in at least 10 unrelated cases (summarized in PMID 28494813, additional file 7).; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.149 OPA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: OPA1.
Ataxia and cerebellar anomalies - narrow panel v2.149 OPA1 Sarah Leigh Classified gene: OPA1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.149 OPA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.149 OPA1 Sarah Leigh Gene: opa1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.148 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome, MIM# 125250 to Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Ataxia and cerebellar anomalies - narrow panel v2.147 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 28494813; 27150940; 24970096; 11017079; 11017080; 17722006; 25012220
Likely inborn error of metabolism v2.126 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 27604308
Mitochondrial disorders v2.33 OPA1 Sarah Leigh Publications for gene: OPA1 were set to
Ataxia and cerebellar anomalies - narrow panel v2.146 OPA1 Sarah Leigh Publications for gene: OPA1 were set to 28494813
Ataxia and cerebellar anomalies - narrow panel v2.145 OPA1 Sarah Leigh Mode of inheritance for gene: OPA1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Holoprosencephaly - NOT chromosomal v2.17 DISP1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: DISP1.
Holoprosencephaly - NOT chromosomal v2.17 DISP1 Sarah Leigh Publications for gene: DISP1 were set to 27363716
White matter disorders and cerebral calcification - narrow panel v1.50 DEGS1 Eleanor Williams Classified gene: DEGS1 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.50 DEGS1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for green rating at the next GMS review. >3 cases reported with a plausible disease causing variant in DEGS1. Presentation is in young children.
White matter disorders and cerebral calcification - narrow panel v1.50 DEGS1 Eleanor Williams Gene: degs1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.49 DEGS1 Eleanor Williams Tag Q2_21_rating tag was added to gene: DEGS1.
White matter disorders and cerebral calcification - narrow panel v1.49 DEGS1 Eleanor Williams Phenotypes for gene: DEGS1 were changed from Leukodystrophy, hypomyelinating, 18, MIM#618404 to Leukodystrophy, hypomyelinating, 18, OMIM:618404
White matter disorders and cerebral calcification - narrow panel v1.48 DEGS1 Eleanor Williams Publications for gene: DEGS1 were set to 30620338; 30620337
White matter disorders and cerebral calcification - narrow panel v1.47 DEGS1 Eleanor Williams reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30620338, 30620337, 31186544; Phenotypes: Leukodystrophy, hypomyelinating, 18, OMIM:618404; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.641 FKBP8 Rhiannon Mellis reviewed gene: FKBP8: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29261186; Phenotypes: Vertebral segmentation defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.144 OPA1 Sarah Leigh Mode of inheritance for gene: OPA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.143 NKX2-1 Sarah Leigh edited their review of gene: NKX2-1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in unrelated cases of Choreoathetosis, hypothyroidism, and neonatal respiratory distress OMIM:610978.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.143 NKX2-1 Sarah Leigh Tag Q2_21_rating tag was added to gene: NKX2-1.
Ataxia and cerebellar anomalies - narrow panel v2.143 NKX2-1 Sarah Leigh Classified gene: NKX2-1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.143 NKX2-1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.143 NKX2-1 Sarah Leigh Gene: nkx2-1 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.47 DCAF17 Eleanor Williams Phenotypes for gene: DCAF17 were changed from Woodhouse-Sakati syndrome, MIM# 241080 to Woodhouse-Sakati syndrome, OMIM:241080
White matter disorders and cerebral calcification - narrow panel v1.46 DCAF17 Eleanor Williams Publications for gene: DCAF17 were set to 19026396; 20507343
White matter disorders and cerebral calcification - narrow panel v1.45 DCAF17 Eleanor Williams changed review comment from: Associated with Woodhouse-Sakati syndrome in OMIM (#241080 (AR))
DCAF17 is also known as C2ORF37

PMID: 19026396 - Alazami et al 2008 - report single bp deletion in C2orf37 in 8 families of Saudi origin (identified as a founder mutation). Patients phenotypes included hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (Woodhouse-Sakati syndrome). 3 other variants were then found in patients of different ethnicities (another 1 bp deletion leading to a frameshift and 2 variants affecting splice donor sites). The variants segregated with the disease in all families. The two 1 bp changes are predicted to affect the beta isoform only.

PMID: 20507343 - Alazami et al 2010 - report 7 new patients from 4 families (3 ethnic backgrounds, Italian, French Gypsy and Turkish) who present with Woodhouse-Sakati syndrome. Each family had a different variant in C2orf37 - 3 nonsense mutations and a splice site ablation.

PMID: 30409855 - Abusrair et al 2018 - reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome. All participants had confirmed homozygous pathogenic variants in DCAF17. White matter lesions were observed in 18 patients (69.2%).; to: Associated with Woodhouse-Sakati syndrome in OMIM (#241080 (AR))
DCAF17 is also known as C2ORF37

PMID: 19026396 - Alazami et al 2008 - report single bp deletion in C2orf37 in 8 families of Saudi origin (identified as a founder mutation). Patients phenotypes included hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (Woodhouse-Sakati syndrome). 3 other variants were then found in patients of different ethnicities (another 1 bp deletion leading to a frameshift and 2 variants affecting splice donor sites). The variants segregated with the disease in all families. The two 1 bp changes are predicted to affect the beta isoform only.

PMID: 20507343 - Alazami et al 2010 - report 7 new patients from 4 families (3 ethnic backgrounds, Italian, French Gypsy and Turkish) who present with Woodhouse-Sakati syndrome. Each family had a different variant in C2orf37 - 3 nonsense mutations and a splice site ablation.

PMID: 30409855 - Abusrair et al 2018 - reviewed brain MR images of 26 patients with a clinical and genetic diagnosis of Woodhouse-Sakati syndrome. All participants had confirmed homozygous pathogenic variants in DCAF17. White matter lesions were observed in 18 patients (69.2%).

PMID: 31726291 - Bohlega et al 2019 - report on 38 individuals from 17 families were identified as having a clinically and genetically confirmed diagnosis of WSS. All patients shared the same founder DCAF17: NM_001164821:exon4: c.436delC:p.L146fs frameshift deletion. Two groups identified based on phenotype. The age of onset of neurological symptoms for the group with the more severe phenotype was 12.6 ± 4.5 years (range, 9–17 years).
Ataxia and cerebellar anomalies - narrow panel v2.142 NKX2-1 Sarah Leigh Phenotypes for gene: NKX2-1 were changed from Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978; Chorea, hereditary benign MIM#118700 to Choreoathetosis, hypothyroidism, and neonatal respiratory distress OMIM; hereditary progressive chorea without dementia MONDO:0021011:610978; brain-lung-thyroid syndrome MONDO:0012593; Chorea, hereditary benign OMIM:118700
Ataxia and cerebellar anomalies - narrow panel v2.141 MVK Sarah Leigh edited their review of gene: MVK: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene for Mevalonic aciduria OMIM:610377. At least nine variants reported at least seven unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.141 MVK Sarah Leigh Tag Q2_21_rating tag was added to gene: MVK.
White matter disorders and cerebral calcification - narrow panel v1.45 DCAF17 Eleanor Williams Classified gene: DCAF17 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.45 DCAF17 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for green rating following GMS review. >3 cases of variants in DCAF17 in patients with Woodhouse-Sakati syndrome and white matter lesions observed in approx 70% of patients.
White matter disorders and cerebral calcification - narrow panel v1.45 DCAF17 Eleanor Williams Gene: dcaf17 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.44 DCAF17 Eleanor Williams Tag Q2_21_rating tag was added to gene: DCAF17.
Ataxia and cerebellar anomalies - narrow panel v2.141 MVK Sarah Leigh Publications for gene: MVK were set to 24896178; 26503795
Ataxia and cerebellar anomalies - narrow panel v2.140 MVK Sarah Leigh Added comment: Comment on phenotypes: Variants are associated with Hyper-IgD syndrome OMIM:260920 (biallelic) & Porokeratosis 3, multiple types OMIM:175900 (monoallelic).
Ataxia and cerebellar anomalies - narrow panel v2.140 MVK Sarah Leigh Phenotypes for gene: MVK were changed from Mevalonic aciduria 610377 to Mevalonic aciduria OMIM:610377; mevalonic aciduria MONDO:0012481
White matter disorders and cerebral calcification - narrow panel v1.44 DCAF17 Eleanor Williams reviewed gene: DCAF17: Rating: ; Mode of pathogenicity: None; Publications: 19026396, 20507343, 30409855; Phenotypes: Woodhouse-Sakati syndrome OMIM:241080; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.139 MTFMT Sarah Leigh edited their review of gene: MTFMT: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in at least eight unrelated cases of Combined oxidative phosphorylation deficiency 15 OMIM:614947.; Changed rating: GREEN
Intellectual disability v3.1041 PIGC Arina Puzriakova Classified gene: PIGC as Amber List (moderate evidence)
Intellectual disability v3.1041 PIGC Arina Puzriakova Added comment: Comment on list classification: There are now at least 3 unrelated families with biallelic variants in this gene, and severe DD/ID is evident in all cases (PMIDs: 27694521; 32707268) . Therefore, PIGC can be upgraded to Green status at the next GMS panel update.
Intellectual disability v3.1041 PIGC Arina Puzriakova Gene: pigc has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.139 MTFMT Sarah Leigh Tag Q2_21_rating tag was added to gene: MTFMT.
Ataxia and cerebellar anomalies - narrow panel v2.139 MTFMT Sarah Leigh Classified gene: MTFMT as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.139 MTFMT Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.139 MTFMT Sarah Leigh Gene: mtfmt has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.138 MTFMT Sarah Leigh Publications for gene: MTFMT were set to 26060307; 24461907
Intellectual disability v3.1040 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Intellectual disability v3.1039 PIGC Arina Puzriakova Publications for gene: PIGC were set to 27694521
Ataxia and cerebellar anomalies - narrow panel v2.137 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15 MIM#614947; Mitochondrial complex I deficiency, nuclear type 27 MIM#618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Intellectual disability v3.1038 PIGC Arina Puzriakova Tag Q2_21_rating tag was added to gene: PIGC.
Mitochondrial disorders v2.32 MTFMT Sarah Leigh Added comment: Comment on phenotypes: Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Mitochondrial disorders v2.32 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Early onset or syndromic epilepsy v2.330 PIGC Arina Puzriakova Phenotypes for gene: PIGC were changed from Glycosylphosphatidylinositol biosynthesis defect 16, 617816 to Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816
Early onset or syndromic epilepsy v2.329 PIGC Arina Puzriakova Publications for gene: PIGC were set to
Early onset or syndromic epilepsy v2.328 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1038 PIGC Arina Puzriakova reviewed gene: PIGC: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707268; Phenotypes: Glycosylphosphatidylinositol biosynthesis defect 16, OMIM:617816; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.91 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27, 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Intellectual disability v3.1038 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Likely inborn error of metabolism v2.125 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15 614947; Mitochondrial complex I deficiency, nuclear type 27 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Possible mitochondrial disorder - nuclear genes v1.41 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15, 614947; Mitochondrial complex I deficiency, nuclear type 27, 618248 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Inherited white matter disorders v1.91 MTFMT Sarah Leigh Phenotypes for gene: MTFMT were changed from Combined oxidative phosphorylation deficiency 15; 614947; 22499348; 23499752 to Combined oxidative phosphorylation deficiency 15 OMIM:614947; combined oxidative phosphorylation defect type 15 MONDO:0013987; Mitochondrial complex I deficiency, nuclear type 27 OMIM:618248; mitochondrial complex 1 deficiency, nuclear type 27 MONDO:0032631
Primary immunodeficiency or monogenic inflammatory bowel disease v2.419 MPEG1 Arina Puzriakova Phenotypes for gene: MPEG1 were changed from Immunodeficiency 77, MIM# 619223 to Immunodeficiency 77, OMIM:619223
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Classified gene: MPEG1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Sufficient number of unrelated cases (5 - PMIDs: 33224153; 28422754) with immunopathology and distinct biallelic variants in this gene to rate as Green at the next GMS panel update. Supported by functional evidence and animal model.

MPEG1 is also associated with a relevant phenotype in OMIM (MIM# 619223)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.418 MPEG1 Arina Puzriakova Gene: mpeg1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 MPEG1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: MPEG1.
Intestinal failure or congenital diarrhoea v1.36 IL37 Arina Puzriakova gene: IL37 was added
gene: IL37 was added to Intestinal failure. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Classified gene: IL37 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Added comment: Comment on list classification: Rating Red awaiting further evidence, as only a single case reported to date (PMID: 33674380)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.417 IL37 Arina Puzriakova Gene: il37 has been classified as Red List (Low Evidence).
Adult onset hereditary spastic paraplegia v1.17 CYP2U1 Sarah Leigh changed review comment from: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of CYP2U1 on the this - Hereditary spastic paraplegia - adult onset, as variants in CYP2U1 are usually associated with Spastic paraplegia 56, autosomal recessive OMIM:615030 in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of CYP2U1 on the Hereditary spastic paraplegia - adult onset panel, as variants in CYP2U1 are usually associated with Spastic paraplegia 56, autosomal recessive OMIM:615030 in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Adult onset hereditary spastic paraplegia v1.17 CYP2U1 Sarah Leigh reviewed gene: CYP2U1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Adult onset hereditary spastic paraplegia v1.17 CYP2U1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CYP2U1.
Ataxia and cerebellar anomalies - narrow panel v2.136 ADPRHL2 Sarah Leigh Tag Q2_21_rating tag was added to gene: ADPRHL2.
Hereditary ataxia with onset in adulthood v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justifyied inorder to ensure that edge cases may be identified.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justified to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Hereditary ataxia with onset in adulthood v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review tag has been added to this gene as there is a conflict of opinion of the rating of ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood. The green rating may be justifyied inorder to ensure that edge cases may be identified.
GMS opinion is sort on this issue.
Hereditary ataxia with onset in adulthood v2.42 ADPRHL2 Sarah Leigh changed review comment from: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel.as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.; to: The Q2_21_expert_review has been added to this gene as there is a conflict of opinion of the rating of this ADPRHL2 on the this - Hereditary ataxia - adult onset - panel, as variants in ADPRHL2 are usually associated with Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures OMIM:618170 in infancy or in childhood.
GMS opinion is sort on this issue.
Hereditary ataxia with onset in adulthood v2.42 ADPRHL2 Sarah Leigh reviewed gene: ADPRHL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Hereditary ataxia with onset in adulthood v2.42 ADPRHL2 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: ADPRHL2.
Ataxia and cerebellar anomalies - narrow panel v2.136 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.136 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Ataxia and cerebellar anomalies - narrow panel v2.136 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.135 EEF2 Eleanor Williams gene: EEF2 was added
gene: EEF2 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EEF2 were set to 23001565; 33355653
Phenotypes for gene: EEF2 were set to Spinocerebellar ataxia 26 OMIM:609306
Review for gene: EEF2 was set to AMBER
Added comment: Provisionally associated with ?Spinocerebellar ataxia 26 #609306 (AD) in OMIM based on Hekman et al 2012 case.

PMID: 23001565 - Hekman et al 2012 - report a six-generation kindred of Norwegian ancestry with a late-onset pure cerebellar ataxia in which a heterozygous P596H substitution in eEF2 was found to segregate with the disease phenotype in 24 individuals and two currently asymptomatic individuals. Functional studies in yeast showed that the variant (P580H in the EFT2 gene in yeast) affected translational fidelity.

PMID: 33355653 - Nabais Sá et al 2021 - identified de novo EEF2 missense variants in 3 unrelated children (3, 6 and 9 years of age) with a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly.
Sources: Literature
Hereditary ataxia with onset in adulthood v2.42 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Hereditary ataxia with onset in adulthood v2.42 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Hereditary ataxia with onset in adulthood v2.42 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Hereditary ataxia with onset in adulthood v2.41 EEF2 Eleanor Williams gene: EEF2 was added
gene: EEF2 was added to Hereditary ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: EEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: EEF2 were set to 23001565; 33355653
Phenotypes for gene: EEF2 were set to Spinocerebellar ataxia 26 OMIM:609306
Review for gene: EEF2 was set to AMBER
Added comment: Provisionally associated with ?Spinocerebellar ataxia 26 #609306 (AD) in OMIM based on Hekman et al 2012 case.

PMID: 23001565 - Hekman et al 2012 - report a six-generation kindred of Norwegian ancestry with a late-onset pure cerebellar ataxia in which a heterozygous P596H substitution in eEF2 was found to segregate with the disease phenotype in 24 individuals and two currently asymptomatic individuals. Functional studies in yeast showed that the variant (P580H in the EFT2 gene in yeast) affected translational fidelity.

PMID: 33355653 - Nabais Sá et al 2021 - identified de novo EEF2 missense variants in 3 unrelated children (3, 6 and 9 years of age) with a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly.
Sources: Literature
Lipodystrophy - childhood onset v2.9 OTULIN Zornitza Stark gene: OTULIN was added
gene: OTULIN was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OTULIN were set to 27523608; 27559085
Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Review for gene: OTULIN was set to GREEN
gene: OTULIN was marked as current diagnostic
Added comment: Autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein, leukocytosis, and neutrophilia in the absence of any infection.

At least 3 unrelated families reported.
Sources: Expert Review
Lipodystrophy - childhood onset v2.9 KCNJ6 Zornitza Stark gene: KCNJ6 was added
gene: KCNJ6 was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: KCNJ6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ6 were set to 25620207; 29852244
Phenotypes for gene: KCNJ6 were set to Keppen-Lubinsky syndrome, MIM# 614098; MONDO:0013572
Review for gene: KCNJ6 was set to GREEN
gene: KCNJ6 was marked as current diagnostic
Added comment: Keppen-Lubinsky syndrome characterised by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth.

Four unrelated individuals reported with de novo variants in this gene (one recurred in 2), mouse model. One of the individuals did not have lipodystrophy but had a prominent hyperkinetic movement disorder.
Sources: Expert Review
Lipodystrophy - childhood onset v2.9 FBN1 Zornitza Stark gene: FBN1 was added
gene: FBN1 was added to Lipodystrophy - childhood onset. Sources: Expert Review
Mode of inheritance for gene: FBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBN1 were set to 20979188; 21594992; 21594993; 24613577; 26860060; 29666143
Phenotypes for gene: FBN1 were set to Marfan lipodystrophy syndrome, MIM# 616914
Review for gene: FBN1 was set to GREEN
gene: FBN1 was marked as current diagnostic
Added comment: The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development.

This specific phenotype is caused by variants occurring in or affecting exon 64.

More than 5 unrelated individuals reported, rabbit model.
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Classified gene: ZNFX1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Sufficient number of unrelated cases (10 - PMIDs: 33876776; 33872655) with immunopathology and biallelic variants in this gene to rate as Green at the next GMS panel update.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.416 ZNFX1 Arina Puzriakova Gene: znfx1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.415 ZNFX1 Arina Puzriakova Publications for gene: ZNFX1 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 ZNFX1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ZNFX1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 ZNFX1 Arina Puzriakova reviewed gene: ZNFX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33876776, 33872655; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.134 CYP2U1 Sarah Leigh changed review comment from: Comment on phenotypes: Autosomal recessive spastic paraplegia 56 (#615030) complex form of disorder, ataxia not yet identified in affected patients.; to: Comment on phenotypes: Autosomal recessive spastic paraplegia 56 (#615030) is a complex form of disorder, ataxia not yet identified in affected patients (Table 1 in PMID: 27292318 provides a review of cases reported so far).
Ataxia and cerebellar anomalies - narrow panel v2.134 CYP2U1 Sarah Leigh Tag Q2_21_expert_review tag was added to gene: CYP2U1.
Intellectual disability v3.1037 JMJD1C Zornitza Stark gene: JMJD1C was added
gene: JMJD1C was added to Intellectual disability. Sources: Expert Review
Mode of inheritance for gene: JMJD1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JMJD1C were set to 26181491; 32996679
Phenotypes for gene: JMJD1C were set to Intellectual disability
Review for gene: JMJD1C was set to GREEN
gene: JMJD1C was marked as current diagnostic
Added comment: Reported in ID cohort (with Rett-like phenotypic overlap) with supporting functional studies (PMID: 26181491). 7 individuals with rare variants identified, and variants demonstrated to be de novo in 2, one with a Rett-like phenotype and the other with ID. Functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. JMJD1C protein shown to be widely expressed in brain regions and that its depletion compromised dendritic activity.

Splice-disrupting JMJD1C variant reported in association with learning disability and myoclonic epilepsy (PMID 32996679).

Disruption of gene due to balanced translocation (PMID 33591602) implicated in autism spectrum disease phenotype.
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Tag Q2_21_rating tag was added to gene: SYK.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Classified gene: SYK as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - PMID:33782605 report distinct monoallelic GoF variants in 5 families (6 individuals) with immune dysregulation and inflammation. Expression of one of these variants in a mouse model replicated aspects of the human immunopathology.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.414 SYK Arina Puzriakova Gene: syk has been classified as Amber List (Moderate Evidence).
Holoprosencephaly - NOT chromosomal v2.16 DISP1 Zornitza Stark reviewed gene: DISP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19184110, 26748417, 23542665; Phenotypes: Holoprosencephaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Haematological malignancies for rare disease v1.1 RAD51 Zornitza Stark reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: None; Publications: 30907510; Phenotypes: Fanconi anemia, complementation group R 617244; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Rare multisystem ciliopathy disorders v1.142 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1037 LAMA1 Sarah Leigh reviewed gene: LAMA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Ataxia and cerebellar anomalies - narrow panel v2.134 LAMA1 Sarah Leigh edited their review of gene: LAMA1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least five variants reported in at least three unrelated cases.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.134 LAMA1 Sarah Leigh Tag Q2_21_rating tag was added to gene: LAMA1.
Intellectual disability v3.1037 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Rare multisystem ciliopathy disorders v1.142 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from cerebellar cysts; myopia; cerebellar vermis hypoplasia; gaze palsy; retinitis pigments to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Intellectual disability v3.1036 LAMA1 Sarah Leigh Publications for gene: LAMA1 were set to 21937992; 30244536
Rare multisystem ciliopathy disorders v1.141 LAMA1 Sarah Leigh Publications for gene: LAMA1 were set to https://www.ncbi.nlm.nih.gov/pubmed/25105227
Rare multisystem ciliopathy disorders v1.140 LAMA1 Sarah Leigh Classified gene: LAMA1 as Green List (high evidence)
Rare multisystem ciliopathy disorders v1.140 LAMA1 Sarah Leigh Gene: lama1 has been classified as Green List (High Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.134 LAMA1 Sarah Leigh Phenotypes for gene: LAMA1 were changed from Cerebellar ataxia, intellectual disability, oculomotor apraxia, cerebellar cysts; Poretti Boltshauser syndrome MIM#615960 to Poretti-Boltshauser syndrome OMIM:615960; ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome MONDO:0014419
Ataxia and cerebellar anomalies - narrow panel v2.133 LAMA1 Sarah Leigh Classified gene: LAMA1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.133 LAMA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.133 LAMA1 Sarah Leigh Gene: lama1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.132 KCNA2 Sarah Leigh edited their review of gene: KCNA2: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported in numberous cases, together with supportive functional studies, demonstrating GOF and LOF mechanisms.; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.132 KCNA2 Sarah Leigh Classified gene: KCNA2 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.132 KCNA2 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.132 KCNA2 Sarah Leigh Gene: kcna2 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.131 KCNA2 Sarah Leigh Tag Q2_21_rating tag was added to gene: KCNA2.
Ataxia and cerebellar anomalies - narrow panel v2.131 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 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
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Early onset or syndromic epilepsy v2.328 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Hereditary ataxia v1.216 EEF2 Eleanor Williams Classified gene: EEF2 as Amber List (moderate evidence)
Hereditary ataxia v1.216 EEF2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from red to amber on advice of Genomics England clinical team. Amber rating selected pending further cases and delineation of the phenotype
Hereditary ataxia v1.216 EEF2 Eleanor Williams Gene: eef2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.327 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Epileptic encephalopathy, early infantile, 32; EPILEPTIC ENCEPHALOPATHY to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Ataxia and cerebellar anomalies - narrow panel v2.130 KCNA2 Sarah Leigh Phenotypes for gene: KCNA2 were changed from Early infantile encephalopathy 32, MIM#616366 to Developmental and epileptic encephalopathy 32 OMIM:616366; developmental and epileptic encephalopathy, 32 MONDO:0014607
Ataxia and cerebellar anomalies - narrow panel v2.129 KCNA2 Sarah Leigh Added comment: Comment on mode of pathogenicity: Both dominant negative variants that result in LOF effect (RCV000170511, rs786205231) and GOF variants (rs786205231, rs786205232) have been associated with Developmental and epileptic encephalopathy 32 OMIM:616366
Ataxia and cerebellar anomalies - narrow panel v2.129 KCNA2 Sarah Leigh Mode of pathogenicity for gene: KCNA2 was changed from None to None
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene as Green at the next GMS panel update - sufficient number of unrelated cases (4, plus 1 unpublished), all presenting GDD as an early feature. Particularly pertinent to less severely affected individuals who do not develop seizures.
Intellectual disability v3.1035 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.326 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to Syrbe et al (2015) Nat Genet 47(4): 393-9
Ataxia and cerebellar anomalies - narrow panel v2.128 KCNA2 Sarah Leigh Publications for gene: KCNA2 were set to 29050392
Intellectual disability v3.1034 NEUROD2 Arina Puzriakova gene: NEUROD2 was added
gene: NEUROD2 was added to Intellectual disability. Sources: Literature
Q2_21_rating tags were added to gene: NEUROD2.
Mode of inheritance for gene: NEUROD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NEUROD2 were set to 16504944; 30323019; 33438828
Phenotypes for gene: NEUROD2 were set to Developmental and epileptic encephalopathy 72, OMIM:618374
Review for gene: NEUROD2 was set to GREEN
Added comment: NEUROD2 is associated with a relevant phenotype in OMIM (MIM# 618374), but is not yet listed in Gene2Phenotype.

- PMID: 30323019 (2019) - Two unrelated children with refractory early-infantile epileptic encephalopathy. Developmental delay (DD) preceded onset of seizures in both cases, with signs of DD becoming evident at 2-4 months and seizures arising at 5 months of age. Patient 1 became seizure-free after introducing a ketogenic diet at 16 months; however, an EEG at 22 months remained abnormal and she continues to have severe GDD with no independent sitting, walking or speaking at the chronological age of 3 years and 2 months. Patient 2 became seizure-free when a vagal nerve stimulator (VNS) was placed at 16 months of age. He displayed significant improvement on EEG and subsequently began regaining neurodevelopmental milestones.
WES revealed different de novo variants in the NEUROD2 gene (P1: c.388G>C, p.E130Q; P2: c.401T>C, p.M134T, respectively). Knockdown of the neurod2 in Xenopus tropicalis tadpoles resulted in abnormal swimming behaviour and progressive seizures followed by periods of immobility. Overexpression of wild-type human NEUROD2 in tadpoles induced non-neuronal cells to differentiate into neurons - on the other hand, overexpression of the mutant alleles failed to to cause any (p.E130Q) or a comparable degree (p.M134T) of ectopic neuronal induction as seen with the wild-type protein.

- Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word)

----- Cases without seizures -

- PMID: 33438828 (2021) - Adolescent (14 yrs old) with GDD but without seizures who was found to have a novel de novo NEUROD2 missense variant (c.488 T > C, p.L163P). An additional individual (12 yrs) with DD and a different missense NEUROD2 (c.703G>A, p.A235T) was also identified, but lacking parental samples for segregation analysis.
Functional analysis in Xenopus laevis revealed that injection of the p.L163P mRNA variant resulted in a defective ability to induce ectopic neurons in tadpoles as compared with wild-type NEUROD2 mRNA, while the p.A235T variant functioned similarly to wild-type.
Sources: Literature
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Classified gene: NEUROD2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 2 cases in literature (plus 1 unpublished case) with infantile seizures and heterozygous variants in this gene, supported by animal models.

