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Whole-genome sequencing of quartet families with autism spectrum disorder

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Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.

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Figure 1: Schematic of genetic and phenotypic data processing in 85 multiplex families with ASD.
Figure 2: Quality of whole genome sequencing for all samples.
Figure 3: Mutation burden in families with two siblings with ASD.
Figure 4: Families with underlying genetic etiology resolved.

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Acknowledgements

We thank S.S. Gross, M. Bookman and D. Glazer from Google for the development of the MSSNG database. We thank the families for their participation in the study and we thank The Centre for Applied Genomics for informatics support. We would also like to acknowledge the Autism Sequencing Consortium (AASC) principal investigators for the use of data. This work was supported by Autism Speaks (S.W.S., R.K.C.Y.), Autism Speaks Canada (S.W.S.), Neurodevelopment Network (NeuroDevNet) (S.W.S.), the Canadian Institutes for Advanced Research (S.W.S.), the University of Toronto McLaughlin Centre (S.W.S.), Genome Canada and Ontario Genomics Institute (S.W.S.), the government of Ontario (S.W.S., P.S.), the Canadian Institutes of Health Research (S.W.S., P.S.), and The Hospital for Sick Children Foundation (S.W.S.). R.K.C.Y. holds the Autism Speaks Meixner Postdoctoral Fellowship in Translational Research and a NARSAD Young Investigator award. K.T. holds a fellowship from the Swedish Research Council. E.D. holds the Banting Postdoctoral Fellowship. P.S. holds the Patsy and Jamie Anderson Chair in Child and Youth Mental Health. S.W.S. holds the GlaxoSmithKline–Canadian Institutes of Health Research (CIHR) Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children.

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Contributions

R.K.C.Y. and S.W.S. conceived and designed the experiments. R.K.C.Y., B.T., D.M. and T.N. processed and analyzed the whole genome sequencing data. S.W. and K.T. designed and performed experiments for variants characterization and validation. N.H., C.C., J.L.H. and A.T. collected phenotypic information from the participants. G.P., Y.L., M.J.G., L.D., E.D., R.S.C.L., M.Z., M.U. and C.R.M. helped perform different components of whole genome sequencing analysis and validation experiments. R.K.C.Y., R.H.R. and S.W.S. conceived and coordinated the project. L.Z., P.N.R., R.W., M.T.C., B.A.F., W.R. and P.S. recruited, diagnosed and examined the recruited participants. R.K.C.Y. and S.W.S. wrote the manuscript.

Corresponding author

Correspondence to Stephen W Scherer.

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The authors declare no competing financial interests.

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Yuen, R., Thiruvahindrapuram, B., Merico, D. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med 21, 185–191 (2015). https://doi.org/10.1038/nm.3792

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