New CACNA1D missense variants causing a neurodevelopmental disorder show increased dihydropyridine sensitivity

Germline de novo missense variants in the pore-forming α1-subunit (CACNA1D gene) of Cav1.3 voltage-gated L-type calcium-channels (LTCC) confer high risk for a severe neurodevelopmental disorder (ND) with or without endocrine symptoms (ES). Pathogenic gating changes enable a channel gain-of-function. Licensed, brain-permeable LTCC blockers (e.g. dihydropyridines, DHPs) may improve symptoms in affected individuals but drug-sensitivity of mutant channels is unknown. We investigated the pathogenicity of three novel germline Cav1.3 missense variants from patients with ND with (F747S, L271H) and without (A749T) ES and examined their DHP sensitivity.