De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.
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DOI：
10.1186/s13229-021-00473-3
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发表时间：
2021-10-26
期刊：
影响因子：
6.2
通讯作者：
Superti-Furga A
中科院分区：
文献类型：
--
作者：
Royer-Bertrand B;Jequier Gygax M;Cisarova K;Rosenfeld JA;Bassetti JA;Moldovan O;O'Heir E;Burrage LC;Allen J;Emrick LT;Eastman E;Kumps C;Abbas S;Van Winckel G;Undiagnosed Diseases Network;Chabane N;Zackai EH;Lebon S;Keena B;Bhoj EJ;Umair M;Li D;Donald KA;Superti-Furga A
电压门控钙通道亚单位α1 E基因（CACNA 1 E）的新生变异被描述为癫痫性脑病伴挛缩、大头畸形和运动障碍的病因。在观察了患有发育迟缓和自闭症谱系障碍（ASD）但没有癫痫发作的索引患者后，我们筛选了GeneMatcher用于其他患有CACNA 1 E变体和神经发育表型但没有癫痫发作的个体。将致病性CACNA 1 E变体的谱与gnomAD对照群体数据库中变体的突变景观进行比较。我们确定了7名智力残疾、发育退化和ASD样行为特征的不相关个体，特别是没有癫痫的个体，他们在CACNA 1 E中具有新生杂合性puppal致病性变体。临床表现的发病年龄、有无退化和严重程度是可变的，并且没有明确的基因型-表型关联可以被识别。对疾病相关变异的分析及其与对照人群中良性变异的比较，允许鉴定CACNA 1 E蛋白中似乎不耐受取代的区域，因此更可能含有致病性变异。在少数报告的CACNA 1 E变异和癫痫病例中，1例患者对托吡酯（一种特异性钙通道调节剂）显示出阳性临床行为反应。我们的研究的意义是有限的，缺乏功能实验的影响，确定的变体，小样本量和缺乏系统的ASD评估在所有参与者。此外，托吡酯仅用于一名患者，且使用时间较短。我们的研究结果表明，CACNA 1 E变异体可能会导致神经发育障碍没有癫痫和扩大该基因的突变和表型谱。CACNA 1 E值得纳入非特异性发育障碍（包括ASD）的基因组，而不仅限于癫痫患者，以提高诊断识别率并探索托吡酯的可能疗效。在线版本包含补充材料，可通过10.1186/s13229-021-00473-3获得。
De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate. The online version contains supplementary material available at 10.1186/s13229-021-00473-3.
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9.1
作者：
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