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Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations

Molecular Psychiatry volume 19, pages 784–790 (2014)Cite this article

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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.

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Acknowledgements

We are grateful to all families for their participation in our study. We thank Patricia Romarís (Hospital Universitari Mútua de Terrassa) for contributing to clinical delineation of patients and Lara Nonell and Eulàlia Puigdecanet (Servei d'Anàlisi de Micorarrays, IMIM-Hospital del Mar, Parc de Recerca Biomèdica de Barcelona) for their contribution to the CNV studies. Exome sequencing services were provided by the National Centre for Genomic Analysis (CNAG). CT was supported by the European Union (Marie Curie, PIEF-GA-2009-254930) and BT by AGAUR (FI grant). Financial support was received from ‘Fundació La Marató de TV3’ (092010), ‘Fundación Alicia Koplowitz’, AGAUR (2009SGR00971) and ‘Ministerio de Economía y Competitividad, Spain’ (SAF2012-33484, SAF2010-21165).

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Authors and Affiliations

  1. Department of Genetics, University of Barcelona, Barcelona, Spain

    C Toma, B Torrico, A Tristán-Noguero & B Cormand

  2. Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain

    C Toma, B Torrico & B Cormand

  3. Child and Adolescent Mental Health Unit, Hospital Universitari Mútua de Terrassa, Barcelona, Spain

    A Hervás & M Salgado

  4. Department of Biochemistry and Molecular Biology, University of Oviedo-IUOPA, Barcelona, Spain

    R Valdés-Mas & X S Puente

  5. Developmental Disorders Unit (UETD), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

    V Padillo & M Maristany

  6. Department of Statistics, University of Barcelona, Barcelona, Spain

    C Arenas

  7. National Centre for Genomic Analysis (CNAG), Barcelona, Spain

    M Bayés

  8. Institute of Biomedicine, University of Barcelona, Barcelona, Spain

    B Cormand

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Toma, C., Torrico, B., Hervás, A. et al. Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol Psychiatry 19, 784–790 (2014). https://doi.org/10.1038/mp.2013.106

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