Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach.

Autor:	de Bruijn SE; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Panneman DM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Weisschuh N; Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany., Cadena EL; Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, United States., Boonen EGM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Holtes LK; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Astuti GDN; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Cremers FPM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Leijsten N; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Corominas J; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Skowronska A; West Midlands Regional Genetics Laboratory, Birmingham Woman's and Children's NHS Foundation Trust, Birmingham, United Kingdom., Woodley J; West Midlands Regional Genetics Laboratory, Birmingham Woman's and Children's NHS Foundation Trust, Birmingham, United Kingdom., Beggs AD; Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, United Kingdom., Toulis V; UCL Institute of Ophthalmology, University College London, London, United Kingdom., Chen D; UCL Institute of Ophthalmology, University College London, London, United Kingdom., Cheetham ME; UCL Institute of Ophthalmology, University College London, London, United Kingdom., Hardcastle AJ; UCL Institute of Ophthalmology, University College London, London, United Kingdom., McLaren TL; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia., Lamey TM; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia., Thompson JA; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia., Chen FK; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia.; Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia., de Roach JN; Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia., Urwin IR; Department of Medical Technology and Physics, Australian Inherited Retinal Disease Registry and DNA Bank, Sir Charles Gairdner Hospital, Perth, WA, Australia., Sullivan LS; Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, TX, United States., Roosing S; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2024 Oct 23; Vol. 15, pp. 1469686. Date of Electronic Publication: 2024 Oct 23 (Print Publication: 2024).
DOI:	10.3389/fgene.2024.1469686
Abstrakt:	Introduction: Autosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow. Methods: Genetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using a smMIPs or genomic qPCR-based approach tailored for the RP17 locus. Suspected copy number changes were validated using high-density SNP-array genotyping, and SV breakpoint characterization was performed by mutation-specific breakpoint PCR, genome sequencing and, if required, optical genome mapping. In silico modeling of novel SVs was performed to predict the formation of neo-TADs and whether ectopic contacts between the retinal enhancers and the GDPD1 -promoter could be formed. Results: Using this workflow, potential RP17-SVs were detected in eight probands of which seven were confirmed. Two novel SVs were identified that are predicted to cause TAD rearrangement and retinal enhancer- GDPD1 contact, one from Germany (DE-SV9) and three with the same SV from the United States (US-SV10). Previously reported RP17-SVs were also identified in three Australian probands, one with UK-SV2 and two with SA-SV3. Discussion: In summary, we describe a validated multi-step pipeline for reliable and efficient RP17-SV discovery and expand the range of disease-associated SVs. Based on these data, RP17-SVs can be considered a frequent cause of adRP which warrants the inclusion of RP17-screening as a standard diagnostic test for this disease. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 de Bruijn, Panneman, Weisschuh, Cadena, Boonen, Holtes, Astuti, Cremers, Leijsten, Corominas, Gilissen, Skowronska, Woodley, Beggs, Toulis, Chen, Cheetham, Hardcastle, McLaren, Lamey, Thompson, Chen, de Roach, Urwin, Sullivan, Roosing.)
Databáze:	MEDLINE
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