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.

中文翻译：

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发育迟缓和早发性癫痫性脑病中的从头 CACNA1G 变异

引言据报道，编码 CaV3.1 的 CACNA1G 变体与各种神经系统疾病有关。方法 对 348 名日本神经发育障碍患者及其父母的基因组 DNA 进行全外显子组测序，提取 CACNA1G 从头变异。通过对过表达这些通道的 HEK293T 细胞进行电压钳和电流钳分析，研究了每个突变通道的电生理特性。结果发现两名诊断为 Rett 综合征和 West 综合征的患者在小脑共济失调队列中报告了已知的病理性 CACNA1G 突变：分别为 c.2881G > A，p.Ala961Thr 和 c.4591A > G，p.Met1531Val。一名 Lennox-Gastaut 综合征患者被发现携带以前未报道的杂合变异：c.3817A > T，p。Ile1273Phe。两名具有已知突变的患者的临床症状包括严重的发育迟缓，没有获得独立行走的能力。具有潜在新突变的患者在 MRI 上表现出发育迟缓、顽固性癫痫发作和轻度脑萎缩，但症状的严重程度比前两例要轻。使用 HEK293T 细胞的电生理研究表明，p.Ala961Thr 和 p.Met1531Val SNVs 的 T 型 Ca2+ 电流发生显着变化，这可能会增强膜电位在低频下的振荡。相比之下，p.Ile1273Phe 在我们的电生理评估中没有显示出显着影响，其发病机制仍未确定。结论 CACNA1G 的从头变异解释了一些神经发育障碍。