Journal
HUMAN MUTATION
Volume 36, Issue 12, Pages 1197-1204Publisher
WILEY
DOI: 10.1002/humu.22901
Keywords
intellectual disability; next-generation sequencing; Mendelian disease; developmental delay
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Funding
- Action Medical Research [SP4640]
- Newlife Foundation for Disabled Children [RG45448]
- Cambridge National Institute for Health Research Biomedical Research Centre [RG64219]
- NIHR Rare Diseases BioResource [RBAG163]
- Wellcome Trust [WT091310]
- Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases (Telethon Network of Genetic Biobanks) [GTB12001]
- Genetic Origins of Congenital Heart Disease Study (GO-CHD) - British Heart Foundation (BHF)
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To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in similar to 11% of the cases (113 variants in 107/986 individuals: similar to 8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas similar to 3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone. Published 2015 Wiley Periodicals, Inc.
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