Associated with relevant phenotype in OMIM (MIM# 618374) but not yet listed in Gene2Phenotype.
Early onset or syndromic epilepsy v2.325 NEUROD2 Arina Puzriakova Gene: neurod2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NEUROD2.
Early onset or syndromic epilepsy v2.324 NEUROD2 Arina Puzriakova edited their review of gene: NEUROD2: Added comment: - Conference poster (Genomics of Rare Disease 2021) - 'Neuronal Differentiation Factor 2 (NEUROD2) Pathogenic Variant as a Molecular Aetiology of Infantile Spasm ' by Sakpichaisakul et al, QSNICH, Thailand -
In a 15 month-old female with infantile spasm, trio exome sequencing revealed a de novo variant in NEUROD2 (c.388G>C, p.E130Q). She was born of non-consanguineous healthy parents with no family history of epilepsy. Poor eye contact and no social smile were noted in the first few months, followed by the first infantile spasm at 5 months of age. This was initially controlled by combined vigabatrin and prednisolone therapy - however relapsing seizures were detected at 15 months. Sequential treatment with vigabatrin following prednisolone resulted in cessation of seizures, and subsequently regaining of neurodevelopmental milestones (sitting without support, grabbing objects without pincer grasp and speaking one single word); Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.127 EXOSC1 Sarah Leigh Added comment: Comment on phenotypes: No phenotype in OMIM or in MONDO (21/04/2021)
Ataxia and cerebellar anomalies - narrow panel v2.127 EXOSC1 Sarah Leigh Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - narrow panel v2.126 EXOSC1 Sarah Leigh Classified gene: EXOSC1 as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.126 EXOSC1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic variant reported.
Ataxia and cerebellar anomalies - narrow panel v2.126 EXOSC1 Sarah Leigh Gene: exosc1 has been classified as Red List (Low Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.125 EXOSC1 Sarah Leigh Added comment: Comment on phenotypes: No phenotype listed in OMIM or in MONDO (21/04/2021)
Ataxia and cerebellar anomalies - narrow panel v2.125 EXOSC1 Sarah Leigh Phenotypes for gene: EXOSC1 were changed from Pontocerebellar hypoplasia to Pontocerebellar hypoplasia
Ataxia and cerebellar anomalies - narrow panel v2.124 EXOSC1 Sarah Leigh Classified gene: EXOSC1 as Red List (low evidence)
Ataxia and cerebellar anomalies - narrow panel v2.124 EXOSC1 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic variant reported (PMID 33463720).
Ataxia and cerebellar anomalies - narrow panel v2.124 EXOSC1 Sarah Leigh Gene: exosc1 has been classified as Red List (Low Evidence).
Likely inborn error of metabolism v2.124 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Likely inborn error of metabolism v2.124 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from No OMIM phenotype; Isolated complex I deficiency to Congenital lactic acidosis; hypertrophic cardiomyopathy
Mitochondrial disorders v2.31 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Mitochondrial disorders v2.31 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from Isolated complex I deficiency; No OMIM phenotype to Congenital lactic acidosis; hypertrophic cardiomyopathy
Likely inborn error of metabolism v2.123 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Mitochondrial disorder with complex I deficiency v1.13 NDUFB7 Sarah Leigh Added comment: Comment on phenotypes: No OMIM or MONDO phenotype (21/4/2021)
Mitochondrial disorder with complex I deficiency v1.13 NDUFB7 Sarah Leigh Phenotypes for gene: NDUFB7 were changed from No OMIM phenotype to Congenital lactic acidosis; hypertrophic cardiomyopathy
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Likely inborn error of metabolism v2.122 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorder with complex I deficiency v1.12 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Likely inborn error of metabolism v2.121 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to 33502047; 27626371
Mitochondrial disorders v2.30 NDUFB7 Sarah Leigh Tag watchlist tag was added to gene: NDUFB7.
Likely inborn error of metabolism v2.121 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Mitochondrial disorder with complex I deficiency v1.12 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Mitochondrial disorders v2.30 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.11 NDUFB7 Sarah Leigh Mode of inheritance for gene: NDUFB7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Mitochondrial disorder with complex I deficiency v1.10 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Classified gene: NDUFB7 as Amber List (moderate evidence)
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Added comment: Comment on list classification: Not associated with relevant phenotype in OMIM or Gen2Phen. At least one biallelic splicing variant reported. RNA sequencing revealed that this variant disrupted normal splicing (PMID 33502047) and human knock-out cells have shown that NDUFB7 is one of the subunits strictly required for assembly of a functional mitochondrial complex I subunit, which is essential for cell viability (PMID 27626371).
Mitochondrial disorders v2.29 NDUFB7 Sarah Leigh Gene: ndufb7 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.28 NDUFB7 Sarah Leigh Publications for gene: NDUFB7 were set to
Clefting v2.28 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Red List (low evidence)
Clefting v2.28 ACBD5 Arina Puzriakova Added comment: Comment on list classification: Only a single patient reported with a cleft palate to date, and therefore rating Red on this panel.
Clefting v2.28 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Red List (Low Evidence).
Clefting v2.27 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Cleft palate to Retinal dystrophy with leukodystrophy, OMIM:618863
Clefting v2.26 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to
Clefting v2.25 ACBD5 Arina Puzriakova Mode of inheritance for gene: ACBD5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Inherited white matter disorders v1.90 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409, 27899449, 23105016
Inherited white matter disorders v1.89 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from to Retinal dystrophy with leukodystrophy, OMIM:618863
Inherited white matter disorders v1.88 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Green List (high evidence)
Inherited white matter disorders v1.88 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Green List (High Evidence).
Inherited white matter disorders v1.87 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23105016, 27899449, 27799409, 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.44 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Retinal dystrophy with leukodystrophy, OMIM:618863 to Retinal dystrophy with leukodystrophy, OMIM:618863
White matter disorders and cerebral calcification - narrow panel v1.43 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 23105016; 27899449; 27799409; 33427402
Peroxisomal disorders v1.12 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016; 33427402
White matter disorders and cerebral calcification - narrow panel v1.42 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409, 27899449, 23105016
White matter disorders and cerebral calcification - narrow panel v1.41 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from to Retinal dystrophy with leukodystrophy, OMIM:618863
White matter disorders and cerebral calcification - narrow panel v1.40 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.40 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are sufficient unrelated cases (3) to support a diagnostic-grade classification (Green) at the next GMS panel update
White matter disorders and cerebral calcification - narrow panel v1.40 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
White matter disorders and cerebral calcification - narrow panel v1.39 ACBD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ACBD5.
White matter disorders and cerebral calcification - narrow panel v1.39 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23105016, 27799409, 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Tag Q2_21_rating was removed from gene: ACBD5.
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova changed review comment from: Comment on list classification: There is are sufficient unrelated cases (4) to promote this gene to Green at the next GMS panel update.; to: Comment on list classification: There is are sufficient unrelated cases (4) to support a diagnostic-grade classification (Green)
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Green List (high evidence)
Peroxisomal disorders v1.11 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Green List (High Evidence).
Peroxisomal disorders v1.10 ACBD5 Arina Puzriakova Phenotypes for gene: ACBD5 were changed from Retinal dystrophy with leukodystrophy (MIM#618863) to Retinal dystrophy with leukodystrophy, OMIM:618863
Peroxisomal disorders v1.9 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are sufficient unrelated cases (4) to promote this gene to Green at the next GMS panel update.
Peroxisomal disorders v1.8 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova Tag Q2_21_rating tag was added to gene: ACBD5.
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova commented on gene: ACBD5: A fourth individual was identified by Dr Helen Brittain (Genomics England Clinical Fellow) who presented with retinal dystrophy, ataxia and developmental regression at 2 yrs old
Peroxisomal disorders v1.7 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.184 ACBD5 Arina Puzriakova Publications for gene: ACBD5 were set to 27799409; 23105016
Retinal disorders v2.183 ACBD5 Arina Puzriakova Classified gene: ACBD5 as Amber List (moderate evidence)
Retinal disorders v2.183 ACBD5 Arina Puzriakova Added comment: Comment on list classification: There is are now sufficient unrelated cases (4) of retinal dystrophy in patients with biallelic ACBD5 variants to promote this gene to Green at the next GMS panel update.
Retinal disorders v2.183 ACBD5 Arina Puzriakova Gene: acbd5 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.182 ACBD5 Arina Puzriakova Tag watchlist was removed from gene: ACBD5.
Tag Q2_21_rating tag was added to gene: ACBD5.
Retinal disorders v2.182 ACBD5 Arina Puzriakova commented on gene: ACBD5: A fourth individual was identified by Dr Helen Brittain (Genomics England Clinical Fellow) who presented with retinal dystrophy, ataxia and developmental regression at 2 yrs old
Retinal disorders v2.182 ACBD5 Arina Puzriakova reviewed gene: ACBD5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427402; Phenotypes: Retinal dystrophy with leukodystrophy, OMIM:618863; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v2.120 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Likely inborn error of metabolism v2.119 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.119 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.118 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.118 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308; 33715266
Likely inborn error of metabolism v2.117 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from ?Mitochondrial complex I deficiency, nuclear type 23 618244 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Likely inborn error of metabolism v2.117 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257; 27604308
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh edited their review of gene: NDUFA12: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in five unrelated cases, together with supportive studies. Phenotypic variability was evident in the cases reported (PMID: 21617257; 33715266).; Changed rating: GREEN
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Tag Q2_21_rating tag was added to gene: NDUFA12.
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Likely inborn error of metabolism v2.116 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh edited their review of gene: NDUFA12: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five variants reported in five unrelated cases, together with supportive studies. Phenotypic variability was evident in the cases reported (PMID: 21617257; 33715266).; Changed rating: GREEN
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Classified gene: NDUFA12 as Amber List (moderate evidence)
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Mitochondrial disorders v2.27 NDUFA12 Sarah Leigh Gene: ndufa12 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Tag Q2_21_rating tag was added to gene: NDUFA12.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 SASH3 Boaz Palterer gene: SASH3 was added
gene: SASH3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SASH3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: SASH3 were set to Combined immunodeficiency; lymphopenia; neutropenia; immunodysregulation; autoimmune cytopenias
Penetrance for gene: SASH3 were set to unknown
Review for gene: SASH3 was set to GREEN
Added comment: Delmonte et al. described three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias.
Functional data: Lentivirus-mediated transfer of SASH3 cDNA in KO Jurkat cells and patient's cell lines restored protein expression and cell proliferation. The KO mouse phenotype is compatible.
https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2020008629/475781/SASH3-variants-cause-a-novel-form-of-X-linked?redirectedFrom=fulltext
Sources: Literature
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Tag Q2_21_rating tag was added to gene: NCKAP1.
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Classified gene: NCKAP1 as Amber List (moderate evidence)
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Guo et al 2020 (PMID:33157009) describe multiple families with inherited and de novo deleterious NCKAP1 variants. Neurodevelopmental features represent the core phenotypes, including autistic features, psychomotor delays, and ID or learning disabilities (10/16 individuals had a diagnosis of mild to severe ID)
Intellectual disability v3.1033 NCKAP1 Arina Puzriakova Gene: nckap1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1032 NCKAP1 Arina Puzriakova Phenotypes for gene: NCKAP1 were changed from to Intellectual disability; Autism
Intellectual disability v3.1031 NCKAP1 Arina Puzriakova Publications for gene: NCKAP1 were set to
Intellectual disability v3.1030 NCKAP1 Arina Puzriakova Mode of inheritance for gene: NCKAP1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1029 DPYS Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: DPYS.
Intellectual disability v3.1029 DPYS Arina Puzriakova Publications for gene: DPYS were set to
Intellectual disability v3.1028 DPYS Arina Puzriakova Classified gene: DPYS as Amber List (moderate evidence)
Intellectual disability v3.1028 DPYS Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. Overall variable clinical presentation, even including asymptomatic subjects. However, DD and/or ID have been reported in multiple published cases (PMIDs: 9266350; 17383919; 20362666; 27604308; 26771602; 29054612). Sufficient unrelated cases (>3) to rate Green but will seek opinion from the GMS expert group due to highly variable penetrance of this phenotype.
Intellectual disability v3.1028 DPYS Arina Puzriakova Gene: dpys has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Added comment: Comment on phenotypes: Isolated complex I deficiency;
Mitochondrial disorders v2.26 NDUFA12 Sarah Leigh Phenotypes for gene: NDUFA12 were changed from Isolated complex I deficiency; ?Mitochondrial complex I deficiency, nuclear type 23, 618244 to ?Mitochondrial complex I deficiency, nuclear type 23 OMIM:618244; mitochondrial complex 1 deficiency, nuclear type 23 MONDO:0032627
Mitochondrial disorders v2.25 NDUFA12 Sarah Leigh Publications for gene: NDUFA12 were set to 21617257
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh changed review comment from: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.; to: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh edited their review of gene: CLDN11: Added comment: Not associated with relevant phenotype in OMIM (entry last edited on 01/14/2013) or Gen2Phen. Two stop loss variants reported in three unrelated cases. Both variants resulted in an 39aa extension - c.622T>C, p.(208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay (PMID 33313762). The reporting authors predict that the extended claudin-11 forms an alpha helix which is not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins.; Changed rating: GREEN
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh Tag Q2_21_rating tag was added to gene: CLDN11.
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh Classified gene: CLDN11 as Amber List (moderate evidence)
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
White matter disorders and cerebral calcification - narrow panel v1.39 CLDN11 Sarah Leigh Gene: cldn11 has been classified as Amber List (Moderate Evidence).
Retinal disorders v2.182 FAM57B Ivone Leong Phenotypes for gene: FAM57B were changed from Cone-rod dystrophy to Cone-rod dystrophy, MONDO:0015993; Maculopathy
Retinal disorders v2.181 FAM57B Ivone Leong Publications for gene: FAM57B were set to 28041643
Retinal disorders v2.180 FAM57B Ivone Leong Mode of inheritance for gene: FAM57B was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v2.179 CTNNA1 Ivone Leong Phenotypes for gene: CTNNA1 were changed from Macular dystrophy, patterned, 2, OMIM:608970 to Macular dystrophy, patterned, 2, OMIM:608970; exudative vitreoretinopathy, MONDO:0019516
Retinal disorders v2.178 CTNNA1 Ivone Leong Publications for gene: CTNNA1 were set to 26691986
Likely inborn error of metabolism v2.115 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism) to Dihydropyrimidinuria, OMIM:222748; Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism)
Intellectual disability v3.1027 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinuria, MIM#222748 to Dihydropyrimidinuria, OMIM:222748
Undiagnosed metabolic disorders v1.454 DPYS Arina Puzriakova Phenotypes for gene: DPYS were changed from Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism) to Dihydropyrimidinuria, OMIM:222748; Dihydropyrimidinase deficiency (Disorders of pyrimidine metabolism)
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Tag watchlist tag was added to gene: RHBDF1.
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Classified gene: RHBDF1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Paediatric or syndromic cardiomyopathy v1.37 RHBDF1 Ivone Leong Gene: rhbdf1 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v2.114 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Likely inborn error of metabolism v2.113 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.36 RHBDF1 Ivone Leong Phenotypes for gene: RHBDF1 were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Congenital muscular dystrophy v2.8 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from musclular dystrophy dystroglycanopathy syndrome with severe epilepsy; Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Dilated and arrhythmogenic cardiomyopathy v1.22 MYLK3 Ivone Leong Classified gene: MYLK3 as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.22 MYLK3 Ivone Leong Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.21 MYLK3 Ivone Leong gene: MYLK3 was added
gene: MYLK3 was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: MYLK3.
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709; 30690923
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy, MONDO:0005021
Review for gene: MYLK3 was set to GREEN
Added comment: This gene is also on the Cardiomyopathies - including childhood onset (Version 1.35) as an Amber gene with a recommendation of promoting to Green. This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

Review from Zornitza Stark:
"Rating: I don't know

Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Created: 16 Apr 2021, 9:24 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Arthrogryposis v3.92 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from congenital muscular dystrophies; congenital muscular dystrophies. DPM2-CDG . Musclular dystrophy dystroglycanopathy syndrome with severe epilepsy. to Congenital disorder of glycosylation, type Iu, OMIM:615042
Early onset or syndromic epilepsy v2.324 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042; seizures to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Classified gene: MYLK3 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Gene: mylk3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.323 DPM2 Arina Puzriakova commented on gene: DPM2
Congenital disorders of glycosylation v2.70 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu 615042 to Congenital disorder of glycosylation, type Iu, OMIM:615042
Congenital disorders of glycosylation v2.69 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Classified gene: DPM2 as Amber List (moderate evidence)
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 615042). Sufficient number of unrelated cases (3) with DPM2-CDG to rate Green at the next GMS panel update (PMIDs: 23109149; 33129689)
Congenital disorders of glycosylation v2.68 DPM2 Arina Puzriakova Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.34 MYLK3 Ivone Leong Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Paediatric or syndromic cardiomyopathy v1.33 MYLK3 Ivone Leong Tag Q2_21_rating tag was added to gene: MYLK3.
Paediatric or syndromic cardiomyopathy v1.33 MYLK3 Ivone Leong Phenotypes for gene: MYLK3 were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Congenital disorders of glycosylation v2.67 DPM2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM2.
Intellectual disability v3.1026 DPM2 Arina Puzriakova Tag Q2_21_rating tag was added to gene: DPM2.
Intellectual disability v3.1026 DPM2 Arina Puzriakova Publications for gene: DPM2 were set to 23109149
Intellectual disability v3.1025 DPM2 Arina Puzriakova Classified gene: DPM2 as Amber List (moderate evidence)
Intellectual disability v3.1025 DPM2 Arina Puzriakova Added comment: Comment on list classification: Associated with relevant phenotype in OMIM (MIM# 615042). Sufficient number of unrelated cases (3) with DPM2-CDG to rate Green at the next GMS panel update. Phenotypes include intellectual disability in all affected individuals.
Intellectual disability v3.1025 DPM2 Arina Puzriakova Gene: dpm2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1024 DPM2 Arina Puzriakova Phenotypes for gene: DPM2 were changed from Congenital disorder of glycosylation, type Iu to Congenital disorder of glycosylation, type Iu, OMIM:615042
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Classified gene: MCM10 as Red List (low evidence)
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. Therefore this gene has been given a Red rating.
Paediatric or syndromic cardiomyopathy v1.32 MCM10 Ivone Leong Gene: mcm10 has been classified as Red List (Low Evidence).
Paediatric or syndromic cardiomyopathy v1.31 MCM10 Ivone Leong Phenotypes for gene: MCM10 were changed from Restrictive cardiomyopathy to Restrictive cardiomyopathy, MONDO:0005201
Dilated and arrhythmogenic cardiomyopathy v1.20 NRAP Ivone Leong Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 ZNFX1 Boaz Palterer edited their review of gene: ZNFX1: Added comment: Multisystem Inflammation and Susceptibility to Viral infections in Human ZNFX1 Deficiency
15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic-lymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease.
https://www.jacionline.org/article/S0091-6749(21)00613-8/fulltext; Changed rating: GREEN; Changed phenotypes: Multisystem inflammatory disoder, viral infections, HLH
Likely inborn error of metabolism v2.112 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IId 607091 to Congenital disorder of glycosylation, type IId, OMIM:607091
Undiagnosed metabolic disorders v1.453 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IId 607091; Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type IId, OMIM:607091
Congenital disorders of glycosylation v2.67 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Congenital disorder of glycosylation, type IId 607091; Beta-1,4-galactosyltransferase 1 deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Congenital disorder of glycosylation, type IId, OMIM:607091
Intellectual disability v3.1023 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538; 30653653
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Classified gene: B4GALT1 as Amber List (moderate evidence)
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Added comment: Comment on list classification: Upgraded from Red to Amber as now there are 2 families (4 total) exhibiting severe cognitive impairment, albeit this resolved in the singleton by age 11 (remaining patients were age 2.5, 11 and 11 years at the time of reporting)
Intellectual disability v3.1022 B4GALT1 Arina Puzriakova Gene: b4galt1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.1021 B4GALT1 Arina Puzriakova reviewed gene: B4GALT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 11901181, 21920538, 30653653, 32157688; Phenotypes: Congenital disorder of glycosylation, type IId, OMIM:607091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - narrow panel v2.123 TDP2 Ivone Leong Phenotypes for gene: TDP2 were changed from Spinocerebellar ataxia, autosomal recessive 23, 616949 to Spinocerebellar ataxia, autosomal recessive 23, OMIM:616949
Structural eye disease v1.66 TBC1D23 Ivone Leong gene: TBC1D23 was added
gene: TBC1D23 was added to Structural eye disease. Sources: Literature
Mode of inheritance for gene: TBC1D23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D23 were set to 28823707; 28823706; 32360255
Phenotypes for gene: TBC1D23 were set to coloboma, MONDO:0001476; strabismus, MONDO:0003432
Review for gene: TBC1D23 was set to RED
Added comment: PMID:28823707. 2 of 3 unrelated families (4 of 7 affected individuals) had ataxia. 1 family (3 affected individuals) had coloboma and strabismus. 1 family (1 individual) had hyperopia and strabismus.

