Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/135019
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Type: | Journal article |
Title: | Whole genome sequencing, focused assays and functional studies increasing understanding in cryptic inherited retinal dystrophies |
Author: | Nash, B.M. Ma, A. Ho, G. Farnsworth, E. Minoche, A.E. Cowley, M.J. Barnett, C. Smith, J.M. Loi, T.H. Wong, K. Heaps, L.S. Wright, D. Dinger, M.E. Bennetts, B. Grigg, J.R. Jamieson, R.V. |
Citation: | International Journal of Molecular Sciences, 2022; 23(7) |
Publisher: | MDPI AG |
Issue Date: | 2022 |
ISSN: | 1661-6596 1422-0067 |
Statement of Responsibility: | Benjamin M. Nash, Alan Ma, Gladys Ho, Elizabeth Farnsworth, Andre E. Minoche, Mark J. Cowley, Christopher Barnett, Janine M. Smith, To Ha Loi, Karen Wong, Luke St Heaps, Dale Wright, Marcel E. Dinger, Bruce Bennetts, John R. Grigg, and Robyn V. Jamieson |
Abstract: | The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or under investigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs. |
Keywords: | gene panels inherited retinal dystrophy RNA analysis whole genome sequencing |
Rights: | © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). |
DOI: | 10.3390/ijms23073905 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1116360 |
Published version: | http://dx.doi.org/10.3390/ijms23073905 |
Appears in Collections: | Medicine publications |
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hdl_135019.pdf | 7.35 MB | Adobe PDF | View/Open |
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