Early onset or syndromic epilepsy
Gene: CACNA1AThe 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
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
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
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
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.
Currently on Amplexa CHE-113 epilepsy diagnostic panelCreated: 12 Feb 2019, 2:06 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Absence epilepsy; Familial hemiplegic migraine 1
Publications
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 183086Created: 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
Tag Q3_22_MOI was removed from gene: CACNA1A. Tag Q3_22_NHS_review was removed from gene: CACNA1A.
Mode of inheritance for gene CACNA1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tag Q3_22_NHS_review tag was added to gene: CACNA1A.
Phenotypes for gene: CACNA1A were changed from Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500 to Developmental and epileptic encephalopathy 42, OMIM:617106; developmental and epileptic encephalopathy, 42, MONDO:0014917; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Tag Q3_22_MOI tag was added to gene: CACNA1A.
Publications for gene: CACNA1A were set to 29056246; 27476654; 11564488; 20071244; 15452324; 8898206
Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM) to Developmental and epileptic encephalopathy 42, OMIM:617106; Episodic ataxia, type 2, OMIM:108500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, OMIM:141500
Source Wessex and West Midlands GLH was added to CACNA1A.
Source NHS GMS was added to CACNA1A.
Gene: cacna1a has been classified as Green List (High Evidence).
Phenotypes for gene: CACNA1A were changed from Epileptic encephalopathy, early infantile, 42 617106 to Epileptic encephalopathy, early infantile, 42, 617106; Epilepsy and migraine; Absence epilepsy; Migraine, familial hemiplegic, 1, 141500; Familial hemiplegic migraine 1 (FHM)
Publications for gene: CACNA1A were set to 29056246; 27476654
Sarah Leigh: Comment on phenotypes: Variant
Gene: cacna1a has been classified as Green List (High Evidence).
Gene: cacna1a has been classified as Green List (High Evidence).
Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CACNA1A were set to 29056246; 27476654
Phenotypes for gene: CACNA1A were set to Epileptic encephalopathy, early infantile, 42 617106
Publications for gene: CACNA1A were set to 29056246
Expert Review Amber was added to CACNA1A. Panel: Genetic Epilepsy Syndromes
Victorian Clinical Genetics Services was added to CACNA1A. Panel: Genetic Epilepsy Syndromes
CACNA1A was added to Genetic Epilepsy Syndromes panel. Sources: Expert Review Red,Expert
CACNA1A was created by Sarah Leigh