Early onset or syndromic epilepsy

Gene: CACNA1G

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD SCA42. In OMIM for the early onset severe SCA42 with neurodevelopmental deficits it mentions that there are seizures in some patients. Chemin et al, 2018 - 4 unrelated girls - 2 had early onset seizures. De novo het missense variants identified in all individuals (A196T in 3 cases). Functional studies done.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia, 616795; Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits, 618087

Publications

• 17397049
• 29878067

Green List (high evidence)

Comment on mode of pathogenicity: Gain of function missense variants c.2881G>A p.Ala961Thr and c.4591A>G, p.Met1531Val reported so far

Created: 20 Jun 2018, 3:18 p.m.

Comment on list classification: Based on additional information received from Ian Berry (Leeds): "CACNA1G now appears to be cerebellar atrophy and epilepsy gene (PMID 29878067). The cohort of 4 patients with ID, two of whom had EIEE have variants in CACNA1G. Functional characterization shows modification in gating and channel function, supportive of a pathogenic consequence. An additional case has also been reported displaying the same phenotypic features as those published in PMID 29878067 and carrying one of the reported variants.

Created: 20 Jun 2018, 9:18 a.m.

PMID: 17397049 reports one variant, c.1709C>T (Ala570Val), is present in a sporadic case of juvenile myoclonic epilepsy (JME) with early childhood absence and astatic seizures, but was not found in control samples. Another variant, c.3265G>T (Ala1089Ser), was observed in three family members affected with JME, and also in one control individual. Two JME patients and three control individuals harbored a third variant, c.2968G>A (Asp980Asn). Although not statistically significant, slightly faster inactivation decay rates were observed in some mutant channels.

Created: 19 Dec 2017, 2:06 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spinocerebellar ataxia 42 616795

Publications

• 17397049