Epileptic encephalopathyGene: CACNA1E
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.
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).
Seems to be complete for missense SNVs and possibly incomplete for LoF ones.
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).
Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db:
As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
19 Oct 2018, 8:03 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly
Mode of pathogenicity
gene: CACNA1E was added gene: CACNA1E was added to Epileptic encephalopathy. Sources: Expert Review,Literature Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CACNA1E were set to 29942082 Phenotypes for gene: CACNA1E were set to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly Penetrance for gene: CACNA1E were set to Incomplete Mode of pathogenicity for gene: CACNA1E was set to Other Review for gene: CACNA1E was set to GREEN