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.

This work was funded by grants from the Spanish Ministry of Health (FIS PI1002512, PI1302481, and PI1300823 cofunded by FEDER), Fundación Alicia Koplowitz and Generalitat de Catalunya (2014SGR1468). The ‘Medical Genome Project’ is a joint initiative of the Consejería de Salud de la Junta de Andalucía and Roche, supported by the ‘Programa Nacional de Proyectos de investigación Aplicada’, I + D + i 2008, ‘Subprograma de actuaciones Científicas y Tecnológicas en Parques Científicos y Tecnológicos’ (ACTEPARQ 2009) and FEDER. The CIBER de Enfermedades Raras is an initiative of the ISCIII. CDTI FEDER-Innterconecta EXP00052887/ITC-20111037.