Wang Jiaping, Gao Hua, Bao Xinhua, Zhang Qingping, Li Jiarui, Wei Liping, Wu Xiru, Chen Yan, Yu Shujie
Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
BMC Med Genet. 2017 Sep 18;18(1):104. doi: 10.1186/s12881-017-0460-1.
SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.
To identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.
A heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.
Our findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.
SCN8A突变最近被认为与癫痫和神经发育障碍有关。本研究旨在拓宽与SCN8A突变相关疾病的表型谱。
为确定一个有6名成员患癫痫的中国家系的致病基因，进行了全外显子测序。此外，对178例出生后6个月内病因不明的散发性癫痫患者进行了靶向二代测序（NGS）。获取了详细的临床病史。
在中国家系中鉴定出SCN8A的一个杂合错义突变。在6例散发性癫痫患者中检测到6个SCN8A的新发突变。在家系中，6名成员在出生后几年内出现癫痫发作。其中5名临床表现较轻，认知和发育里程碑正常，单药治疗可实现无癫痫发作。另一名受影响成员表现为难治性癫痫和发育倒退。她17岁时死于癫痫性猝死（SUDEP）。6例SCN8A突变散发性患者的临床特征各不相同，从严重癫痫性脑病到认知正常的良性癫痫。癫痫发作开始的平均年龄为3.9个月（2个月至6个月）。其中4例通过单药或多药抗癫痫药物实现无癫痫发作。其中5例表现为轻度或重度精神运动发育迟缓，而另1例发育和智力正常。
我们的研究结果扩展了SCN8A突变谱以及SCN8A突变患者的临床特征。大多数SCN8A突变是新发的，也可能发生来自杂合子父母的遗传突变。SCN8A突变的表型谱差异很大。大多数受影响患者表现为难治性癫痫和严重智力残疾，只有少数患者表现为较轻的临床类型。此外，我们的研究证实相同的突变可导致不同的表型。
