Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, along with restricted and repetitive behaviour patterns, interests or activities. Its prevalence has risen over the past few years, being four times more common in boys than girls. The cause of ASD is unclear, its etiology involves genetic, environmental, and gene-environment interactions. While past studies highlighted clinical genetic risks, genetic complexity of ASD, with variants of diverse frequencies, type, and inheritance patterns, requires further exploration for better management of disease. Researches have shown that the whole exome sequencing can be used to identify genetic variants associated with genetically heterogeneous conditions. The purpose of this study is to identify genetic variants by employing whole exome sequencing in an Indian ASD patient. Methods: A female patient of age within 0-5 years, having characteristic features like hyperactivity and language impairment, was investigated and diagnosed using DSM-5 criteria. Peripheral blood sample collection was done followed by DNA extraction and whole exome sequencing. Variants analysis, identification and annotation were done using bioinformatics tools and databases. Identified pathogenic variants were reconfirmed by Sanger sequencing. Results and conclusion: Our study uncover four genetic variations, comprising three missense variations in KIF1A (c.3839C>T), SETD5 (c.314A>C), MAPK81P3 (c.2849C>T), and one-stop gain variation in ERMARD (c.1523G>A). The ERMARD stop gain variation, predicted to induce nonsense-mediated decay, alter normal protein function through truncation and classified as likely pathogenic based on the ACMG guidelines and current available scientific evidence. In conclusion, we identified a likely pathogenic variant in ERMARD along with three missense variants in KIF1A, SETD5 and MAPK81P3 respectively. These findings suggest the potential contribution of ERMARD mutations to ASD susceptibility, emphasizing the need for further validation through functional studies. Keywords: Autism spectrum disorder, neurodevelopmental disorder, whole exome sequencing, language impairment, bioinformatics, missense variation

中文翻译：

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使用全外显子组测序鉴定印度患者自闭症谱系障碍的新基因变异

背景：自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交沟通和互动持续缺陷，以及受限和重复的行为模式、兴趣或活动。在过去几年中，其患病率有所上升，男孩的患病率是女孩的四倍。ASD 的病因尚不清楚，其病因涉及遗传、环境以及基因与环境的相互作用。虽然过去的研究强调了临床遗传风险，但自闭症谱系障碍的遗传复杂性以及不同频率、类型和遗传模式的变异，需要进一步探索以更好地管理疾病。研究表明，全外显子组测序可用于识别与遗传异质性条件相关的遗传变异。本研究的目的是通过对印度 ASD 患者进行全外显子组测序来识别遗传变异。方法：对1例0~5岁女性患者进行调查，采用DSM-5标准对具有多动、语言障碍等特征的患者进行调查和诊断。采集外周血样本，然后进行 DNA 提取和全外显子组测序。使用生物信息学工具和数据库进行变异分析、鉴定和注释。通过桑格测序再次确认了已识别的致病变异。结果和结论：我们的研究发现了四种遗传变异，包括 KIF1A (c.3839C>T)、SETD5 (c.314A>C)、MAPK81P3 (c.2849C>T) 的三种错义变异，以及埃马德 (c.1523G>A)。ERMARD 停止增益变异，预计会诱导无义介导的衰变，通过截断改变正常蛋白质功能，并根据 ACMG 指南和当前可用的科学证据被归类为可能致病的。总之，我们在 ERMARD 中发现了一个可能的致病变异，并分别在 KIF1A、SETD5 和 MAPK81P3 中发现了三个错义变异。这些发现表明 ERMARD 突变对 ASD 易感性的潜在贡献，强调需要通过功能研究进一步验证。关键词: 自闭症谱系障碍, 神经发育障碍, 全外显子组测序, 语言障碍, 生物信息学, 错义变异