PDF(Pubmed)
Abstract：
Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.
摘要：
发育性和癫痫性脑病（DEE）是以复发性为特征的严重神经发育障碍，通常是早期发作，伴随发育障碍的癫痫发作通常与潜在的遗传病因和异常的癫痫样活动有关。今天,下一代测序技术(NGS)使我们能够以低成本快速测序大部分DNA.这项研究的目的是评估使用全外显子组测序（WES）作为一线分子遗传学测试，在具有DEE的受试者样本中以早发性耐药癫痫为特征，与全球发育迟缓和/或智力残疾(ID)相关。我们进行了82次wess,鉴定35种致病变异，检出率为43%。在29个不同的基因上突出了识别出的变体，包括，3个新的DEEs候选基因(KCNC2、STXBP6、DHRS9)以前从未鉴定。总的来说,鉴定了35个(66%)从头变体中的23个。最常见的遗传类型是常染色体显性从头（60％），其次是纯合性（17％）和杂合性（11％）的常染色体隐性遗传，常染色体显性遗传自父母镶嵌（6％）和X连锁显性从头（6％）。发现的最常见的突变是错义（75％），其次是移码缺失（16％）。移码重复(5%)，和剪接突变（3％）。考虑到本研究中获得的结果，我们支持使用WES作为DEE中一线分子遗传测试的一种形式。
