Lee Seungbok, Jang Sesong, Kim Jong-Il, Chae Jong Hee, Kim Ki Joong, Lim Byung Chan
Department of Genomic Medicine, Seoul National University Hospital, Seoul, South Korea.
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, South Korea.
Front Neurol. 2022 Jul 22;13:944905. doi: 10.3389/fneur.2022.944905. eCollection 2022.
Infantile spasms (IS) are a clinically and genetically heterogeneous group of epilepsy disorders in early infancy. The genetic backgrounds of IS have been gradually unraveled along with the increased application of next-generation sequencing (NGS). However, to date, only selected genomic regions have been sequenced using a targeted approach in most cases of IS, and the genetic etiologies of the majority of patients remain unknown. We conducted a proof-of-concept study using whole-genome sequencing (WGS) for the genetic diagnosis of IS. We included 16 patients with IS for this study, and WGS was applied as a first-tier test for genetic diagnosis. In total, we sequenced the whole genomes of 28 participants, including the genomes of six patients, which were sequenced with those of their parents. Among variants identified, we focused on those located in epilepsy or seizure-associated genes. We used two different methods to call relevant large deletions from WGS results. We found pathogenic or likely pathogenic variants in four patients (25.0%); a variant in , compound heterozygous variants in , and heterozygous variants in and . We also selected two more candidate variants in and intronic regions. Although there are currently several difficulties in applying WGS for genetic diagnosis, especially in clinical interpretation of non-coding variants, we believe that developing sequencing technologies would overcome these hurdles in the near future. Considering the vast genetic heterogeneity and the substantial portion of patients with unknown etiologies, further studies using whole genomic approaches are necessary for patients with IS.
婴儿痉挛症（IS）是婴儿早期临床上和基因上异质性的癫痫疾病组。随着下一代测序（NGS）应用的增加，IS的遗传背景已逐渐被揭示。然而，迄今为止，在大多数IS病例中，仅使用靶向方法对选定的基因组区域进行了测序，大多数患者的遗传病因仍然未知。我们进行了一项概念验证研究，使用全基因组测序（WGS）对IS进行基因诊断。本研究纳入了16例IS患者，并将WGS用作基因诊断的一线检测方法。我们总共对28名参与者的全基因组进行了测序，其中包括6例患者的基因组，这些患者的基因组与其父母的基因组一起进行了测序。在鉴定出的变异中，我们重点关注位于癫痫或癫痫发作相关基因中的变异。我们使用两种不同的方法从WGS结果中检测相关的大片段缺失。我们在4例患者（25.0%）中发现了致病或可能致病的变异；一个位于[具体基因名称1]的变异，[具体基因名称2]中的复合杂合变异，以及[具体基因名称3]和[具体基因名称4]中的杂合变异。我们还在[具体基因名称5]和[具体基因名称6]的内含子区域中选择了另外两个候选变异。尽管目前将WGS应用于基因诊断存在一些困难，特别是在非编码变异的临床解释方面，但我们相信测序技术的发展将在不久的将来克服这些障碍。考虑到巨大的遗传异质性和病因不明患者的相当比例，对于IS患者，使用全基因组方法进行进一步研究是必要的。
