A de novo paradigm for mental retardation

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Abstract

The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.

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Figure 1: Experimental work flow for detecting and prioritizing sequence variants.

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Acknowledgements

We thank R. de Reuver and J. Hehir-Kwa for bioinformatics support in data analysis and personnel from the Sequencing Facility of our department for timely completion of Sanger sequencing of validation experiments. This work was funded in part by grants from The Netherlands Organization for Health Research and Development (ZonMW grants 916-86-016 to L.E.L.M.V., 917-66-36 and 911-08-025 to J.A.V. and 917-86-319 to B.B.A.d.V.), the EU-funded TECHGENE project (Health-F5-2009-223143 to J.d.L. and J.A.V.) and the AnEUploidy project (LSHG-CT-2006-37627 to A.H., B.W.M.v.B., H.G.B., B.B.A.d.V. and J.A.V.).

Author information

J.A.V., L.E.L.M.V. and H.G.B. conceived the project and planned the experiments. B.B.A.d.V. and B.W.M.v.B. performed sample collection and reviewed phenotypes. L.E.L.M.V., A.H., I.J., M.S., P.d.V., B.v.L. and P.A. performed next-generation sequencing experiments using a custom pipeline set up by C.G. and A.H. J.d.L. and C.G. analyzed and interpreted the data with support from N.W. and M.d.R. L.E.L.M.V., P.d.V., I.J. and M.S. performed validation experiments. L.E.L.M.V., J.d.L. and J.A.V. prepared the first draft of the manuscript. All authors contributed to the final manuscript.

Correspondence to Han G Brunner or Joris A Veltman.

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The authors declare no competing financial interests.

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