A de novo paradigm for mental retardation.

Nat Genet 2010 Dec 14;42(12):1109-12. Epub 2010 Nov 14.

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.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.712DOI Listing
December 2010

Publication Analysis

Top Keywords

mental retardation
16
paradigm mental
8
novo mutations
8
novo paradigm
8
novo
7
unique non-synonymous
4
validated unique
4
identified validated
4
non-synonymous novo
4
identified individuals
4
pathogenic based
4
based gene
4
individuals pathogenic
4
retardation identified
4
genes identified
4
mutations genes
4
ten individuals
4
sequencing approach
4
exome sequencing
4
based exome
4

Similar Publications