Abstract
In recent years, chromosomal microarrays have been widely adopted by clinical diagnostic laboratories for postnatal constitutional genome analysis and have been recommended as the first-line test for patients with intellectual disability, developmental delay, autism and/or congenital abnormalities. Traditionally, array platforms have been designed with probes evenly spaced throughout the genome and increased probe density in regions associated with specific disorders with a resolution at the level of whole genes or multiple exons. However, this level of resolution often cannot detect pathogenic intragenic deletions or duplications, which represent a significant disease-causing mechanism. Therefore, new high-resolution oligonucleotide comparative genomic hybridisation arrays (oligo-array CGH) have been developed with probes targeting single exons of disease relevant genes. Here we present a retrospective study on 27,756 patient samples from a consortium of state-funded diagnostic UK genomic centres assayed by either oligo-array CGH of a traditional design (Cytosure ISCA v2) or by an oligo-array CGH with enhanced exon-level coverage of genes associated with developmental disorders (CytoSure Constitutional v3). The new targeted design used in Cytosure v3 array has been designed to capture intragenic aberrations that would have been missed on the v2 array. To assess the relative performance of the two array designs, data on a subset of samples (n = 19,675), generated only by laboratories using both array designs, were compared. Our results demonstrate that the new high-density exon-focused targeted array design that uses updated information from large scale genomic studies is a powerful tool for detection of intragenic deletions and duplications that leads to a significant improvement in diagnostic yield.