A De Novo Paradigm for Mental Retardation

Overview

Journal Nat Genet

Specialty Genetics

Date 2010 Nov 16

PMID 21076407

Citations 386

Authors

Lisenka E L M Vissers

Joep de Ligt

Christian Gilissen

Irene Janssen

Marloes Steehouwer

Petra De Vries

Bart van Lier

Peer Arts

Nienke Wieskamp

Marisol Del Rosario

Bregje W M van Bon

Alexander Hoischen

Bert B A de Vries

Han G Brunner

Joris A Veltman

Affiliations

Soon will be listed here.

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.

Citing Articles

YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs.

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PMID: 39987231 DOI: 10.1038/s41380-025-02929-x.

Novel De Novo Intronic Variant of SYNGAP1 Associated With the Neurodevelopmental Disorders.

Xie W, Liao B, Shuai M, Liu R, Hong M, He S Mol Genet Genomic Med. 2025; 13(2):e70066.

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eNSMBL-PASD: Spearheading early autism spectrum disorder detection through advanced genomic computational frameworks utilizing ensemble learning models.

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Ruiz I, Wiltrout K, Stredny C, Mahida S Genes (Basel). 2024; 15(11).

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Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield.

Furukawa S, Kato M, Ishiyama A, Kumada T, Yoshida T, Takeshita E J Hum Genet. 2024; 69(12):629-637.

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