Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Clin Genet. 2018 Mar;93(3):577-587. doi: 10.1111/cge.13144. Epub 2018 Jan 25.
Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.
癫痫是常见的神经障碍，遗传因素是其发病机制的重要因素之一。拷贝数变异（CNVs）作为许多人类疾病（包括癫痫）的重要病因已被广泛认可。全外显子组测序（WES）是检测致病突变的标准工具，最近已被用于检测 CNVs。在此，我们使用 WES 分析了 294 个癫痫家系，重点分析了 168 个已知癫痫相关基因中无致病单核苷酸变异的家系，以使用两种不同的基于 WES 数据的 CNV 检测工具进一步验证 CNVs。我们确认了 18 个致病性 CNVs，以及 2 个临床意义未知的 chr15q11.2 缺失和 2 个重复。值得注意的是，我们能够鉴定到小于 10kb 的小 CNVs，这可能很难用传统的微阵列检测到。我们发现了 2 个具有致病性 CNVs 的病例，其中一个 CNV 检测工具未能发现，这表明建议使用不同的 CNV 工具以提高诊断率。考虑到 CNVs 的发现率相对较高（168 个家系中有 18 个，10.7%），并且能够检测到小于 10kb 的 CNV，WES 检测 CNVs 可能能够替代或至少补充传统的微阵列分析。
