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Article

Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies

1
Eye Genetics Research Unit, Sydney Children’s Hospitals Network, Save Sight Institute, Children’s Medical Research Institute, University of Sydney, Sydney, NSW 2000, Australia
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Specialty of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2000, Australia
3
Sydney Genome Diagnostics, Western Sydney Genetics Program, Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
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Western Sydney Genetics Program, Department of Clinical Genetics, Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
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Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
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Lowy Cancer Research Centre, Children’s Cancer Institute, University of New South Wales, Randwick, NSW 2031, Australia
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St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Randwick, NSW 2031, Australia
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South Australian Clinical Genetics Service, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia
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Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Randwick, NSW 2031, Australia
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Department of Ophthalmology, The Children’s Hospital at Westmead, Sydney Children’s Hospitals Network, Westmead, NSW 2145, Australia
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Save Sight Institute and Specialty of Ophthalmology, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2000, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Toshihide Kurihara
Int. J. Mol. Sci. 2022, 23(7), 3905; https://doi.org/10.3390/ijms23073905
Received: 11 February 2022 / Revised: 24 March 2022 / Accepted: 30 March 2022 / Published: 31 March 2022
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 underinvestigated 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. View Full-Text
Keywords: inherited retinal dystrophy; whole genome sequencing; gene panels; RNA analysis inherited retinal dystrophy; whole genome sequencing; gene panels; RNA analysis
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MDPI and ACS Style

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.; St Heaps, L.; Wright, D.; Dinger, M.E.; Bennetts, B.; Grigg, J.R.; Jamieson, R.V. Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies. Int. J. Mol. Sci. 2022, 23, 3905. https://doi.org/10.3390/ijms23073905

AMA Style

Nash BM, Ma A, Ho G, Farnsworth E, Minoche AE, Cowley MJ, Barnett C, Smith JM, Loi TH, Wong K, St Heaps L, Wright D, Dinger ME, Bennetts B, Grigg JR, Jamieson RV. Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies. International Journal of Molecular Sciences. 2022; 23(7):3905. https://doi.org/10.3390/ijms23073905

Chicago/Turabian Style

Nash, Benjamin M., 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. 2022. "Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies" International Journal of Molecular Sciences 23, no. 7: 3905. https://doi.org/10.3390/ijms23073905

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