电压门控钙通道亚基α1E基因(CACNA1E)的从头变异已被描述为挛缩性癫痫性脑病的病因,大头畸形和运动障碍.
在观察一名患有发育迟缓和自闭症谱系障碍(ASD)但没有癫痫发作的患者,该患者具有从头有害的CACNA1E变异体,我们筛选了其他有CACNA1E变异和无癫痫的神经发育表型的个体GeneMatcher.将致病性CACNA1E变体的谱与gnomAD对照种群数据库中变体的突变景观进行了比较。
我们确定了7名智力残疾的无关个体,发育回归和ASD样行为特征,特别是没有癫痫,在CACNA1E中具有从头杂合推定致病性变异。临床表现的发病年龄,是否存在回归和严重程度是可变的,并且无法识别明确的基因型-表型关联。疾病相关变体的分析及其与来自对照群体的良性变体的比较允许鉴定CACNA1E蛋白中似乎对取代不耐受并且因此更可能携带致病性变体的区域。如在少数报道的CACNA1E变异和癫痫病例中,一名患者对托吡酯表现出积极的临床行为反应,一种特定的钙通道调节剂。
我们的研究的意义是有限的缺乏功能实验的作用的鉴定变体,所有参与者的样本量小,缺乏系统的ASD评估。此外,托吡酯仅给予1例患者,治疗时间较短.
我们的结果表明,CACNA1E变异可能导致无癫痫的神经发育障碍,并扩大了该基因的突变和表型谱。CACNA1E值得纳入非特异性发育障碍的基因小组,包括ASD,并不限于癫痫患者,目的提高诊断认识并探讨托吡酯的可能疗效。
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.