Optical genome mapping and revisiting short-read genome sequencing data reveal previously overlooked structural variants disrupting retinal disease−associated genes

• DOI: 10.1016/j.gim.2022.11.013
• Publication Date: 2022-12-16T20:27:10Z
• Authors: Suzanne E. de Bruijn; Kim Rodenburg; Jordi Corominas; Tamar Ben-Yosef; Janine Reurink; Hannie Kremer; Laura Whelan; Astrid S. Plomp; Wolfgang Berger; G. Jane Farrar; Árpád Ferenc Kovács; Isabelle Fajardy; Rebekkah J. Hitti...; Nicole Weisschuh; Marianna E. Weener; Dror Sharon; Ronald J.E. Pennings; Lonneke Haer-Wigman; Carel B. Hoyng; Marcel R. Nelen; Lisenka E.L.M. Vi...; L. Ingeborgh van ...; Christian Gilissen; Frans P.M. Cremers; Alexander Hoischen; Kornelia Neveling; Susanne Roosing
• Keywords: Cancer genome sequencing; Structural Variation; Prioritization

Structural variants (SVs) play an important role in inherited retinal diseases (IRD). Although the identification of SVs significantly improved upon availability genome sequencing, it is expected that involvement IRDs higher than anticipated. We revisited short-read sequencing data to enhance gene-disruptive SVs.Optical mapping was performed improve SV detection sequencing-negative cases. In addition, reanalysis interpretation and re-establish prioritization criteria.In a monoallelic USH2A case, optical identified pericentric inversion (173 megabase), with 1 breakpoint disrupting USH2A. Retrospectively, variant could be observed but previously deemed false positive. Reanalysis (427 IRD cases) which yielded 30 pathogenic affecting, among other genes, (n = 15), PRPF31 3), EYS 2). Eight these (>25%) were overlooked during previous analyses.Critical evaluation our findings allowed us guidelines, will prevent missing events future analyses. Our suggest more attention should paid current contribution still underestimated.