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

• Published in: Journal of the neurological sciences Vol. 416; p. 117047
• Main Authors: Kunii, Misako, Doi, Hiroshi, Hashiguchi, Shunta, Matsuishi, Toyojiro, Sakai, Yasunari, Iai, Mizue, Okubo, Masaki, Nakamura, Haruko, Takahashi, Keita, Katsumoto, Atsuko, Tada, Mikiko, Takeuchi, Hideyuki, Ishikawa, Taro, Miyake, Noriko, Saitsu, Hirotomo, Matsumoto, Naomichi, Tanaka, Fumiaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2020
• Subjects: CACNA1G; Calcium Channels, T-Type - genetics; CaV3.1; Cerebellar Ataxia; Developmental delay; Early-onset epileptic encephalopathy; HEK293 Cells; Humans; Infant, Newborn; Mutation - genetics; Patch-clamp; Phenotype; Spasms, Infantile - genetics; T-type voltage-gated calcium channel; Whole Exome Sequencing; Early-onset epileptic encephalopathy; T-type voltage-gated calcium channel; Patch-clamp; CaV3.1; Developmental delay; CACNA1G; Ca(V)3.1
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2020.117047

Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. 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. 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. 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. •WES analysis for 348 Japanese neurodevelopmental disorders has been conducted.•Two patients with known de novo CACNA1G variants showed Rett and West syndrome.•One patient with an unreported variant exhibited Lennox–Gastaut syndrome.•Two known variants affected electrophysiological properties of CaV3.1.•The pathogenesis of unreported I1273F variant remains uncertain in our evaluations.