Early onset or syndromic epilepsy

Gene: CACNA1A

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' 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)

Updating mode of inheritance to also include biallelic variants. Compound heterozygous variants were first reported in two
siblings with DEE plus progressive cerebral, cerebellar, and optic nerve atrophy (Reinson et al., 2016). Family members with heterozygous variants manifested ID and ataxia. A similar patient has since been reported (Ko et al., 2021). Recently, a CACNA1A homozygous truncating variant (p.Arg932*) was reported in a consanguineous family. Four children with these biallelic variants presented with DEE, leading to death by 6 months of age, whilst both carrier parents had symptoms consistent with EA2 (Arteche-Lopez et al., 2021). Finally, and more speculatively, a family has been reported in which an insertion/deletion in exon 47, predicted to be deleterious to protein function, is associated with adult-onset progressive myoclonic epilepsy, cognitive decline and ataxia (Lv et al., 2017). Wong-Spracklen et al. (2022) report a fifth family in which biallelic CACNA1A variants are associated with a severe neurodevelopmental phenotype. However, family members with heterozygous CACNA1A variants are either asymptomatic or have mild and non-specific features. Reduced penetrance and high degrees of intra-familial variability have been reported across all CACNA1A phenotypes.
Sufficient evidence for biallelic inheritance and overlap for this panel.

Created: 6 Sep 2022, 10:36 a.m. | Last Modified: 6 Sep 2022, 10:36 a.m.

Panel Version: 2.590

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 36063114
• PMID: 34267336
• PMID: 33445191
• PMID: 27250579

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

AD EIEE42, AD Episodic ataxia 2, AD familial hemiplegic migraine (seizures less common feature - OMIM)and AD SCA6 (CAG repeat tract expansions). AD EIEE42 - Epi4K consorium5 patients including 2 sibs - identified 4 diff heterozygous missense mutations in the CACNA1A gene. Functional studies not done.Mutations de novo apart from in the sibs who inherited it from their unaffected mother who was a mosaic carrier. SeVeral other cases on HGMD Pro associated with epilepsy as the phenotype.

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
Epileptic encephalopathy early infantile, 42 617106; Episodic ataxia, 108500; Migraine, familial hemiplegic, 141500; Migraine, familial hemiplegic, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia,183086

Publications

• 11061267
• 25735478

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

Comment on list classification: The Green review by Professor Deb Pal (KCL) supports the current Green rating of CACNA1A on this epilepsy panel.

Created: 16 May 2019, 3:23 p.m.

Comment on publications: CACNA1A is called CACNL1A4 (the previous gene symbol) in PMID:8898206 (Ophoff et al., 1996).

Created: 16 May 2019, 3:19 p.m.

Green List (high evidence)

Currently on Amplexa CHE-113 epilepsy diagnostic panel

Created: 12 Feb 2019, 2:06 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Absence epilepsy; Familial hemiplegic migraine 1

Publications

• 11564488
• 20071244
• 15452324

Variants in this GENE are reported as part of current diagnostic practice

PMIDs: 36063114; 34267336; 33445191; 27250579 all report biallelic CACNA1A variants in cases of Developmental and epileptic encephalopathy 42 (OMIM:617106), therefore the mode of inheritance should be changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 13 Sep 2022, 2:04 p.m. | Last Modified: 13 Sep 2022, 2:04 p.m.

Panel Version: 2.594

Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 3 variants reported in 4 unrelated cases.

Created: 8 Nov 2018, 5:16 p.m.

Comment on phenotypes: Variants also associated with Episodic ataxia, type 2 108500;Migraine, familial hemiplegic, 1 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia 141500; Spinocerebellar ataxia 6 183086

Created: 17 Jul 2018, 4:21 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 42, OMIM:617106

Publications

• 36063114
• 34267336
• 33445191
• 27250579

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)