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

Abstract

Purpose Chromosomal microarray analysis to assess copy number variation (CNV) has become a first tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA). Over 100 cytogenetic labs 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 CNV resource from a new population sample, which 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 CNVs. Reproducibility and validation metrics were quantified using sample replicates and quantitative-PCR, respectively. Results DNA from 873 individuals passed quality control and we identified 71,178 CNVs (81 CNVs/individual); 9.8% (6,984) of these CNVs were previously unreported. After applying three layers of filtering criteria, from our highest confidence CNVs dataset we obtained >95% reproducibility and >90% validation rate (73% of these CNVs overlapped at least one gene). Conclusion The genotype data and annotated CNVs for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics.

Exploration of large, rare copy number variants associated with psychiatric and neurodevelopmental disorders in individuals with anorexia nervosa

“…Of note, there is no frequency information available for the 13q12 deletion in 1000 Genomes, which suggests that the precise population frequency of this CNV is not well known. However, we found three studies in DGV, which reported CNVs in controls with > 50% reciprocal overlap with the CNV in our study (Cooper et al , 2011, Uddin et al , 2015, Pinto et al , 2007). While we cannot rule out a possible AN diagnosis in these individuals, 13q12 deletion does not appear to be AN specific, and its presence in one AN case should be interpreted with caution as larger case-control samples are required to rigorously evaluate the validity of this deletion in AN.…”

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge

“…The deletion of 22q13.3 is a definitive cause for ASD and deletion of the SHANK3 gene specifically is a major cause of the Phelan-McDermid syndrome. The de novo duplication of 16p13.2 has been associated with ASD in a recent report [36] and also found rarely in a control population[37]. The patient's overall clinical presentation is consistent with PMS.…”

Genomewide analysis of copy number variants in alopecia areata in a Central European cohort reveals association with MCHR2

“…These duplications spanned the genes MCHR2 and MCHR2‐AS1 . In the Database of Genomic Variants (DGV; http://dgv.tcag.ca/dgv/app/home), five studies report at least one duplication affecting MCHR2 (http://www.1000genomes.org/home). In total, 12 duplications were observed in 57 328 individuals (0.02%).…”

“…This strategy reduces type I errors, whereas type II errors are expected to increase. http://dgv.tcag.ca/dgv/app/home), 26 five studies report at least one duplication affecting MCHR2 [27][28][29][30] (http://www.1000genomes.org/ home). In total, 12 duplications were observed in 57 328 individuals (0.02%).…”