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Jana Jezkova, Jade Heath, Angharad Williams, Deborah Barrell, Jessica Norton, Morag N. Collinson, Sarah J. Beal, Sian Corrin & Sian Morgan



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.



Over the last decade, the implementation of comparative genomic hybridisation arrays (array CGH) as a first-tier test for detecting chromosomal aberrations associated with developmental delay (DD), intellectual disability (ID), autism spectrum disorder, multiple congenital anomalies and other neurodevelopmental phenotypes has shown a marked improvement in diagnostic yields1,2. G-band karyotyping, the previously recommended test for patients with such phenotypes, provides a diagnostic yield of approximately 3%, while chromosomal microarray (CMA)-based testing has been shown to offer yields of 10–20%1,2.

Modern oligonucleotide-based array designs have typically focused on providing broad genome coverage with higher probe density in regions associated with specific disorders. More recently, newer array designs have been introduced that incorporate the findings of large-scale genomic studies (e.g., Deciphering Developmental Disorders study3,4) and the cumulative knowledge gained through the sharing of high-resolution, highly-curated genomic data in easily accessible public databases (e.g., ClinVar). A number of research groups have also advocated the use of exon-level probe coverage for specific genes, allowing further increases in diagnostic yield through the detection of smaller intragenic copy number variants (CNVs)5,6.

In order to understand the diagnostic impact of these array design strategies, we present here a large-scale in silico retrospective analysis of data derived from multiple state-funded UK based genomic centres who implemented the CytoSure Constitutional v3 array (CytoSure v3) for diagnostic testing of National Health Service (NHS) patients. The previous version, the CytoSure International Standards for Cytogenomic Arrays (ISCA) v2 (hereafter referred to as CytoSure v2), focuses on known diseasecausing genes and has a “backbone” of probes across the entire genome. The new CytoSure v3 is a more focused, exon-centric oligo-array design that incorporates novel content from the DDD study and ClinVar database. Similar to the CytoSure v2 design, the v3 array has a reduced coverage of probes across uninformative regions to avoid detection of variants of unknown significance and incidental findings. We compare the performance of the CytoSure v3 array with that of the CytoSure v2 array; and also interrogate the entire post-natal proband dataset, providing further information on the type (i.e., duplication and deletion), size, frequency and chromosomal distribution of CNVs across the population tested.

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Examining the medical exome

  • Resource type: White paper
  • Application: Cytogenetics & rare disease
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