Whibley, AC and Plagnol, V and Tarpey, PS and Abidi, F and Fullston, T and Choma, MK and Boucher, CA and Shepherd, L and Willatt, L and Parkin, G and Smith, R and Futreal, PA and Shaw, M and Boyle, J and Licata, A and Skinner, C and Stevenson, RE and Turner, G and Field, M and Hackett, A and Schwartz, CE and Gecz, J and Stratton, MR and Raymond, FL (2010) Fine-Scale Survey of X Chromosome Copy Number Variants and Indels Underlying Intellectual Disability. AM J HUM GENET , 87 (2) 173 - 188. 10.1016/j.ajhg.2010.06.017.
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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 non-coding 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.
|Title:||Fine-Scale Survey of X Chromosome Copy Number Variants and Indels Underlying Intellectual Disability|
|Keywords:||LINKED MENTAL-RETARDATION, ACID AMIDE HYDROLASE, HUMAN GENOME, STRUCTURAL VARIATION, GENE-EXPRESSION, ARRAY-CGH, DEVELOPMENTAL DELAY, MESSENGER-RNA, IL1RAPL1 GENE, XLMR GENES|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute|
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