title: Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.
abstract: Autism is a severe neurodevelopmental disorder, the aetiology of which remains mainly unknown. Family and twin studies provide strong evidence that genetic factors have a major role in the aetiology of this disease. Recently, whole exome sequencing (WES) efforts have focused mainly on rare de novo variants in singleton families. Although these studies have provided pioneering insights, de novo variants probably explain only a small proportion of the autism risk variance. In this study, we performed exome sequencing of 10 autism multiplex families with the aim of investigating the role of rare variants that are coinherited in the affected sibs. The pool of variants selected in our study is enriched with genes involved in neuronal functions or previously reported in psychiatric disorders, as shown by Gene Ontology analysis and by browsing the Neurocarta database. Our data suggest that rare truncating heterozygous variants have a predominant role in the aetiology of autism. Using a multiple linear regression model, we found that the burden of truncating mutations correlates with a lower non-verbal intelligence quotient (NVIQ). Also, the number of truncating mutations that were transmitted to the affected sibs was significantly higher (twofold) than those not transmitted. Protein-protein interaction analysis performed with our list of mutated genes revealed that the postsynaptic YWHAZ is the most interconnected node of the network. Among the genes found disrupted in our study, there is evidence suggesting that YWHAZ and also the X-linked DRP2 may be considered as novel autism candidate genes.
authors.affiliation: 1] Department of Genetics, University of Barcelona, Barcelona, Spain [2] Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Toma
authors.affiliation: 1] Department of Genetics, University of Barcelona, Barcelona, Spain [2] Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Torrico
authors.affiliation: Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Hervás
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oviedo-IUOPA, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Valdés-Mas
authors.affiliation: Department of Genetics, University of Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Tristán-Noguero
authors.affiliation: Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Padillo
authors.affiliation: Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Maristany
authors.affiliation: Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Salgado
authors.affiliation: Department of Statistics, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Arenas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oviedo-IUOPA, Barcelona, Spain.
authors.forename: X S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: National Centre for Genomic Analysis (CNAG), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Bayés
authors.affiliation: 1] Department of Genetics, University of Barcelona, Barcelona, Spain [2] Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain [3] Institute of Biomedicine, University of Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Cormand
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007360:Intelligence / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics; D055815:Young Adult
chemical_list: D048948:14-3-3 Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C572235:YWHAZ protein, human; C095114:collapsin response mediator protein-2