Early onset or syndromic epilepsy

Gene: CACNA1E

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)

No real information on OMIM. On Panel App - paper Helbig et al 2018: https://www.cell.com/ajhg/fulltext/S0002-9297(18)30317-3. de novo CACNA1E variants were identified in 30 individuals with developmental and epileptic encepalopathy characterised by refractory infantile-onsdet seizures, severe hypotonia and profound developmental impairement often with congenital contractures, macrocephaly, hyperkinetic movement disorders and early death. Most of the 14 partially recurring variants cluster within the cytoplasmic ends of all 4 S6 segments. Functional analysis of several S6 variants revealed consistent GOF effects comprising facilitated voltage-dependent activation and slowed inactivation (abstract).

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, 618285

Publications

• 30343943

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. PMID reports 30343943 "de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death."

Created: 7 Nov 2018, 1:54 p.m.

Green List (high evidence)

30 individuals reported with early onset refractory seizures, hypotonia, macrocephaly, contractures, movement disorder, and de novo variants in this gene. Functional data.

Created: 23 Oct 2018, 5:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epileptic encephalopathy

Publications

• Am J Hum Genet, Helbig et al, not yet on PubMed

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

Green List (high evidence)

Helbig et al. (https://doi.org/10.1016/j.ajhg.2018.09.006) report on 30 individuals with pathogenic variants in CACNA1E.

The phenotype was consistent with a developmental and epileptic encephalopathy, with hypotonia, early-onset and refractory seizures, severe to profound developmental delay and intellectual disability. Additional relatively common features included hyperkinetic movement disorder (severe dystonia which was observed in 40%, other dyskinesias in another 20%), congenital joint contractures of variable degree and joint involvement (approx. 40% of individuals) and macrocephaly (approx. 40%). There were no common facial dysmorphic features observed.

Of note, epilepsy was not a feature in 4 cases (age 1 to 4 years) so few of these individuals may be investigated for their developmental delay/intellectual disability or other features.

Missense variants:
All the 30 subjects described harbored a missense variant in CACNA1E which in all cases where parental studies were possible (29/30) occurred as a de novo event. There were 4 recurrent variants, explaining the phenotype in 20 patients in total while the rest of the individuals had private mutations. Functional studies were performed and suggested a gain-of-function effect for these variants (increased calcium inward currents).

Loss-of-function (LoF) variants:
Apart from the main cohort of patients, the authors note the presence of 3 individuals with such variants incl.:
- one individual with a nonsense variant present in the mosaic state (6/22 reads) in peripheral blood.
- one individual with a frameshift variant inherited from his unaffected parent.
- one individual with a nonsense variant for whom parental studies were not possible.

The authors comment that these indivdiduals presented with milder phenotype compared to those with missense variants. More information on these subjects is provided in the supplement as the article focuses on missense SNVs.

As the authors also note, several LoF variants exist in gnomAD, although the gene appears to be LoF intolerant (pLI=1).

Penetrance:
Seems to be complete for missense SNVs and possibly incomplete for LoF ones.

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A previous study by Heyne et al. (PMID: 29942082) implicated de novo variants (DNVs) in CACNA1E with neurodevelopmental disorders for the first time. This study however does not provide clinical details on the phenotype of the affected individuals, while it seems to present overlap as to the individuals reported (eg. includes subjects from the DDD study and others).

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Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db:
http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CACNA1E

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As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature

Created: 19 Oct 2018, 8:01 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly

Publications

• 29942082

Mode of pathogenicity
Other