BACKGROUND Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits. METHODS We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants. RESULTS We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and non-sense-mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance. CONCLUSIONS Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.

中文翻译：

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男性自闭症谱系障碍的全外显子组测序和转录组分析的综合分析。

背景技术自闭症谱系障碍（ASD）是一组具有高遗传力的神经发育障碍。最近的发现支持高度异质和复杂的遗传病因，包括罕见的从头发生和遗传突变或染色体重排以及两次或多次命中。方法我们通过RNAseq技术对一部分特发性ASD（n = 36）的男性患者进行了全外显子测序（WES）和血细胞转录组分析，以鉴定致病基因，转录组改变和易感性变异。结果我们在7例病例中发现了可能的单基因病因：5例从头（SCN2A，MED13L，KCNV1，CUL3和PTEN）和两个遗传的X连锁变体（MAOA和CDKL5）。转录组学分析可以鉴定出通常被WES过滤遗漏的内含子致病突变，并揭示了一些罕见突变的功能后果。这些包括异常的转录本（PTEN，POLR3C），1.7％突变基因（即SEMA6B，MECP2，ANK3，CREBBP）的表达失调，等位基因特异性表达（FUS，MTOR，TAF1C）和无义介导的衰变（RIT1，ALG9）。对罕见遗传变异的分析显示，在相关途径（例如PI3K-Akt信号转导和轴突指导）中富集。结论已证明，对WES和血液RNAseq数据进行综合分析是一种有效的策略，可识别可能的单基因形式的ASD（在我们的队列中为19％），以及其他可以通过多因素方式导致ASD风险的罕见遗传突变。血液转录组数据