Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability

• Published in: Human mutation Vol. 36; no. 12; pp. 1197 - 1204
• Main Authors: Grozeva, Detelina, Carss, Keren, Spasic-Boskovic, Olivera, Tejada, Maria-Isabel, Gecz, Jozef, Shaw, Marie, Corbett, Mark, Haan, Eric, Thompson, Elizabeth, Friend, Kathryn, Hussain, Zaamin, Hackett, Anna, Field, Michael, Renieri, Alessandra, Stevenson, Roger, Schwartz, Charles, Floyd, James A.B., Bentham, Jamie, Cosgrove, Catherine, Keavney, Bernard, Bhattacharya, Shoumo, Hurles, Matthew, Raymond, F. Lucy
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2015; Hindawi Limited; Wiley; John Wiley and Sons Inc
• Subjects: Alleles; Cohort Studies; Computational Biology - methods; developmental delay; Female; Genetic Association Studies; Genetic disorders; Genetics; High-Throughput Nucleotide Sequencing; Human genetics; Humans; Inheritance Patterns; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; Life Sciences; Male; Mendelian disease; Mutation; next-generation sequencing; Polymorphism, Single Nucleotide; developmental delay; next-generation sequencing; Mendelian disease; intellectual disability
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22901

ABSTRACT 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. For diseases caused by high new mutation rates e.g. intellectual disability, the availability of DNA from both parents for trio analysis is invaluable. However, in single parent households, a loss of function variant analysis of a panel of known disease‐causing genes plus analysis of a limited list of previously established pathogenic missense variants can yield a diagnostic rate of 11%. This strategy has significant clinical utility where samples from both parents are unavailable.