Early onset or syndromic epilepsy

Gene: ASH1L

Green List (high evidence)

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

Green List (high evidence)

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

• 34373061
• 25961944
• 34782621
• 32469098

I don't know

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 panel

Created: 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: Literature

Created: 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

• 34373061
• 25961944