A de novo paradigm for mental retardation

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Nature Genetics (Impact Factor: 29.35). 11/2010; 42(12):1109-12. DOI: 10.1038/ng.712
Source: PubMed


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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    • ". Mutations of the RAB39B gene associated with X-linked intellectual disability (Andersen et al., 2014; Giannandrea et al., 2010; Vissers et al., 2010; Wilson et al., 2014). Asterisks designate mutations identified in patients with X-linked intellectual disability and Parkinson's disease. "

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