Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability.
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.
Whibley
Annabel C
AC
Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge CB2 0XY, UK.
Plagnol
Vincent
V
Tarpey
Patrick S
PS
Abidi
Fatima
F
Fullston
Tod
T
Choma
Maja K
MK
Boucher
Catherine A
CA
Shepherd
Lorraine
L
Willatt
Lionel
L
Parkin
Georgina
G
Smith
Raffaella
R
Futreal
P Andrew
PA
Shaw
Marie
M
Boyle
Jackie
J
Licata
Andrea
A
Skinner
Cindy
C
Stevenson
Roger E
RE
Turner
Gillian
G
Field
Michael
M
Hackett
Anna
A
Schwartz
Charles E
CE
Gecz
Jozef
J
Stratton
Michael R
MR
Raymond
F Lucy
FL
D019457:Chromosome Breakage; D020090:Chromosome Segregation / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D004194:Disease / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D050172:Genes, X-Linked / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D015203:Reproducibility of Results; D018626:Retroelements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics
D018626:Retroelements