Submission Details

Autosomal dominant

07/30/2020

The CACNA1E gene is located on chromosome 1 at 1q25.3 and encodes calcium voltage-gated channel subunit alpha1 E. This subunit is part of the CaV2.3 calcium channel. CaV2.3 channels are widely expressed throughout the central nervous system and conduct voltage-activated, rapidly inactivating R-type calcium currents, which are used to initiate rapid synaptic transmission. CACNA1E was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2018 (30343943: Helbig et al. 2018). At least 14 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 30 probands in a single multi-institutional publication (30343943: Helbig et al. 2018). In the majority of cases, variants were demonstrated to have occurred de novo. The reported missense variants are also highly clustered in the cytoplasmic ends of all four S6 transmembrane segments, which line the inner pore of the channel and form the activation gate. The mechanism of disease is gain of function; a small number of cases with predicted null variants of uncertain significance have also been reported (30343943: Helbig et al. 2018). This gene-disease relationship is supported by enriched expression in the brain, a shared biochemical function with another gene, CACNA1A, that is associated with a similar early onset epileptic encephalopathy, and in vitro analyses in a human cell line demonstrating and gain of function effect for four missense variants. In summary, there is strong evidence to support the relationship between CACNA1E and autosomal dominant developmental and epileptic encephalopathy. Additional evidence published three years from the first proposal of the association is needed to reach a definitive classification.

30343943 21139605