PMID:28823706. 2 of 4 unrelated families (4 of 6 affected individuals) had ataxia. 2 of 6 individuals with eye phenotype (strabismus or esotropia of the left eye). Zebrafish morpholino knockout model showed reduced eye size.

PMID: 32360255. 1 case with ataxia. No eye phenotype reported.

Despite there being a zebrafish model with an eye phenotype, there is only 1 family out of 8 who had coloboma, therefore this gene is given a Red rating until more evidence is available.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.122 TBC1D23 Ivone Leong Phenotypes for gene: TBC1D23 were changed from Pontocerebellar hypoplasia, type 11, MIM# 617695 to Pontocerebellar hypoplasia, type 11, OMIM:617695
Ataxia and cerebellar anomalies - narrow panel v2.121 TBC1D23 Ivone Leong Classified gene: TBC1D23 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.121 TBC1D23 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.121 TBC1D23 Ivone Leong Gene: tbc1d23 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.120 TBC1D23 Ivone Leong Tag Q2_21_rating tag was added to gene: TBC1D23.
Ataxia and cerebellar anomalies - narrow panel v2.120 TBC1D23 Ivone Leong Added comment: Comment on publications: PMID:28823707. 2 of 3 unrelated families (4 of 7 affected individuals) had ataxia. 1 family (3 affected individuals) had coloboma and strabismus. 1 family (1 individual) had hyperopia and strabismus.

PMID:28823706. 2 of 4 unrelated families (4 of 6 affected individuals) had ataxia. 2 of 6 individuals with eye phenotype (strabismus or esotropia of the left eye).

PMID: 32360255. 1 case with ataxia. No eye phenotype reported.
Ataxia and cerebellar anomalies - narrow panel v2.120 TBC1D23 Ivone Leong Publications for gene: TBC1D23 were set to 28823707; 28823706
Intellectual disability v3.1021 B4GALT1 Arina Puzriakova Publications for gene: B4GALT1 were set to 26503795; 24896178; 11901181; 21920538
Intellectual disability v3.1020 B4GALT1 Arina Puzriakova Phenotypes for gene: B4GALT1 were changed from Congenital disorder of glycosylation, type IId 607091 to Congenital disorder of glycosylation, type IId, OMIM:607091
Intellectual disability v3.1019 AGO1 Arina Puzriakova Tag Q2_21_expert_review tag was added to gene: AGO1.
Intellectual disability v3.1019 AGO1 Arina Puzriakova commented on gene: AGO1
Intellectual disability v3.1019 AGO1 Arina Puzriakova Publications for gene: AGO1 were set to 26350204; 30213762; 22495306; 23020937; 25363768; 25356899; 27620904; 29346770
Ataxia and cerebellar anomalies - narrow panel v2.119 SQSTM1 Ivone Leong Classified gene: SQSTM1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.119 SQSTM1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.119 SQSTM1 Ivone Leong Gene: sqstm1 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.118 SQSTM1 Ivone Leong Tag Q2_21_rating tag was added to gene: SQSTM1.
Ataxia and cerebellar anomalies - narrow panel v2.118 SQSTM1 Ivone Leong Publications for gene: SQSTM1 were set to 27545679
Ataxia and cerebellar anomalies - narrow panel v2.117 SQSTM1 Ivone Leong Phenotypes for gene: SQSTM1 were changed from Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, MIM# 617145 to Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, OMIM:617145
Ataxia and cerebellar anomalies - narrow panel v2.116 SPR Ivone Leong Classified gene: SPR as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.116 SPR Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.116 SPR Ivone Leong Gene: spr has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.115 SPR Ivone Leong Tag Q2_21_rating tag was added to gene: SPR.
Ataxia and cerebellar anomalies - narrow panel v2.115 SPR Ivone Leong Phenotypes for gene: SPR were changed from Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, MIM# 612716 to Dystonia, dopa-responsive, due to sepiapterin reductase deficiency, OMIM:612716
Ataxia and cerebellar anomalies - narrow panel v2.114 SPG7 Ivone Leong Added comment: Comment on phenotypes: Previous phenotypes:
Spastic paraplegia 7 (#607259) complex forms of the disease. Actually associated with a range of phenotypes including adult-onset ataxia
Ataxia and cerebellar anomalies - narrow panel v2.114 SPG7 Ivone Leong Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7 (#607259) complex forms of the disease. Actually associated with a range of phenotypes including adult-onset ataxia to Spastic paraplegia 7, autosomal recessive, OMIM:607259
Ataxia and cerebellar anomalies - narrow panel v2.113 SPG7 Ivone Leong Publications for gene: SPG7 were set to PMID: 25681447
Ataxia and cerebellar anomalies - narrow panel v2.112 SNAP25 Ivone Leong Classified gene: SNAP25 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.112 SNAP25 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Ataxia and cerebellar anomalies - narrow panel v2.112 SNAP25 Ivone Leong Gene: snap25 has been classified as Amber List (Moderate Evidence).
Ataxia and cerebellar anomalies - narrow panel v2.111 SNAP25 Ivone Leong Tag Q2_21_rating tag was added to gene: SNAP25.
Ataxia and cerebellar anomalies - narrow panel v2.111 SNAP25 Ivone Leong Phenotypes for gene: SNAP25 were changed from Myasthenic syndrome, congenital, 18, 616330; cerebellar ataxia and seizures to ?Myasthenic syndrome, congenital, 18, OMIM:616330; cerebellar ataxia, MONDO:0000437; seizures, HP:0001250
Skeletal ciliopathies v1.10 PDIA6 Zornitza Stark gene: PDIA6 was added
gene: PDIA6 was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: PDIA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDIA6 were set to 33495992
Phenotypes for gene: PDIA6 were set to Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes
Review for gene: PDIA6 was set to AMBER
Added comment: 1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans.

Rated Amber in view of the high impact variant combined with functional data including a mouse model.
Sources: Literature
Ataxia and cerebellar anomalies - narrow panel v2.110 EXOSC1 Zornitza Stark gene: EXOSC1 was added
gene: EXOSC1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: EXOSC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC1 were set to 33463720
Phenotypes for gene: EXOSC1 were set to Pontocerebellar hypoplasia
Review for gene: EXOSC1 was set to RED
Added comment: An 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism, hypotonia, pontocerebellar hypoplasia and delayed myelination. Similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Exome sequencing revealed a homozygous missense variant (c.104C >T, p.Ser35Leu) in EXOSC1. In silico mutagenesis revealed loss of a polar contact with neighbouring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. Of note, bi‐allelic variants in other exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively.
Sources: Literature
Clefting v2.24 MED12 Zornitza Stark reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33244166; Phenotypes: Hardikar syndrome, OMIM #612726; 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 v3.1018 UBE4A Zornitza Stark gene: UBE4A was added
gene: UBE4A was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UBE4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE4A were set to 33420346
Phenotypes for gene: UBE4A were set to Intellectual disability
Review for gene: UBE4A was set to GREEN
gene: UBE4A was marked as current diagnostic
Added comment: 8 individuals, from 4 unrelated families, with syndromic intellectual disability and global developmental delay (other clinical features included hypotonia, short stature, seizures, and behaviour disorder. Exome sequencing identified biallelic loss-of-function variants in UBE4A in the 4 families, with variants segregating with disease and parents carriers. They demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioural abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.
Sources: Literature
Intellectual disability v3.1018 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 3344202
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphism
Review for gene: MAPKAPK5 was set to GREEN
gene: MAPKAPK5 was marked as current diagnostic
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.

Borderline Amber/Green but high impact variants and a distinctive phenotype with some functional data.
Sources: Literature
Intellectual disability v3.1018 FAR1 Zornitza Stark edited their review of gene: FAR1: Added comment: PMID 33239752: 12 patients with paediatric onset spastic paraparesis and bilateral congenital/juvenile cataracts. Most also had speech and gross motor developmental delay and truncal hypotonia. Exome sequencing identified de novo variants affecting the Arg480 residue in FAR1 (p.Arg480Cys/His/Leu). Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.; Changed rating: GREEN; Changed publications: 25439727, 33239752; Changed phenotypes: Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM#616154, spastic paraparesis and bilateral cataracts; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Distal myopathies v1.29 GIPC1 Zornitza Stark edited their review of gene: GIPC1: Added comment: PMID 33374016: a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases). The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident.; Changed publications: 32413282, 33374016
Retinal disorders v2.177 CTNNA1 Zornitza Stark edited their review of gene: CTNNA1: Added comment: In addition, three independent families reported with familial exudative vitreoretinopathy (FEVR) in PMID33497368.; Changed publications: 26691986, 33497368; Changed phenotypes: Macular dystrophy, butterfly-shaped pigmentary, 2, MIM# 608970, Familial exudative vitreoretinopathy
Arthrogryposis v3.91 ERBB3 Zornitza Stark reviewed gene: ERBB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 33720042; Phenotypes: Hirschsprung disease, arthrogryposis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
White matter disorders and cerebral calcification - narrow panel v1.38 CLDN11 Zornitza Stark gene: CLDN11 was added
gene: CLDN11 was added to White matter disorders and cerebral calcification - narrow panel. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Hypomyelinating leukodystrophy
Review for gene: CLDN11 was set to GREEN
gene: CLDN11 was marked as current diagnostic
Added comment: In three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia, 2 different heterozygous de novo stop-loss variants were identified. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 SYK Zornitza Stark reviewed gene: SYK: Rating: GREEN; Mode of pathogenicity: None; Publications: 33782605; Phenotypes: Immune dysregulation and systemic inflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability v3.1018 NCDN Zornitza Stark gene: NCDN was added
gene: NCDN was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NCDN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NCDN were set to 33711248
Phenotypes for gene: NCDN were set to Intellectual disability; epilepsy
Review for gene: NCDN was set to GREEN
Added comment: Four families reported, all with de novo missense variants except for 1 consanguineous family where 3 affecteds were homozygous and carrier parents unaffected. ID ranged from mild to severe, several had seizures. Green for mono-allelic disease, Red for bi-allelic.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.90 TSPOAP1 Zornitza Stark gene: TSPOAP1 was added
gene: TSPOAP1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: TSPOAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSPOAP1 were set to 33539324
Phenotypes for gene: TSPOAP1 were set to Dystonia, intellectual disability and cerebellar atrophy
Review for gene: TSPOAP1 was set to GREEN
Added comment: 7 affecteds from 3 families (1 consanguineous)
2x null, 1x missense

