Purpose

CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.

Methods

We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.

Results

Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.

Conclusion

We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

中文翻译：

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CACNA1C 相关疾病的表型扩展包括孤立的神经系统表现

 目的

CACNA1C编码在人类心脏和大脑中表达的电压依赖性 L 型钙通道的 alpha-1 亚基。此前曾报道过CACNA1C杂合变异与 Timothy 综合征和长 QT 综合征相关。一些病例报告表明CACNA1C变异也可能与主要的神经表型相关。

 方法

我们描述了来自 22 个家族的 25 名具有CACNA1C杂合变异的个体，他们主要表现为神经系统症状。

 结果

14 名个体患有新发非截短变异，并表现出不同程度的发育迟缓、智力障碍、自闭症、肌张力减退、共济失调和癫痫。通过膜片钳实验对错义变体亚组进行的功能研究证明了对体外通道功能的不同影响，包括功能丧失 (p.Leu1408Val)、中性效应 (p.Leu614Arg) 和功能获得 (p.Leu657Phe，p. 10)。 Leu614Pro)。来自 8 个家族的其余 11 个人具有CACNA1C截短变体。这些人中的大多数都有语言表达障碍，其中一半患有自闭症。

 结论

我们将与CACNA1C变异相关的表型扩展到包括神经发育异常和癫痫，但不存在蒂莫西综合征或长 QT 综合征的经典特征。