Autism is a neurodevelopmental condition with genetic heterogeneity. It is characterized by difficulties in reciprocal social interactions with strong repetitive behaviors and stereotyped interests. Copy number variations (CNVs) are genomic structural variations altering the genomic structure either by duplication or deletion. De novo or inherited CNVs are found in 5–10% of autistic subjects with a size range of few kilobases to several megabases. CNVs predispose humans to various diseases by altering gene regulation, generation of chimeric genes, and disruption of the coding region or through position effect. Although, CNVs are not the initiating event in pathogenesis; additional preceding mutations might be essential for disease manifestation. The present study is aimed to identify the primary CNVs responsible for autism susceptibility in healthy cohorts to sensitize secondary-hits. In the current investigation, primary-hit autism gene CNVs are characterized in 1715 healthy cohorts of varying ethnicities across 12 populations using Affymetrix high-resolution array study. Thirty-eight individuals from twelve families residing in Karnataka, India, with the age group of 13–73 years are included for the comparative CNV analysis. The findings are validated against global 179 autism whole-exome sequence datasets derived from Simons Simplex Collection. These datasets are deposited at the Simons Foundation Autism Research Initiative (SFARI) database. The study revealed that 34.8% of the subjects carried 2% primary-hit CNV burden with 73 singleton-autism genes in different clusters. Of these, three conserved CNV breakpoints were identified with ARHGAP11B, DUSP22, and CHRNA7 as the target genes across 12 populations. Enrichment analysis of the population-specific autism genes revealed two signaling pathways—calcium and mitogen-activated protein kinases (MAPK) in the CNV identified regions. These impaired pathways affected the downstream cascades of neuronal function and physiology, leading to autism behavior. The pathway analysis of enriched genes unravelled complex protein interaction networks, which sensitized secondary sites for autism. Further, the identification of miRNA targets associated with autism gene CNVs added severity to the condition. These findings contribute to an atlas of primary-hit genes to detect autism susceptibility in healthy cohorts, indicating their impact on secondary sites for manifestation.

中文翻译：

---

初级拷贝数变异的鉴定揭示了钙的富集，以及使自闭症次级位点敏感的 MAPK 通路

自闭症是一种具有遗传异质性的神经发育疾病。它的特点是互惠社会互动困难，具有强烈的重复行为和刻板的兴趣。拷贝数变异 (CNV) 是通过复制或删除改变基因组结构的基因组结构变异。在 5% 到 10% 的自闭症受试者中发现了从头或遗传性 CNV，大小范围从几千个碱基到几兆个碱基。CNV 通过改变基因调控、产生嵌合基因和破坏编码区或通过位置效应使人类易患各种疾病。虽然，CNVs 不是发病机制的起始事件；额外的先前突变可能对疾病表现至关重要。本研究旨在确定导致健康队列中自闭症易感性的主要 CNV，以致敏二次打击。在当前的调查中，使用 Affymetrix 高分辨率阵列研究在 12 个人群中不同种族的 1715 个健康队列中表征了原发性自闭症基因 CNV。来自居住在印度卡纳塔克邦的 13-73 岁年龄组的 12 个家庭的 38 个人被纳入比较 CNV 分析。这些发现针对源自 Simons Simplex Collection 的全球 179 个自闭症全外显子组序列数据集进行了验证。这些数据集存放在西蒙斯基金会自闭症研究计划 (SFARI) 数据库中。研究表明，34.8% 的受试者携带 2% 的原发性 CNV 负担，其中有 73 个单独的自闭症基因位于不同的簇中。这些，以 ARHGAP11B、DUSP22 和 CHRNA7 作为靶基因，鉴定了三个保守的 CNV 断点，跨越 12 个群体。人群特异性自闭症基因的富集分析揭示了 CNV 识别区域中的两种信号通路——钙和丝裂原活化蛋白激酶 (MAPK)。这些受损的通路影响神经元功能和生理学的下游级联，导致自闭症行为。富集基因的通路分析揭示了复杂的蛋白质相互作用网络，这使自闭症的继发性位点敏感。此外，与自闭症基因 CNV 相关的 miRNA 靶标的鉴定增加了病情的严重性。这些发现有助于构建主要基因图谱，以检测健康人群中的自闭症易感性，表明它们对次要表现部位的影响。