Affecteds with the null variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy while those with the missense p.(Gly1808Ser) presented with isolated adult-onset focal dystonia (mild cognitive impairment noted). Mouse model.
Sources: Literature
Mitochondrial disorders v2.24 NDUFA12 Zornitza Stark reviewed gene: NDUFA12: Rating: GREEN; Mode of pathogenicity: None; Publications: 33715266; Phenotypes: Mitochondrial complex I deficiency, nuclear type 23 MIM#618244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v3.91 FBN2 Zornitza Stark reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33571691; Phenotypes: Contractural arachnodactyly, congenital MIM#121050; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mitochondrial disorders v2.24 NDUFB7 Zornitza Stark reviewed gene: NDUFB7: Rating: AMBER; Mode of pathogenicity: None; Publications: 33502047, 27626371; Phenotypes: Congenital lactic acidosis, hypertrophic cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1018 CDH11 Zornitza Stark reviewed gene: CDH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811546, 27431290, 28988429, 29271567, 33811546; Phenotypes: Elsahy-Waters syndrome, MIM# 211380, Teebi hypertelorism syndrome; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v2.87 NMNAT1 Zornitza Stark gene: NMNAT1 was added
gene: NMNAT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: NMNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NMNAT1 were set to 32533184
Phenotypes for gene: NMNAT1 were set to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260
Review for gene: NMNAT1 was set to GREEN
gene: NMNAT1 was marked as current diagnostic
Added comment: The association with LCA is well established.

New report of a syndromic LCA disorder and note also unusual variant type. Three families, but two are distantly related (shared haplotype). The affected children in those two families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant.
Sources: Literature
Primary lymphoedema v2.8 RORC Zornitza Stark gene: RORC was added
gene: RORC was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: RORC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RORC were set to 32960152
Phenotypes for gene: RORC were set to Lymphoedema
Review for gene: RORC was set to AMBER
Added comment: Two individuals reported with LoF variants as part of a large cohort. Note gene is depleted for LoF in gnomad, and bi-allelic variants have been associated with immunodeficiency. Moderate/limited evidence for gene-disease association.
Sources: Literature
Primary lymphoedema v2.8 ARAP3 Zornitza Stark gene: ARAP3 was added
gene: ARAP3 was added to Primary lymphoedema. Sources: Literature
Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARAP3 were set to 32908855
Phenotypes for gene: ARAP3 were set to Lymphoedema
Review for gene: ARAP3 was set to AMBER
Added comment: Three unrelated families reported with rare missense variants in this gene as part of a lymphoedema cohort. However, incomplete information regarding segregation and no supporting functional data.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 MCM10 Zornitza Stark gene: MCM10 was added
gene: MCM10 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM10 were set to 33712616
Phenotypes for gene: MCM10 were set to Restrictive cardiomyopathy
Review for gene: MCM10 was set to RED
Added comment: PMID 33712616: three affected sibs with restrictive cardiomyopathy and hypoplasia of the spleen and thymus. Functional data suggested that MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion.
Sources: Literature
Malformations of cortical development v2.44 ATP1A3 Zornitza Stark gene: ATP1A3 was added
gene: ATP1A3 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP1A3 were set to 33762331
Phenotypes for gene: ATP1A3 were set to Polymicrogyria; epilepsy; developmental delay
Review for gene: ATP1A3 was set to GREEN
gene: ATP1A3 was marked as current diagnostic
Added comment: Eight individuals with de novo variants reported and a phenotype distinct from those previously reported in association with this gene.
Sources: Literature
Primary ovarian insufficiency v1.22 HSF2BP Zornitza Stark gene: HSF2BP was added
gene: HSF2BP was added to Primary ovarian insufficiency. Sources: Literature
Mode of inheritance for gene: HSF2BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSF2BP were set to 32845237
Phenotypes for gene: HSF2BP were set to Premature ovarian failure, OMIM#619245
Review for gene: HSF2BP was set to RED
Added comment: Single family reported where homozygous missense variant segregated with POF in three sisters.
Sources: Literature
Malformations of cortical development v2.44 SLC35A2 Zornitza Stark changed review comment from: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic.
Sources: Literature; to: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic. Rated as Amber as uncertain whether panel only caters to germline sequencing.
Sources: Literature
Malformations of cortical development v2.44 SLC35A2 Zornitza Stark gene: SLC35A2 was added
gene: SLC35A2 was added to Malformations of cortical development. Sources: Literature
Mode of inheritance for gene: SLC35A2 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: SLC35A2 were set to 33407896
Phenotypes for gene: SLC35A2 were set to Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)
Review for gene: SLC35A2 was set to AMBER
Added comment: >20 individuals reported. However note variants were identified on deep sequencing of affected tissue, and are somatic.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 IL37 Zornitza Stark gene: IL37 was added
gene: IL37 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL37 were set to 33674380
Phenotypes for gene: IL37 were set to Infantile inflammatory bowel disease
Review for gene: IL37 was set to RED
Added comment: Single family reported with homozygous truncating variant this gene and infantile-onset of IBD, some functional data.
Sources: Literature
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.114 ABCC9 Ivone Leong Phenotypes for gene: ABCC9 were changed from Hypertrichotic osteochondrodysplasia, MIM# 239850; Cantu syndrome to Hypertrichotic osteochondrodysplasia, OMIM:239850; Cantu syndrome
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.113 ASXL2 Ivone Leong Publications for gene: ASXL2 were set to 27693232
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Classified gene: PDGFRB as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.112 PDGFRB Ivone Leong Gene: pdgfrb has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.111 PDGFRB Ivone Leong Phenotypes for gene: PDGFRB were changed from Kosaki overgrowth syndrome, MIM# 616592 to Kosaki overgrowth syndrome, OMIM:616592
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Classified gene: PIK3CA as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert reviews. This gene is associated with a relevant phenotype in OMIM and Gen2Phenotype.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.110 PIK3CA Ivone Leong Gene: pik3ca has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.109 PIK3CA Ivone Leong Phenotypes for gene: PIK3CA were changed from Human overgrowth syndrome type; Overgrowth with Intellectual disability to Human overgrowth syndrome type; Overgrowth with Intellectual disability; CLOVES: CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.108 PIK3CA Ivone Leong Mode of inheritance for gene: PIK3CA was changed from Other to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Classified gene: RNF125 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.107 RNF125 Ivone Leong Gene: rnf125 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.106 RNF125 Ivone Leong Phenotypes for gene: RNF125 were changed from Tenorio syndrome, MIM# 616260 to Tenorio syndrome, OMIM:616260
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Classified gene: SETD2 as Green List (high evidence)
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.105 SETD2 Ivone Leong Gene: setd2 has been classified as Green List (High Evidence).
Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders v1.104 SETD2 Ivone Leong Phenotypes for gene: SETD2 were changed from Luscan-Lumish syndrome, 616831 to Luscan-Lumish syndrome, OMIM:616831
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Classified gene: FOXD3 as Amber List (moderate evidence)
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Amber. Based on the expert reviews, this gene has been demoted from Green to Amber until new evidence is available.
Glaucoma (developmental) v1.34 FOXD3 Ivone Leong Gene: foxd3 has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.65 LMX1B Ivone Leong Classified gene: LMX1B as Amber List (moderate evidence)
Structural eye disease v1.65 LMX1B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. This gene is Green on Glaucoma (developmental) (Version 1.33).

"Glaucoma is a key feature of this condition. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Structural eye disease v1.65 LMX1B Ivone Leong Gene: lmx1b has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.64 LMX1B Ivone Leong Phenotypes for gene: LMX1B were changed from Nail-patella syndrome, 161200 to Nail-patella syndrome, OMIM:161200
Structural eye disease v1.63 LMX1B Ivone Leong Tag Q2_21_rating tag was added to gene: LMX1B.
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Classified gene: LMX1B as Green List (high evidence)
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.33 LMX1B Ivone Leong Gene: lmx1b has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.32 LMX1B Ivone Leong Phenotypes for gene: LMX1B were changed from Nail-patella syndrome, MIM# 161200 to Nail-patella syndrome, OMIM:161200
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Classified gene: PAX6 as Green List (high evidence)
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.31 PAX6 Ivone Leong Gene: pax6 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Classified gene: SH3PXD2B as Green List (high evidence)
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is also Green on Structural eye disease (Version 1.63). Macrocornea could present with or without glaucoma. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.30 SH3PXD2B Ivone Leong Gene: sh3pxd2b has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.29 SH3PXD2B Ivone Leong Publications for gene: SH3PXD2B were set to
Glaucoma (developmental) v1.28 SH3PXD2B Ivone Leong Phenotypes for gene: SH3PXD2B were changed from Frank-ter Haar syndrome, MIM# 249420 to Frank-ter Haar syndrome, OMIM:249420
Structural eye disease v1.63 CREBBP Ivone Leong Classified gene: CREBBP as Amber List (moderate evidence)
Structural eye disease v1.63 CREBBP Ivone Leong Gene: crebbp has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.62 CREBBP Ivone Leong gene: CREBBP was added
gene: CREBBP was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: CREBBP.
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CREBBP were set to 25599811
Phenotypes for gene: CREBBP were set to Rubinstein-Taybi syndrome 1, OMIM:180849
Review for gene: CREBBP was set to GREEN
Added comment: This gene is Green on Glaucoma (developmental) (Version 1.27).

"Glaucoma is a feature of this syndrome. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be given a Green rating at the next review.
Sources: Literature
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Classified gene: CREBBP as Green List (high evidence)
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.27 CREBBP Ivone Leong Gene: crebbp has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.26 CREBBP Ivone Leong Publications for gene: CREBBP were set to
Glaucoma (developmental) v1.25 CREBBP Ivone Leong Phenotypes for gene: CREBBP were changed from Rubinstein Taybi syndrome to Rubinstein-Taybi syndrome 1, OMIM:180849
Structural eye disease v1.61 TEK Ivone Leong Classified gene: TEK as Amber List (moderate evidence)
Structural eye disease v1.61 TEK Ivone Leong Gene: tek has been classified as Amber List (Moderate Evidence).
Structural eye disease v1.60 TEK Ivone Leong gene: TEK was added
gene: TEK was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: TEK.
Mode of inheritance for gene: TEK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TEK were set to 27270174
Phenotypes for gene: TEK were set to Glaucoma 3, primary congenital, E, OMIM:617272
Review for gene: TEK was set to GREEN
Added comment: This gene is also Green on the Glaucoma (developmental) (Version 1.24).

