Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability

Annabel C. Whibley, Vincent Plagnol, Patrick S. Tarpey, Fatima Abidi, Tod Fullston, Maja K. Choma, Catherine A. Boucher, Lorraine Shepherd, Lionel Willatt, Georgina Parkin, Raffaella Smith, P. Andrew Futreal, Marie Shaw, Jackie Boyle, Andrea Licata, Cindy Skinner, Roger E. Stevenson, Gillian Turner, Michael Field, Anna HackettCharles E. Schwartz, Jozef Gecz, Michael R. Stratton, F. Lucy Raymond

Research output: Contribution to journalArticle

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Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families.

Original languageEnglish
Pages (from-to)173-188
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 13 Aug 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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