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Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

Molecular Psychiatry volume 16, pages 867–880 (2011)Cite this article

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Abstract

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n=142; 122 males and 20 females) or SCZ (n=143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

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Acknowledgements

We thank the families involved in our study and the recruitment coordinators (Anne Desjarlais, Caroline Poulin, and Sabrina Diab). We thank Annie Levert, Judith St-Onge, and Isabelle Bachand for performing DNA extraction and paternity and identity testing. We are thankful for the efforts of the members of the McGill University and Genome Quebec Innovation Centre Sequencing (Pierre Lepage, Sébastien Brunet, and Hao Fan Yam) and Bioinformatic (Louis Létourneau and Louis Dumond Joseph) groups. This work was supported by a grant from Genome Canada and Génome Québec and was cofunded by Université de Montréal, for the ‘Synapse-to-disease’ (S2D) project.

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Authors and Affiliations

  1. Department of Medicine, Centre of Excellence in Neuromics, CHUM Research Centre, University of Montreal, Montreal, QC, Canada

    A Piton, J Gauthier, R G Lafrenière, Y Yang, E Henrion, S Laurent, A Noreau, P Thibodeau, L Karemera, D Spiegelman, F Kuku, J Duguay, L Destroismaisons, P Jolivet, M Côté, K Lachapelle, O Diallo, A Raymond, C Marineau, L Xiong, C Gaspar, J-B Rivière, J Tarabeux, P Cossette & G A Rouleau

  2. CHU Sainte-Justine Research Center, Montreal, QC, Canada

    F F Hamdan & G A Rouleau

  3. Department of Pathology and Cell Biology and Groupe de recherche sur le systeme nerveux central, University of Montreal, Montreal, QC, Canada

    N Champagne & P Drapeau

  4. INSERM U796, Physiopathologie des maladies psychiatriques, Universit,

    M-O Krebs

  5. é Paris Descartes and Centre hospitalier Sainte Anne, Paris, France

    M-O Krebs

  6. Child Psychiatry Branch, NIMH/NIH, Bethesda, MD, USA

    J L Rapoport & A Addington

  7. VA Boston Healthcare System and Harvard Medical School, Brockton, MA, USA

    L E DeLisi

  8. The Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA

    L E DeLisi

  9. Centre d’excellence en Troubles envahissants du d,

    L Mottron

  10. é,

    L Mottron

  11. veloppement de l’Universit,

    L Mottron

  12. é de Montr,

    L Mottron

  13. é,

    L Mottron

  14. al (CETEDUM), Montreal, QC, Canada

    L Mottron

  15. Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    R Joober

  16. Department of Psychiatry, Montreal Children's Hospital, Montreal, QC, Canada

    E Fombonne

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  1. A Piton
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Correspondence to G A Rouleau.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Piton, A., Gauthier, J., Hamdan, F. et al. Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16, 867–880 (2011). https://doi.org/10.1038/mp.2010.54

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  • DOI: https://doi.org/10.1038/mp.2010.54

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