"Ten families and a supportive mouse model. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Sources: Literature
Structural eye disease v1.59 IFIH1 Ivone Leong Classified gene: IFIH1 as Amber List (moderate evidence)
Structural eye disease v1.59 IFIH1 Ivone Leong Gene: ifih1 has been classified as Amber List (Moderate Evidence).
Glaucoma (developmental) v1.24 TEK Ivone Leong Classified gene: TEK as Green List (high evidence)
Glaucoma (developmental) v1.24 TEK Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.24 TEK Ivone Leong Gene: tek has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.23 TEK Ivone Leong Phenotypes for gene: TEK were changed from Glaucoma 3, primary congenital, E, MIM# 617272 to Glaucoma 3, primary congenital, E, OMIM:617272
Structural eye disease v1.58 IFIH1 Ivone Leong gene: IFIH1 was added
gene: IFIH1 was added to Structural eye disease. Sources: Literature
Q2_21_rating tags were added to gene: IFIH1.
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: IFIH1 were set to 29703882; 31898846
Phenotypes for gene: IFIH1 were set to Singleton-Merten syndrome 1, OMIM:182250
Review for gene: IFIH1 was set to GREEN
Added comment: This gene is also Green on the Glaucoma (developmental) (Version 1.22) panel.

"Glaucoma is a feature of this condition. Sources: Expert list
Zornitza Stark (Australian Genomics), 2 Aug 2020"

PMID: 29703882. "4-year-old boy with a diagnosis of AGS, global developmental delay, glucose-6-phosphate dehydrogenase (G6PD) deficiency, patent ductus arteriosus (PDA), congenital glaucoma, and aniridia. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents were carriers of congenital glaucoma genes." PMID: 31898846. Glaucoma found as part of the phenotype.

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support gene-disease association. This gene should be given a Green rating at the next review.
Sources: Literature
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Classified gene: IFIH1 as Green List (high evidence)
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is enough evidence to support a gene-disease association. This gene has been given a Green rating.
Glaucoma (developmental) v1.22 IFIH1 Ivone Leong Gene: ifih1 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.21 IFIH1 Ivone Leong Added comment: Comment on publications: PMID: 29703882. "4-year-old boy with a diagnosis of AGS, global developmental delay, glucose-6-phosphate dehydrogenase (G6PD) deficiency, patent ductus arteriosus (PDA), congenital glaucoma, and aniridia. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents were carriers of congenital glaucoma genes."

PMID: 31898846. Glaucoma found as part of the phenotype.
Glaucoma (developmental) v1.21 IFIH1 Ivone Leong Publications for gene: IFIH1 were set to
Glaucoma (developmental) v1.20 IFIH1 Ivone Leong Phenotypes for gene: IFIH1 were changed from Singleton-Merten syndrome 1, MIM# 182250 to Singleton-Merten syndrome 1, OMIM:182250
Structural eye disease v1.57 OCRL Ivone Leong commented on gene: OCRL: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Glaucoma is present in ~50% of cases, GeneReviews. Therefore this gene should be promoted to Green status at the next review.
Structural eye disease v1.57 OCRL Ivone Leong Tag Q2_21_rating tag was added to gene: OCRL.
Structural eye disease v1.57 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, 309000 to Lowe syndrome, OMIM:309000
Glaucoma (developmental) v1.19 OCRL Ivone Leong Classified gene: OCRL as Green List (high evidence)
Glaucoma (developmental) v1.19 OCRL Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association, therefore this gene has been promoted to Green.
Glaucoma (developmental) v1.19 OCRL Ivone Leong Gene: ocrl has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.18 OCRL Ivone Leong Phenotypes for gene: OCRL were changed from Lowe syndrome, MIM# 309000 to Lowe syndrome, OMIM:309000
Glaucoma (developmental) v1.17 OCRL Ivone Leong Publications for gene: OCRL were set to
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Classified gene: SBF2 as Green List (high evidence)
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. This gene is also Green on the Structural eye disease panel (Version 1.56).
Glaucoma (developmental) v1.16 SBF2 Ivone Leong Gene: sbf2 has been classified as Green List (High Evidence).
Glaucoma (developmental) v1.14 SBF2 Ivone Leong Phenotypes for gene: SBF2 were changed from Charcot-Marie-Tooth disease, type 4B2 604563; CMT with early onset glaucoma to Charcot-Marie-Tooth disease, type 4B2, OMIM:604563; CMT with early onset glaucoma
Glaucoma (developmental) v1.13 SBF2 Ivone Leong Publications for gene: SBF2 were set to
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Classified gene: ADAMTS19 as Green List (high evidence)
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene is therefore given a Green rating.
Familial non syndromic congenital heart disease v1.60 ADAMTS19 Ivone Leong Gene: adamts19 has been classified as Green List (High Evidence).
Familial non syndromic congenital heart disease v1.59 ADAMTS19 Ivone Leong Phenotypes for gene: ADAMTS19 were changed from Non-syndromic heart valve disease to Non-syndromic heart valve disease; heart valve disease, MONDO:0002869
Familial non syndromic congenital heart disease v1.58 ADAMTS19 Ivone Leong Publications for gene: ADAMTS19 were set to 31844321
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Classified gene: THSD4 as Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is no phenotypes associated with this gene in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Thoracic aortic aneurysm or dissection (GMS) v1.7 THSD4 Ivone Leong Gene: thsd4 has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.6 THSD4 Ivone Leong Tag Q2_21_rating tag was added to gene: THSD4.
Thoracic aortic aneurysm or dissection (GMS) v1.6 THSD4 Ivone Leong Phenotypes for gene: THSD4 were changed from Thoracic aortic aneurysm and dissection (TAAD) to familial thoracic aortic aneurysm and aortic dissection, MONDO:0019625
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Classified gene: HEY2 as Red List (low evidence)
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is not enough evidence to support a gene-disease association. This gene has been given a Red rating.
Thoracic aortic aneurysm or dissection (GMS) v1.5 HEY2 Ivone Leong Gene: hey2 has been classified as Red List (Low Evidence).
Thoracic aortic aneurysm or dissection (GMS) v1.4 HEY2 Ivone Leong Phenotypes for gene: HEY2 were changed from congenital heart defects and thoracic aortic aneurysms to congenital heart defects, multiple type, MONDO:0000119; thoracic aortic aneurysm, MONDO:0005396
Pulmonary arterial hypertension v2.13 KDR Ivone Leong edited their review of gene: KDR: Added comment: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. This gene is also identified as a novel PAH disease gene in PMID:29650961, which was found in 4 cases and 0 in controls. Clingen has curated this gene-disease association and given it a Strong rating. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; Changed rating: GREEN
Pulmonary arterial hypertension v2.13 KDR Ivone Leong Tag watchlist was removed from gene: KDR.
Tag Q2_21_rating tag was added to gene: KDR.
Pulmonary arterial hypertension v2.13 KDR Ivone Leong Publications for gene: KDR were set to 31980491; 32880713; 33320693
Pulmonary arterial hypertension v2.12 KDR Ivone Leong Phenotypes for gene: KDR were changed from Pulmonary hypertension to Heritable pulmonary arterial hypertension, MONDO:0017148
Pulmonary arterial hypertension v2.11 KDR Ivone Leong Publications for gene: KDR were set to 31980491; 32880713
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong Tag watchlist tag was added to gene: AQP1.
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong reviewed gene: AQP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.1018 INPP4A Zornitza Stark reviewed gene: INPP4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978615, 31938306, 25338135, 20011524; Phenotypes: Intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v1.30 RHBDF1 Zornitza Stark gene: RHBDF1 was added
gene: RHBDF1 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: RHBDF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RHBDF1 were set to 32870709
Phenotypes for gene: RHBDF1 were set to Dilated cardiomyopathy
Review for gene: RHBDF1 was set to AMBER
Added comment: Three families reported with homozygous variants in this gene and onset of DCM in infancy/childhood. Two of the families had the same truncating variant, indicative of founder effect, and one family had a homozygous missense variant.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 MYLK3 Zornitza Stark gene: MYLK3 was added
gene: MYLK3 was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: MYLK3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYLK3 were set to 29235529; 31244672; 32213617; 32870709
Phenotypes for gene: MYLK3 were set to Dilated cardiomyopathy
Review for gene: MYLK3 was set to AMBER
Added comment: Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Pulmonary arterial hypertension v2.10 AQP1 Ivone Leong Phenotypes for gene: AQP1 were changed from Heritable pulmonary arterial hypertension; HPAH to Heritable pulmonary arterial hypertension, HPAH, MONDO:0017148
Dilated and arrhythmogenic cardiomyopathy v1.19 FLII Ivone Leong Classified gene: FLII as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.19 FLII Ivone Leong Gene: flii has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.18 FLII Ivone Leong gene: FLII was added
gene: FLII was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: FLII.
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy, MONDO:0005021
Review for gene: FLII was set to GREEN
Added comment: This gene is also on Cardiomyopathies - including childhood onset (Version 1.30).

"Two unrelated families reported with homozygous missense variants in PMID 32870709. Geng (2021): Shown to affect sarcomere size in Drosophila model. FliI knockdown resulted in disorganised myofibrils and increase filamentous actin. Campbell (2002): Hom mice - lethal, het - normal. K/O mouse model of related genes have cytoskeletal actin alterations. No survivors to observed cardiac phenotypes. We are aware of a third family ascertained through our laboratory. Sources: Literature
Zornitza Stark (Australian Genomics), 15 Apr 2021"

This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Classified gene: FLII as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.30 FLII Ivone Leong Gene: flii has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.29 FLII Ivone Leong Tag Q2_21_rating tag was added to gene: FLII.
Paediatric or syndromic cardiomyopathy v1.29 FLII Ivone Leong Phenotypes for gene: FLII were changed from Dilated cardiomyopathy to Dilated cardiomyopathy, MONDO:0005021
Paediatric disorders - additional genes v1.86 PLD1 Ivone Leong commented on gene: PLD1: This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric disorders - additional genes v1.86 PLD1 Ivone Leong Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental to Cardiac valvular defect, developmental, OMIM:212093
Paediatric disorders - additional genes v1.85 PLD1 Ivone Leong Added comment: Comment on publications: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%). Sources: Literature
Zornitza Stark (Australian Genomics), 15 Apr 2021
Paediatric disorders - additional genes v1.85 PLD1 Ivone Leong Publications for gene: PLD1 were set to 27799408
Paediatric disorders - additional genes v1.84 PLD1 Ivone Leong Tag Q2_21_rating tag was added to gene: PLD1.
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Classified gene: PLD1 as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.28 PLD1 Ivone Leong Gene: pld1 has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.27 PLD1 Ivone Leong Tag Q2_21_rating tag was added to gene: PLD1.
Paediatric or syndromic cardiomyopathy v1.27 PLD1 Ivone Leong Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy to Cardiac valvular defect, developmental, OMIM:212093; neonatal cardiomyopathy
Dilated and arrhythmogenic cardiomyopathy v1.17 RPL3L Ivone Leong Classified gene: RPL3L as Amber List (moderate evidence)
Dilated and arrhythmogenic cardiomyopathy v1.17 RPL3L Ivone Leong Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v1.16 RPL3L Ivone Leong gene: RPL3L was added
gene: RPL3L was added to Dilated cardiomyopathy - adult and teen. Sources: Literature
Q2_21_rating tags were added to gene: RPL3L.
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021
Review for gene: RPL3L was set to GREEN
Added comment: This gene is also present on the Cardiomyopathies - including childhood onset (Version 1.26) panel.

Review by Zornitza Stark:
"PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype."

