1. Molecular inversion probe-based sequencing of ush2a exons and splice sites as a cost-effective screening tool in ush2 and arrp cases
- Author
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Dominika Oziębło, Hanka Venselaar, Helger G. Yntema, Jaap Oostrik, G. Jane Farrar, L. Ingeborgh van den Born, Susanne Roosing, Frans P.M. Cremers, M Imran Khan, Ronald J.E. Pennings, Janine Reurink, Jacoline B. ten Brink, Hannie Kremer, Arthur A.B. Bergen, Monika Ołdak, Tuula Rinne, Marco Aben, Adrian Dockery, Erwin van Wijk, Astrid S Plomp, Human Genetics, ANS - Complex Trait Genetics, and AR&D - Amsterdam Reproduction & Development
- Subjects
0301 basic medicine ,Cost-Benefit Analysis ,Usher syndrome ,030105 genetics & heredity ,Molecular Inversion Probe ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,USH2A ,Exon ,Copy-number variation ,Biology (General) ,Spectroscopy ,Genetics ,Extracellular Matrix Proteins ,medicine.diagnostic_test ,Molecular inversion probes (MIPs) ,Exons ,General Medicine ,Usher syndrome type IIa ,Computer Science Applications ,Retinitis pigmentosa ,Chemistry ,Usher Syndromes ,DNA Copy Number Variations ,QH301-705.5 ,Genetic counseling ,Biology ,Polymorphism, Single Nucleotide ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,medicine ,otorhinolaryngologic diseases ,Humans ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Genetic testing ,Whole genome sequencing ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Base Sequence ,Organic Chemistry ,Sequence Analysis, DNA ,medicine.disease ,eye diseases ,030104 developmental biology ,Molecular Probes ,RNA Splice Sites ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Gene Deletion - Abstract
A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.
- Published
- 2021