Abstract
BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip® array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip® array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip® array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip® array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip® 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip® array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.
Highlights
Array genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects
copy number variants (CNVs) calls on the X-chromosome in a female child were validated by an independent method if they appeared to have occurred de novo; CNV calls on the X-chromosome in a male child were validated by an independent method whether they appeared to be de novo or to have been inherited from the mother
We found a total of 4577 hits in the 462 samples (154 trios) analyzed by 500 K GeneChip® Array Genomic Hybridization (AGH)
Summary
Array genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. Chromosomal imbalance has been recognized as the most frequent cause of intellectual disability (ID) for 50 years [1,2,3]. Our ability to recognize these submicroscopic genomic changes, which are usually called copy number variants (CNVs), as the most frequent cause of ID depends on the use of Array Genomic Hybridization (AGH) ( known as array-comparative genomic hybridization, chromosomal microarray analysis, or copy number analysis). More recent studies have shown that arrays with higher resolution and genomewide coverage provide better detection rates for pathogenic CNVs in children with ID and normal cytogenetic analysis [7,8,9,10,11,12]. Other methods have identified pathogenic CNVs that are too small to have been detected by the array platforms used in most AGH studies [13,14,15], so analysis at even higher resolution may be necessary to detect all pathogenic CNVs in children with ID
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