This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Classified gene: RPL3L as Amber List (moderate evidence)
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with any phenotypes in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v1.26 RPL3L Ivone Leong Gene: rpl3l has been classified as Amber List (Moderate Evidence).
Paediatric or syndromic cardiomyopathy v1.25 RPL3L Ivone Leong Tag Q2_21_rating tag was added to gene: RPL3L.
Paediatric or syndromic cardiomyopathy v1.25 RPL3L Ivone Leong Phenotypes for gene: RPL3L were changed from Neonatal dilated cardiomyopathy to Neonatal dilated cardiomyopathy; dilated cardiomyopathy, MONDO:0005021
Paediatric or syndromic cardiomyopathy v1.24 MIB1 Ivone Leong commented on gene: MIB1: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene has been tagged and will be submitted to the GMS specialist group for review.
Paediatric or syndromic cardiomyopathy v1.24 MIB1 Ivone Leong Phenotypes for gene: MIB1 were changed from Left ventricular noncompaction 7 to Left ventricular noncompaction 7, OMIM:615092
Paediatric or syndromic cardiomyopathy v1.23 MIB1 Ivone Leong Publications for gene: MIB1 were set to
Paediatric or syndromic cardiomyopathy v1.22 MIB1 Ivone Leong Tag Q2_21_rating tag was added to gene: MIB1.
Tag Q2_21_NHS_review tag was added to gene: MIB1.
Paediatric or syndromic cardiomyopathy v1.22 COX6B1 Ivone Leong commented on gene: COX6B1: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. It is recommended that this gene should be demoted to Amber/Red at the next review.
Paediatric or syndromic cardiomyopathy v1.22 COX6B1 Ivone Leong Tag Q2_21_rating tag was added to gene: COX6B1.
Paediatric or syndromic cardiomyopathy v1.22 COX14 Ivone Leong Phenotypes for gene: COX14 were changed from ?Mitochondrial complex IV deficiency, 220110 to ?Mitochondrial complex IV deficiency, OMIM:220110
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong Tag Q2_21_rating tag was added to gene: COX14.
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong commented on gene: COX14: This gene is associated with a phenotype in OMIM and Gene2Phenotype. Currently, there is not enough evidence to support a gene-disease association. It is recommended that this gene should be demoted to Amber/Red at the next review.
Paediatric or syndromic cardiomyopathy v1.21 COX14 Ivone Leong Publications for gene: COX14 were set to
Ataxia and cerebellar anomalies - narrow panel v2.110 MSTO1 Sarah Leigh Tag Q2_21_rating tag was added to gene: MSTO1.
Ataxia and cerebellar anomalies - narrow panel v2.110 MSTO1 Sarah Leigh edited their review of gene: MSTO1: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least eight variants reported in five unrelated cases of recessive Myopathy, mitochondrial, and ataxia and one variant reported in dominant Myopathy, mitochondrial, and ataxia in one family, together with supportive functional studies (PMID 28554942).; Changed rating: GREEN
Ataxia and cerebellar anomalies - narrow panel v2.110 MSTO1 Sarah Leigh Classified gene: MSTO1 as Amber List (moderate evidence)
Ataxia and cerebellar anomalies - narrow panel v2.110 MSTO1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Ataxia and cerebellar anomalies - narrow panel v2.110 MSTO1 Sarah Leigh Gene: msto1 has been classified as Amber List (Moderate Evidence).
Mitochondrial disorders v2.24 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Hereditary ataxia with onset in adulthood v2.40 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Mitochondrial myopathy and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Likely inborn error of metabolism v2.111 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Possible mitochondrial disorder - nuclear genes v1.40 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh changed review comment from: Comment on phenotypes: Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy with Brain involvment; to: Comment on phenotypes:
Congenital muscular dystrophy with Brain involvment
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh Added comment: Comment on phenotypes: Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Congenital muscular dystrophy with Brain involvment
Congenital muscular dystrophy v2.7 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Congenital muscular dystrophy with Brain involvment; Myopathy, mitochondrial, and ataxia, 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Ataxia and cerebellar anomalies - narrow panel v2.109 MSTO1 Sarah Leigh Phenotypes for gene: MSTO1 were changed from Myopathy, mitochondrial, and ataxia, MIM# 617675 to Myopathy, mitochondrial, and ataxia OMIM:617675; mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome MONDO:0044714
Monogenic hearing loss v2.160 LOXHD1 Arina Puzriakova Publications for gene: LOXHD1 were set to PMID:16936105; 19732867; 21465660; 22341973
Monogenic hearing loss v2.159 LOXHD1 Arina Puzriakova Phenotypes for gene: LOXHD1 were changed from Nonsyndromic Hearing Loss, Recessive; Deafness, autosomal recessive 77, 613079; hearing loss to Deafness, autosomal recessive 77, OMIM:613079
Intellectual disability v3.1018 LOXHD1 Arina Puzriakova Mode of inheritance for gene: LOXHD1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Classified gene: KCNH1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Added comment: Comment on list classification: Sufficient number of unrelated cases (>3) of epilepsy in patients with variants in the KCNH1 gene. Inclusion on this panel would be of particular benefit to individuals without typical gingival and/or nail anomalies and only mild developmental delays - who may not be tested under other panels (e.g. Limb disorders, ID) and thus may otherwise be missed in analysis.
Early onset or syndromic epilepsy v2.323 KCNH1 Arina Puzriakova Gene: kcnh1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.322 KCNH1 Arina Puzriakova gene: KCNH1 was added
gene: KCNH1 was added to Genetic epilepsy syndromes. Sources: Literature
Q2_21_rating tags were added to gene: KCNH1.
Mode of inheritance for gene: KCNH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNH1 were set to 18203178; 20009591; 20683999; 21626675; 23994350; 25420144; 33811134
Phenotypes for gene: KCNH1 were set to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Review for gene: KCNH1 was set to GREEN
Added comment: Well-established cause of Temple-Baraitser syndrome (MIM #611816) and Zimmermann-Laband syndrome (MIM #135500) characterised by ID with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia. Overall, sufficient number of cases with epilepsy to rate Green on this panel (PMIDs: 18203178; 20009591; 20683999; 21626675; 23994350; 25420144)

- PMID: 33811134 (2021) - 7 patients with de novo KCNH1 variants presenting mild/moderate to severe DD/ID, but without any distinctive features of TBS/ZLS such as gingival hyperplasia and nail anomalies. Four patients had epilepsy starting in infancy, with generalised tonic–clonic (4/4), myoclonic (2/4), focal motor (2/4) and tonic (1/4) seizures. One patient experienced status epilepticus. Epilepsy was pharmacoresponsive in all individuals. This study provides evidence of KCNH-related encephalopathy even without the presence of other extra-neurological symptoms that are typically associated with pathogenic variants in this gene.
Sources: Literature
Dilated and arrhythmogenic cardiomyopathy v1.15 NRAP Zornitza Stark reviewed gene: NRAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 33534821, 30384889, 28611399, 32870709; Phenotypes: Dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 MPEG1 Zornitza Stark gene: MPEG1 was added
gene: MPEG1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754
Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223
Review for gene: MPEG1 was set to GREEN
gene: MPEG1 was marked as current diagnostic
Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus.

Four individuals reported, functional data, including animal model.
Sources: Literature
Ichthyosis and erythrokeratoderma v1.60 ALDH1L2 Zornitza Stark gene: ALDH1L2 was added
gene: ALDH1L2 was added to Ichthyosis and erythrokeratoderma. Sources: Literature
Mode of inheritance for gene: ALDH1L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1L2 were set to 31341639; 33168096
Phenotypes for gene: ALDH1L2 were set to pruritic ichthyosis, severe diffuse hypomyelination seen on MRI, and abnormal lipid peaks
Review for gene: ALDH1L2 was set to RED
Added comment: Individual reported with bialleleic ALDH1L2 variants (non-canonical splice and a frameshift mutation), who also has a de novo hemizygous RPS6KA3 frameshift mutation. Authors state that not all features of the individual could be explained by the RPS6KA3 variant, and that consideration of Coffin-Lowry sysndrome was only made after identification of the RPS6KA3 variant. Therefore individual has there is a blended phenotype of Coffin–Lowry syndrome and Sjögren–Larsson syndrome. From functional studies authors propose that the ALDH1L2 loss induces mitochondrial dysfunction due to reduced NADPH and increased oxidative stress (PMID: 31341639). Knockout mouse model was viable and did not show an apparent phenotype, however metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Authors therefore postulate that the role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous disease.
Sources: Literature
Intellectual disability v3.1017 KCNH1 Arina Puzriakova Phenotypes for gene: KCNH1 were changed from Temple-Baraitser syndrome, OMIM:611816; Temple-Baraitser syndrome, MONDO:0012735; Zimmermann-Laband syndrome 1, OMIM:135500; Zimmermann-Laband syndrome 1, MONDO:0024526 to Temple-Baraitser syndrome, OMIM:611816; Zimmermann-Laband syndrome 1, OMIM:135500; Intellectual disability; Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1016 KCNH1 Arina Puzriakova Publications for gene: KCNH1 were set to 25420144; 33594261
Clefting v2.24 ESCO2 Zornitza Stark reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32977150; Phenotypes: Juberg-Hayward syndrome, MIM# 216100, Roberts-SC phocomelia syndrome, MIM#268300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1015 KCNH1 Arina Puzriakova edited their review of gene: KCNH1: Changed phenotypes: Intellectual disability, Encephalopathy without features of TBS/ZLS
Intellectual disability v3.1015 KCNH1 Arina Puzriakova reviewed gene: KCNH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33811134; Phenotypes: Intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinal disorders v2.177 FAM57B Zornitza Stark reviewed gene: FAM57B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33077892; Phenotypes: Cone–rod dystrophy, Maculopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Paediatric or syndromic cardiomyopathy v1.20 PDLIM3 Ivone Leong Publications for gene: PDLIM3 were set to 25163546
Paediatric or syndromic cardiomyopathy v1.19 PDLIM3 Ivone Leong Tag Q2_21_rating tag was added to gene: PDLIM3.
Paediatric or syndromic cardiomyopathy v1.19 PDLIM3 Ivone Leong edited their review of gene: PDLIM3: Added comment: This gene is not associated with a phenotype in OMIM or Gene2Phenotype. Variants in this gene seem to confer susceptibility to DCM but may not directly cause it (PMID: 17254821; 31424159). Therefore, this gene should be downgraded from Green to Amber/Red.; Changed publications: 17254821, 31424159
Paediatric or syndromic cardiomyopathy v1.19 FLII Zornitza Stark gene: FLII was added
gene: FLII was added to Cardiomyopathies - including childhood onset. Sources: Literature
Mode of inheritance for gene: FLII was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLII were set to 32870709
Phenotypes for gene: FLII were set to Dilated cardiomyopathy
Review for gene: FLII was set to GREEN
Added comment: Two unrelated families reported with homozygous missense variants in PMID 32870709.

Geng (2021): Shown to affect sarcomere size in Drosophila model. FliI knockdown resulted in disorganised myofibrils and increase filamentous actin.
Campbell (2002): Hom mice - lethal, het - normal. K/O mouse model of related genes have cytoskeletal actin alterations. No survivors to observed cardiac phenotypes.

We are aware of a third family ascertained through our laboratory.
Sources: Literature
Familial pulmonary fibrosis v1.13 ZCCHC8 Zornitza Stark gene: ZCCHC8 was added
gene: ZCCHC8 was added to Familial pulmonary fibrosis. Sources: Literature
Mode of inheritance for gene: ZCCHC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZCCHC8 were set to 31488579
Phenotypes for gene: ZCCHC8 were set to Pulmonary fibrosis
Review for gene: ZCCHC8 was set to AMBER
Added comment: A missense variant (P186L) segregates over 3 generations in a single family, and supporting in vitro assays and mouse model.
Sources: Literature
Intellectual disability v3.1015 COPB1 Zornitza Stark gene: COPB1 was added
gene: COPB1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: COPB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COPB1 were set to 33632302
Phenotypes for gene: COPB1 were set to Baralle-Macken syndrome, MIM# 619255; Severe intellectual disability; variable microcephaly; cataracts
Review for gene: COPB1 was set to AMBER
Added comment: Two unrelated families, some supportive functional data.
Sources: Literature