A De Novo Paradigm for Mental Retardation 2011

Author: J. A. Veltman
Submitted: Tuesday 6th of September 2011 09:23:44 AM
Submitted by: egf
Educational levels: expert, qc2, qc3

Abstract

Recent studies have indicated that humans have an exceptionally high per-generation mutation rate of 7.6 x 10-9 to 2.2 x 10-8. These spontaneous germline mutations can have serious phenotypic consequences when affecting functionally relevant bases in the genome. In fact, their occurrence may explain why diseases with a severely reduced fecundity remain frequent in the human population, especially when the mutational target is large and comprised of many genes. This would explain a major paradox in the evolutionary genetic theory of mental disorders. Here we used a family-based exome sequencing approach to test this de novo mutation hypothesis in 10 patients with unexplained mental retardation. Unique non-synonymous de novo mutations were identified and validated in nine genes. Six of these, identified in different patients, are likely 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. Reference: Vissers LELM, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BWM, Hoischen A, de Vries BBA, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet 42: 1109-12 (2010).

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J. A. Veltman. A De Novo Paradigm for Mental Retardation 2011. EUROGENE portal. September 2011. online: http://eurogene.open.ac.uk/content/de-novo-paradigm-mental-retardation-2011

Keywords

de novo mutation

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