title: Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.
abstract: 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.
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader 88, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Codina-Solà
authors.affiliation: Quantitative Genomic Medicine Laboratories (qGenomics), C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Rodríguez-Santiago
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader 88, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain.
authors.forename: Aïda
authors.initials: A
authors.lastname: Homs
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), C/Albert Einstein, Cartuja Scientific and Technology Park, INSUR Builiding, Sevilla, 41092 Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Santoyo
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Rigau
authors.affiliation: Pediatric Neurology, Hospital del Mar, Passeig Marítim 25-29, Barcelona, 08003 Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Aznar-Laín
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain ; Servicio de Genética, Hospital Vall d'Hebron, Passeig Vall d'Hebron, 119-129, Barcelona, 08015 Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.affiliation: Genetics Service, BioCruces Health Research Institute, Hospital Universitario Cruces, Plaza de Cruces 12, Barakaldo, Bizkaia 48093 Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.affiliation: Pediatrics Service, Corporació Sanitària Parc Taulí, Parc Taulí 1, Sabadell, 08208 Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gabau
authors.affiliation: Pediatric Neurology, Hospital de Txagorritxu, C/José de Atxotegui s/n, Victoria-Gasteiz, 01009 Spain.
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Botella
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader 88, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain.
authors.forename: Armand
authors.initials: A
authors.lastname: Gutiérrez-Arumí
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain ; Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA), C/Albert Einstein, Cartuja Scientific and Technology Park, INSUR Builiding, Sevilla, 41092 Spain ; Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Avda Manuel Siurot s/n, Sevilla, 41013 Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader 88, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain.
authors.forename: Luis Alberto
authors.initials: LA
authors.lastname: Pérez-Jurado
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, C/Doctor Aiguader 88, 422, Barcelona, 08003 Spain ; Hospital del Mar Research Institute (IMIM), C/Doctor Aiguader 88, Barcelona, 08003 Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), C/ Monforte de Lemos 3-5, Madrid, 28029 Spain.
authors.forename: Ivon
authors.initials: I
authors.lastname: Cuscó
keywords: ASD; CNV; SNV; Whole-exome sequencing