Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/60709
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Type: Journal article
Title: Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability
Author: Whibley, A.
Plagnol, V.
Tarpey, P.
Abidi, F.
Fullston, T.
Choma, M.
Boucher, C.
Shepherd, L.
Willatt, L.
Parkin, G.
Smith, R.
Futreal, P.
Shaw, M.
Boyle, J.
Licata, A.
Skinner, C.
Stevenson, R.
Turner, G.
Field, M.
Hackett, A.
et al.
Citation: American Journal of Human Genetics, 2010; 87(2):173-188
Publisher: Univ Chicago Press
Issue Date: 2010
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Annabel C. Whibley... Tod Fullston... Jozef Gecz... et al.
Abstract: 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.
Keywords: Chromosomes, Human, X; Humans; Chromosome Breakage; Disease; Retroelements; Oligonucleotide Array Sequence Analysis; Cohort Studies; Reproducibility of Results; Pedigree; Chromosome Segregation; Gene Rearrangement; Sequence Deletion; Female; Male; Genes, X-Linked; INDEL Mutation; DNA Copy Number Variations; Intellectual Disability
Rights: Copyright © 2010 The American Society of Human Genetics. All rights reserved.
RMID: 0020100398
DOI: 10.1016/j.ajhg.2010.06.017
Appears in Collections:Paediatrics publications

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