Antiñolo, Guillermo

Aznar-Laín, Gemma

Botella, María Pilar

Codina-Solà, Marta

Cuscó, Ivon

del Campo, Miguel

Gabau, Elisabeth

Gener, Blanca

Gutiérrez-Arumí, Armand

Homs, Aïda

Pérez-Jurado, Luis Alberto

Rigau, Maria

Rodríguez-Santiago, Benjamín

Santoyo, Javier

English

BackgroundAutism 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.MethodsWe 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.ResultsWe 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.ConclusionsIntegrative 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

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Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders

https://www.research.ed.ac.uk/files/335811921/s13229_015_0017_0.pdf

Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders

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