CACNA1H variants are not a cause of monogenic epilepsy.,Human Mutation

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CACNA1H variants are not a cause of monogenic epilepsy.
Human Mutation ( IF 3.3 ) Pub Date : 2020-04-14 , DOI: 10.1002/humu.24017
Jeffrey D Calhoun ₁ , Alexandra M Huffman ₂ , Irena Bellinski ₁ , Lisa Kinsley ₁ , Elizabeth Bachman ₁ , Elizabeth Gerard ₁ , Jennifer A Kearney ₂ , Gemma L Carvill ₁

Affiliation

CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent reclassification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the American College of Medical Genetics classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia-induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.

中文翻译：

CACNA1H 变异不是单基因癫痫的原因。

CACNA1H 遗传变异最初是在儿童失神癫痫队列中报道的。随后，CACNA1H 的基因检测变得可用，目前由商业实验室提供。然而，CACNA1H 作为癫痫的单基因病因的当前状态是有争议的，ClinGen 最近将 CACNA1H 重新归类为有争议的，这凸显了这一点。我们分析了已发表的 CACNA1H 变异和 ClinVar 中报告的变异，发现根据美国医学遗传学学会分类标准，没有一个被归类为致病性或可能致病性的。此外，Cacna1h 没有改变 Dravet 综合征小鼠模型的存活率。我们观察到 Cacna1h 表达降低的小鼠对热疗诱发癫痫的易感性轻度增加。总体，

更新日期：2020-04-14

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