De Novo Mutations in Moderate or Severe Intellectual Disability
Open Access
- 30 October 2014
- journal article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 10 (10), e1004772
- https://doi.org/10.1371/journal.pgen.1004772
Abstract
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID. Intellectual disability (ID) is the most frequent severe handicap of childhood. Several observations indicate that genetic factors explain a large fraction of cases with ID. We and others have recently found that de novo mutations (DNMs; genetic changes not transmitted from the parents) represent a common cause of ID. To further assess the contribution of DNMs to the development of ID, we interrogated virtually all the genes of the genome in 41 affected children with moderate or severe ID and in their healthy parents. In 12 of the cases, we identified disease-causing DNMs in genes known to be associated with ID, resulting in a molecular diagnostic yield of 29%. We also found 12 possibly disease-causing DNMs in genes that were not previously causally linked to ID. Interestingly, many of the genes with deleterious DNMs uncovered by this study encode proteins that interact with each other and affect specific processes in brain cells. In contrast, we did not identify any inherited mutations that could explain our cases. We conclude that DNMs play a predominant role in moderate or severe ID.Keywords
This publication has 62 references indexed in Scilit:
- Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIAAmerican Journal of Human Genetics, 2012
- Disruption of an EHMT1-Associated Chromatin-Modification Module Causes Intellectual DisabilityAmerican Journal of Human Genetics, 2012
- De Novo Gene Disruptions in Children on the Autistic SpectrumNeuron, 2012
- Haploinsufficiency of ARID1B, a Member of the SWI/SNF-A Chromatin-Remodeling Complex, Is a Frequent Cause of Intellectual DisabilityAmerican Journal of Human Genetics, 2012
- Assessment of 2q23.1 Microdeletion Syndrome Implicates MBD5 as a Single Causal Locus of Intellectual Disability, Epilepsy, and Autism Spectrum DisorderAmerican Journal of Human Genetics, 2011
- Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11European Journal of Human Genetics, 2011
- Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual DisabilityAmerican Journal of Human Genetics, 2011
- WAC, a Functional Partner of RNF20/40, Regulates Histone H2B Ubiquitination and Gene TranscriptionMolecular Cell, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental RetardationAmerican Journal of Human Genetics, 2008