Background: Pathogenic mutations range from single nucleotide changes to deletions or duplications that encompass a single exon to several genes. The use of gene-centric high-density array comparative genomic hybridization (aCGH) has revolutionized the detection of intragenic copy number variations. We implemented an exon-centric design of high-resolution aCGH to detect single- and multi-exon deletions and duplications in a large set of genes using the OGT 60 K and 180 K arrays. Here we describe the molecular characterization and breakpoint mapping of deletions at the smaller end of the detectable range in several genes using aCGH.Results: The method initially implemented to detect single to multiple exon deletions, was able to detect deletions much smaller than anticipated. The selected deletions we describe vary in size, ranging from over 2 kb to as small as 12 base pairs. The smallest of these deletions are only detectable after careful manual review during data analysis. Suspected deletions smaller than the detection size for which the method was optimized, were rigorously followed up and confirmed with PCR-based investigations to uncover the true detection size limit of intragenic deletions with this technology. False-positive deletion calls often demonstrated single nucleotide changes or an insertion causing lower hybridization of probes demonstrating the sensitivity of aCGH.Conclusions: With optimizing aCGH design and careful review process, aCGH can uncover intragenic deletions as small as dozen bases. These data provide insight that will help optimize probe coverage in array design and illustrate the true assay sensitivity. Mapping of the breakpoints confirms smaller deletions and contributes to the understanding of the mechanism behind these events. Our knowledge of the mutation spectra of several genes can be expected to change as previously unrecognized intragenic deletions are uncovered. © 2013 Askree et al.; licensee BioMed Central Ltd.

Nearly all children with Down syndrome (DS) are born with hypotonia which later improves with age. We present a case of a 32-month-old female with DS who has persistent hypotonia and ligamentous hyperlaxity. She was subsequently diagnosed with Ehlers-Danlos Syndrome-Hypermobility type (EDS-HMT) based on family history, which resulted in the significant global developmental delay compared to age-matched peers with DS. Further clinical investigation is recommended in individuals with DS who appear to have developmental profiles significantly below what would be expected due to typical Trisomy 21 so that additional diagnostic testing and appropriate interventional therapy may be provided. Specifically, timely diagnosis of inherited disorders such as EDS-HMT is important in identifying other family members with the condition.