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Abstract：
Introduction: Epilepsy is a group of neurological disorders characterized by recurring seizures and fits. The Epilepsy genes can be classified into four distinct groups, based on involvement of these genes in different pathways leading to Epilepsy as a phenotype. Genetically the disease has been associated with various pathways, leading to pure epilepsy-related disorders caused by CNTN2 variations, or involving physical or systemic issues along with epilepsy caused by CARS2 and ARSA, or developed by genes that are putatively involved in epilepsy lead by CLCN4 variations. Methods: In this study, five families of Pakistani origin (EP-01, EP-02, EP-04, EP-09, and EP-11) were included for molecular diagnosis. Results: Clinical presentations of these patients included neurological symptoms such as delayed development, seizures, regression, myoclonic epilepsy, progressive spastic tetraparesis, vision and hearing impairment, speech problems, muscle fibrillation, tremors, and cognitive decline. Whole exome sequencing in index patients and Sanger sequencing in all available individuals in each family identified four novel homozygous variants in genes CARS2: c.655G>A p.Ala219Thr (EP-01), ARSA: c.338T>C: p.Leu113Pro (EP-02), c.938G>T p.Arg313Leu (EP-11), CNTN2: c.1699G>T p.Glu567Ter (EP-04), and one novel hemizygous variant in gene CLCN4: c.2167C>T p.Arg723Trp (EP-09). Conclusion: To the best of our knowledge these variants were novel and had not been reported in familial epilepsy. These variants were absent in 200 ethnically matched healthy control chromosomes. Three dimensional protein analyses revealed drastic changes in the normal functions of the variant proteins. Furthermore, these variants were designated as \"pathogenic\" as per guidelines of American College of Medical Genetics 2015. Due to overlapping phenotypes, among the patients, clinical subtyping was not possible. However, whole exome sequencing successfully pinpointed the molecular diagnosis which could be helpful for better management of these patients. Therefore, we recommend that exome sequencing be performed as a first-line molecular diagnostic test in familial cases.
摘要：
简介：癫痫是一组以反复发作和发作为特征的神经系统疾病。癫痫基因可以分为四个不同的组，基于这些基因参与导致癫痫为表型的不同途径。从遗传上讲，这种疾病与各种途径有关，导致由CNTN2变异引起的纯癫痫相关疾病，或涉及身体或全身问题以及由CARS2和ARSA引起的癫痫，或由CLCN4变异与癫痫相关的基因开发。方法:在本研究中,纳入5个巴基斯坦裔家族(EP-01,EP-02,EP-04,EP-09和EP-11)进行分子诊断.结果：这些患者的临床表现包括神经症状，如发育迟缓，癫痫发作,回归，肌阵挛性癫痫,进行性痉挛性四轻瘫,视力和听力障碍，言语问题,肌肉纤颤,震颤,和认知能力下降。索引患者的全外显子组测序和每个家庭中所有可用个体的Sanger测序确定了CARS2基因中的四个新的纯合变体：c.655G>Ap.Ala219Thr（EP-01），ARSA：c.338T>C：p.Leu113Pro（EP-02），c.938G>Tp.Arg313Leu（EP-11），CNTN2:c.1699G>Tp.Glu567Ter(EP-04),和基因CLCN4中的一个新的半合子变体：c.2167C>Tp.Arg723Trp（EP-09）。结论：据我们所知，这些变异是新颖的，在家族性癫痫中尚未报道。这些变体在200个种族匹配的健康对照染色体中不存在。三维蛋白质分析显示变体蛋白质的正常功能发生了巨大变化。此外，根据美国医学遗传学学会2015年指南,这些变异体被指定为"致病性".由于表型重叠，在患者中，无法进行临床分型.然而,整个外显子组测序成功地确定了分子诊断，这可能有助于更好地管理这些患者。因此,我们建议将外显子组测序作为家族性病例的一线分子诊断试验.
