Optical genome mapping and revisiting short-read genome sequencing data reveal previously overlooked structural variants disrupting retinal disease-associated genes
Citation:
de Bruijn, S.E. and Rodenburg, K. and Corominas, J. and Ben-Yosef, T. and Reurink, J. and Kremer, H. and Whelan, L. and Plomp, A.S. and Berger, W. and Farrar, G.J. and Ferenc Kov??cs, ??. and Fajardy, I. and Hitti-Malin, R.J. and Weisschuh, N. and Weener, M.E. and Sharon, D. and Pennings, R.J.E. and Haer-Wigman, L. and Hoyng, C.B. and Nelen, M.R. and Vissers, L.E.L.M. and van den Born, L.I. and Gilissen, C. and Cremers, F.P.M. and Hoischen, A. and Neveling, K. and Roosing, S., Optical genome mapping and revisiting short-read genome sequencing data reveal previously overlooked structural variants disrupting retinal disease-associated genes, Genetics in Medicine, 2023 Mar;25(3):100345Download Item:
Abstract:
Purpose: Structural variants (SVs) play an important role in inherited retinal diseases (IRD).
Although the identification of SVs significantly improved upon the availability of genome
sequencing, it is expected that involvement of SVs in IRDs is higher than anticipated. We
revisited short-read genome sequencing data to enhance the identification of gene-disruptive
SVs.
Methods: Optical genome mapping was performed to improve SV detection in short-read
genome sequencing−negative cases. In addition, reanalysis of short-read genome sequencing
data was performed to improve the interpretation of SVs and to re-establish SV prioritization
criteria.
Results: In a monoallelic USH2A case, optical genome mapping identified a pericentric
inversion (173 megabase), with 1 breakpoint disrupting USH2A. Retrospectively, the variant
could be observed in genome sequencing data but was previously deemed false positive.
Reanalysis of short-read genome sequencing data (427 IRD cases) was performed which yielded
30 pathogenic SVs affecting, among other genes, USH2A (n = 15), PRPF31 (n = 3), and EYS
(n = 2). Eight of these (>25%) were overlooked during previous analyses.
Conclusion: Critical evaluation of our findings allowed us to re-establish and improve our SV
prioritization and interpretation guidelines, which will prevent missing pathogenic events in
future analyses. Our data suggest that more attention should be paid to SV interpretation and
the current contribution of SVs in IRDs is still underestimated.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
16/1A/4452
Author's Homepage:
http://people.tcd.ie/gjfarrar
Author: Farrar, Gwyneth
Sponsor:
Science Foundation Ireland (SFI)Type of material:
Journal ArticleCollections
Series/Report no:
Genetics in Medicine;100345;
Availability:
Full text availableKeywords:
Optical genome mapping, Structural variants (SVs), inherited retinal diseases (IRD)., Short-read genome sequencing, Next-generation sequencingDOI:
http://dx.doi.org/10.1016/j.gim.2022.11.013Metadata
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