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Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction
J. Reurink, N. Weisschuh, A. Garanto, A. Dockery, LI. van den Born, I. Fajardy, L. Haer-Wigman, S. Kohl, B. Wissinger, GJ. Farrar, T. Ben-Yosef, FK. Pfiffner, W. Berger, ME. Weener, L. Dudakova, P. Liskova, D. Sharon, M. Salameh, A. Offenheim, E....
Status neindexováno Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2020
PubMed Central
od 2020
Elsevier Open Access Journals
od 2020-10-22
ROAD: Directory of Open Access Scholarly Resources
od 2020
- Publikační typ
- časopisecké články MeSH
A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected of USH2A-associated disease and no or mono-allelic USH2A variants using whole genome sequencing (WGS) followed by an improved pipeline for variant interpretation to provide a conclusive diagnosis. One hundred subjects were screened using WGS to identify causative variants in USH2A or other USH/arRP-associated genes. In addition to the existing variant interpretation pipeline, a particular focus was put on assessing splice-affecting properties of variants, both in silico and in vitro. Also structural variants were extensively addressed. For variants resulting in pseudoexon inclusion, we designed and evaluated antisense oligonucleotides (AONs) using minigene splice assays and patient-derived photoreceptor precursor cells. Biallelic variants were identified in 49 of 100 subjects, including novel splice-affecting variants and structural variants, in USH2A or arRP/USH-associated genes. Thirteen variants were shown to affect USH2A pre-mRNA splicing, including four deep-intronic USH2A variants resulting in pseudoexon inclusion, which could be corrected upon AON treatment. We have shown that WGS, combined with a thorough variant interpretation pipeline focused on assessing pre-mRNA splicing defects and structural variants, is a powerful method to provide subjects with a rare genetic condition, a (likely) conclusive genetic diagnosis. This is essential for the development of future personalized treatments and for patients to be eligible for such treatments.
Center for Human Genetics University Hospitals Leuven Leuven Belgium
Center for Integrative Human Physiology University of Zurich Zurich Switzerland
Centre de Biologie Pathologie Génétique CHU de Lille Lille France
Department of Clinical Genetics Amsterdam UMC University of Amsterdam 1105 Amsterdam the Netherlands
Department of Epidemiology Erasmus Medical Center Rotterdam the Netherlands
Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands
Department of Medicine Surgery and Health Sciences University of Trieste 34149 Trieste Italy
Department of Ophthalmology Amsterdam UMC University of Amsterdam 1105 Amsterdam the Netherlands
Department of Ophthalmology Erasmus Medical Center Rotterdam the Netherlands
Department of Ophthalmology Radboud University Medical Center Nijmegen the Netherlands
Department of Ophthalmology Rijnstate Hospital Arnhem the Netherlands
Institute for Maternal and Child Health 1 R C C S Burlo Garofolo 34137 Trieste Italy
Institute of Clinical Medicine University of Copenhagen 2200 Copenhagen Denmark
Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
Neuroscience Center Zurich University and ETH Zurich Zurich Switzerland
The Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel
Citace poskytuje Crossref.org
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