CACNA1E encodes the α1 E (Cav2.3) subunit of the high voltage-activated R-type calcium channel that initiates rapid synaptic transmission in the central nervous system. CACNA1E was first reported in relation to developmental and epileptic encephalopathy in 2018 (Helbig et al., PMID: 30343943). The main phenotypic features include severe to profound developmental impairment, often with non-verbal and non-ambulatory presentations, severe hypotonia, infantile-onset seizures, and spastic quadriplegia. More variable features include congenital joint contractures, hyperkinetic movement disorders, macrocephaly, developmental regression, autism spectrum disorder, and early death. Five recurrent and/or functionally validated de novo missense variants reported in 12 individuals are included in this curation (PMIDs: 30343943, 33776624). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is gain of function (PMID: 30343943). De novo missense variants without functional evidence or truncating variants (PMIDs: 30343943, 34702355) were not scored. Additional evidence is needed to clarify the implication of these variants in this condition.
In summary, there is definitive evidence to support the relationship between CACNA1E and autosomal dominant developmental and epileptic encephalopathy. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2023 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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