Early onset or syndromic epilepsy
Gene: ASH1L
The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.
Panel Version: 3.29
Liu et al 2021 - twin sisters with mild intellectual disability and seizures. WES identified a de novo nonsense variant in exon 3.
In this paper they look at previously reported variants and others reported in patients presenting with a seizure phenotype -Table 2:
p.Glu2143* - autism spectrum disorder (seizure) - ref 7
p.Arg2391His - Intellectual disability (seizure) - ref 7
p.Arg2421* - intellectual disability/developmental delay (seizure) - ref 7
(Ref 7 - Krumm et al, 2015, Nat Genet, 47:582-88).
Krumm et al, 2015 - cohort of patients with myoclonic atonic seizures (MAE) - table 2 shows that 1 patient idenitifed in this cohort (de novo) and that two additional patients were identified in the Iossifov proband (family 13678 - nonsense - can't see anything re epilepsy phenotype) and de rubeis proband (no mention in this paper that they had epilepsy pheno - PMID 25363760) - all de novo (2 nonsense 1 fs)
Qin et al 2021 - The elevated PFC pyramidal neuronal excitability, increased E/I ratio, and excessive synchronised cortical network activity of Ash1L-deficient mice is linked to seizures, which recapitulates the phenotype of some autistic children carrying ASH1L variants.
Tang et al, 2020 - table 3 candidate variants - ASH1L - de novo variant p.Arg1342* - 7 year old male with seizure onset at 6 months refractory to treatment, also mod- severe ID, ASD and ADHD.
3 definite families where de novo nonsense/fs variants have been reported in individuals with an epilepsy phenotype as well as ASD/ ID in the literature, patients reported in decipher with seizure phenotype and ASHIL variant (2 de novo nonsense, 1 de novo fs reported as pathogenic), and mouse studies support role for ASHIL in epeilepsy phenotype.Created: 11 Nov 2022, 11:20 a.m. | Last Modified: 11 Nov 2022, 11:20 a.m.
Panel Version: 2.603
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Comment on list classification: The opinion of a GMS expert is required, to decide whether or not this gene can be rated as green on the Genetic epilepsy syndromes panelCreated: 21 Jun 2022, 1:09 p.m. | Last Modified: 21 Jun 2022, 1:09 p.m.
Panel Version: 2.538
Associated with phenotype - OMIM:617796 and as strong Gen2Phen gene for intellectual disability. In addition, PMID 34373061 (table 1) has reported seizures in four unrelated cases with heterozygous ASH1L variants. Decipher also reports four cases with seizures carrying ASH1L variants.
Sources: LiteratureCreated: 21 Jun 2022, 12:56 p.m. | Last Modified: 21 Jun 2022, 1:31 p.m.
Panel Version: 2.538
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual developmental disorder, autosomal dominant 52, OMIM:617796
Publications
Publications for gene: ASH1L were set to 34373061; 25961944
Tag Q3_22_rating was removed from gene: ASH1L. Tag Q3_22_expert_review was removed from gene: ASH1L.
Source Expert Review Green was added to ASH1L. Source NHS GMS was added to ASH1L. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_22_rating tag was added to gene: ASH1L. Tag Q3_22_expert_review tag was added to gene: ASH1L.
Gene: ash1l has been classified as Amber List (Moderate Evidence).
gene: ASH1L was added gene: ASH1L was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: ASH1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASH1L were set to 34373061; 25961944 Phenotypes for gene: ASH1L were set to Intellectual developmental disorder, autosomal dominant 52, OMIM:617796 Review for gene: ASH1L was set to AMBER