title: A de novo paradigm for mental retardation.
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.
authors.affiliation: 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.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Irene
authors.initials: I
authors.lastname: Janssen
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.forename: Petra
authors.initials: P
authors.lastname: de Vries
authors.forename: Bart
authors.initials: B
authors.lastname: van Lier
authors.forename: Peer
authors.initials: P
authors.lastname: Arts
authors.forename: Nienke
authors.initials: N
authors.lastname: Wieskamp
authors.forename: Marisol
authors.initials: M
authors.lastname: del Rosario
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
mesh_terms: D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA