Abstract
In recent years, optical genome mapping (OGM) has developed into a highly promising method of detecting large-scale structural variants in human genomes. It is capable of detecting structural variants considered difficult to detect by other current methods. Hence, it promises to be feasible as a first-line diagnostic tool, permitting insight into a new realm of previously unknown variants. However, due to its novelty, little experience with OGM is available to infer best practices for its application or to clarify which features cannot be detected. In this study, we used the Saphyr system (Bionano Genomics, San Diego, CA, USA), to explore its capabilities in human genetic diagnostics. To this end, we tested 14 DNA samples to confirm a total of 14 different structural or numerical chromosomal variants originally detected by other means, namely, deletions, duplications, inversions, trisomies, and a translocation. Overall, 12 variants could be confirmed; one deletion and one inversion could not. The prerequisites for detection of similar variants were explored by reviewing the OGM data of 54 samples analyzed in our laboratory. Limitations, some owing to the novelty of the method and some inherent to it, were described. Finally, we tested the successful application of OGM in routine diagnostics and described some of the challenges that merit consideration when utilizing OGM as a diagnostic tool.
Highlights
Genomic structural variants (SVs) involve the loss, multiplication, rearrangement, or translocation of large genomic regions
Routine human genetic diagnostics revealed a total of 14 SVs or chromosomal numerical aberrations of potential clinical relevance in 12 of the samples, which were chosen for further analysis
optical genome mapping (OGM) with the Bionano Saphyr system has proven to be a valuable tool to confirm the SVs initially detected by other diagnostic means
Summary
Genomic structural variants (SVs) involve the loss, multiplication, rearrangement, or translocation of large genomic regions. Based on DNA hybridization, aCGH offers a resolution of several hundreds to thousands of base pairs, depending on the number of probes used. This technique is powerful in regard to the identification of losses and gains of genetic material, but it is not able to detect balanced SVs, such as inversions and balanced translocations, or complex structural variants [3]. Whole-genome sequencing (WGS) with second- (i.e., short-read sequencing) and third-generation (i.e., long-read sequencing) technologies are capable of detecting SVs [5,6] Computationally challenging, this technology allows the detection of all types of SVs. the relatively short DNA strands used for sequencing present a significant limitation; as the human genome consists of long regions of highly similar, often repetitive sequences, and these regions tend to be difficult or impossible to analyze using short molecules of DNA only [5]. As repetitive regions are often involved in the formation of SVs, their accurate mapping may contribute to the detection of SVs hitherto missed [7,8]
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