A high-resolution copy-number variation resource for clinical and population genetics

Genet Med. 2015 Sep;17(9):747-52. doi: 10.1038/gim.2014.178. Epub 2014 Dec 11.


Purpose: Chromosomal microarray analysis to assess copy-number variation has become a first-tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders or multiple congenital anomalies. More than 100 cytogenetic laboratories worldwide use the new ultra-high resolution Affymetrix CytoScan-HD array to genotype hundreds of thousands of samples per year. Our aim was to develop a copy-number variation resource from a new population sample that would enable more accurate interpretation of clinical genetics data on this microarray platform and others.

Methods: Genotyping of 1,000 adult volunteers who are broadly representative of the Ontario population (as obtained from the Ontario Population Genomics Platform) was performed with the CytoScan-HD microarray system, which has 2.7 million probes. Four independent algorithms were applied to detect copy-number variations. Reproducibility and validation metrics were quantified using sample replicates and quantitative-polymerase chain reaction, respectively.

Results: DNA from 873 individuals passed quality control and we identified 71,178 copy-number variations (81 copy-number variations/individual); 9.8% (6,984) of these copy-number variations were previously unreported. After applying three layers of filtering criteria, from our highest confidence copy-number variation data set we obtained >95% reproducibility and >90% validation rates (73% of these copy-number variations overlapped at least one gene).

Conclusion: The genotype data and annotated copy-number variations for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Chromosomes
  • Congenital Abnormalities / genetics
  • DNA Copy Number Variations*
  • Data Curation
  • Databases, Genetic*
  • Female
  • Genetics, Population / methods*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neurodevelopmental Disorders / genetics
  • Oligonucleotide Array Sequence Analysis / methods*
  • Reproducibility of Results