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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 ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼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.

Original publication

DOI

10.1002/humu.22901

Type

Journal article

Journal

Hum Mutat

Publication Date

12/2015

Volume

36

Pages

1197 - 1204

Keywords

Mendelian disease, developmental delay, intellectual disability, next-generation sequencing, Alleles, Cohort Studies, Computational Biology, Female, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Intellectual Disability, Male, Mutation, Polymorphism, Single Nucleotide