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Emma Shipstone, James Reid, Sandra Kachhia, John Shovelton, Duarte Molha, Christina Taylor, Jagath Kasturiarachchi, Jolyon Holdstock, Venu Pullabhatla, Laura Parkes, Natalie Milner, Douglas Hurd



Array comparative genomic hybridisation (aCGH) has been used extensively in research to determine the causative copy number variation (CNV) in Intellectual Disability (ID) and Development Delay (DD) cases1. Microarrays have a limitation in that they cannot detect single nucleotide variations (SNVs), which may be causative. Conversely, robust small CNV calling via other genetic techniques, e.g. exome sequencing has remained challenging. To overcome these issues, we have designed an NGS assay and supporting analytical software that reliably detects a wide range of aberration types, including:

  • SNVs within 700 targeted ID and DD genes, exons and UTRs
  • Small (single exon) CNVs within the targeted 700 ID and DD genes
  • Larger CNVs (>190kb) across the genome
  • Loss of Heterozygosity regions with a resolution of <5Mb

The 700 targeted genes known to be important in ID and DD were carefully selected on the basis of ClinGen2 and DDD3 guidelines. The ability to detect these 4 different types of aberration significantly improves the likelihood of detecting causative aberrations compared to aCGH alone.

Outlined here is the design and testing of the assay using research samples obtained from cytogenetic laboratories. A particular focus of the testing has been confirmation that the CNV detection capabilities of the assay are as good as those obtained with aCGH (Figures 1-7). This has included testing with mosaic samples. We have demonstrated excellent concordance between the results obtained with the new assay and aCGH.

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