Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing |
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Authors: | Kirk A J Stephenson Julia Zhu Adrian Dockery Laura Whelan Toms Burke Jacqueline Turner James J OByrne G Jane Farrar David J Keegan |
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Affiliation: | 1.Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland; (T.B.); (J.T.); (J.J.O.); (D.J.K.);2.Next Generation Sequencing Laboratory, Pathology Department, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland;3.The School of Genetics & Microbiology, Trinity College Dublin, D02 PN40 Dublin, Ireland; (L.W.); (G.J.F.) |
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Abstract: | Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70–80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner. |
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Keywords: | inherited retinal degenerations retinal dystrophy genetic testing next generation sequencing whole exome sequencing single gene sequencing unresolved inherited retinal degenerations |
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