Background: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation (MR) and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time-consuming, locus-specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV etiologies as well as new ones.
Methods: Genome-wide copy number analysis on 117 patients has been performed using Affymetrix 250k microarrays.
Results: 434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as ‘potentially pathogenic’. Almost all pathogenic CNVs were larger than 500kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity (LOH) larger than 5Mb were found in 5 patients.
Conclusions: Genome microarray analysis has improved diagnostic success in this group of patients. Several examples of recently discovered ‘new syndromes’ were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of MR. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype-phenotype analysis and review of guidelines for selection of individuals for microarray analysis is emphasised.
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