De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies

Abstract Introduction: Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. Methods: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels. Results: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.(Ala961Thr) and c.4591A > G, p.(Met1531Val), respectively. One patient with Lennox–Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.(Ile1273Phe). Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.(Ala961Thr) and p.(Met1531Val) SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.(Ile1273Phe) showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined. Conclusion: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype–phenotype correlations of patients with CACNA1G mutations.