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

Detelina Grozeva, Keren Carss, Olivera Spasic-Boskovic, Maria Isabel Tejada, Jozef Gecz, Marie Shaw, Mark Corbett, Eric Haan, Elizabeth Thompson, Kathryn Friend, Zaamin Hussain, Anna Hackett, Michael Field, Alessandra Renieri, Roger Stevenson, Charles Schwartz, James A.B. Floyd, Jamie Bentham, Catherine Cosgrove, Bernard KeavneyShoumo Bhattacharya, Matthew Hurles, F. Lucy Raymond, UK10K Consortium, GOLD Consortium, UK10K Consortium, GOLD Consortium, GOLD Consortium, GOLD Consortium, Italian X-linked Mental Retardation Project, Italian X-linked Mental Retardation Project, GOLD Consortium

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)


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 languageEnglish
Pages (from-to)1197-1204
Number of pages8
JournalHuman mutation
Issue number12
Publication statusPublished or Issued - Dec 2015


  • Developmental delay
  • Intellectual disability
  • Mendelian disease
  • Next-generation sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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