Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID
Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID
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DOI：
10.1038/ejhg.2017.52
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发表时间：
2017-06-01
影响因子：
5.2
通讯作者：
Wieczorek, Dagmar
中科院分区：
文献类型：
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作者：
Redler, Silke;Strom, Tim M.;Wieczorek, Dagmar
对于大量的智力残疾（ID）个体，其分子基础仍然是未知的。然而，全外显子组测序（WES）正在为ID的遗传景观提供越来越多的见解。在本研究中，我们对311例未解决的ID和其他临床特征的患者进行了基于三组的WES，并在来自两个不相关家族的3例ID患者中发现了纯合的CPLX1变异。所有患者均表现出明显的发育迟缓和迁移性肌阵挛性癫痫，其中一人还表现出小脑裂。编码的蛋白复合物1在神经元突触调节中起着至关重要的作用，在小鼠模型中，纯合子Cplx1敲除小鼠具有已知最早的共济失调发病。最近，一种纯合子截断型CPLX1被认为是迁移性癫痫和脑结构异常的病因。虽然不能完全排除，但没有报道ID。然而，目前关于CPLX1的有限知识表明，复杂蛋白1功能的丧失可能导致复杂但可变的临床表型，我们的研究结果鼓励进一步研究ID、发育迟缓和肌阵挛性癫痫患者的CPLX1，以揭示CPLX1变异携带者的表型谱。
For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families. All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition. The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation, and homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model. Recently, a homozygous truncating variant in CPLX1 was suggested to be causative for migrating epilepsy and structural brain abnormalities. ID was not reported although it cannot be completely ruled out. However, the currently limited knowledge on CPLX1 suggests that loss of complexin 1 function may lead to a complex but variable clinical phenotype, and our findings encourage further investigations of CPLX1 in patients with ID, developmental delay and myoclonic epilepsy to unravel the phenotypic spectrum of carriers of CPLX1 variants.