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Article

Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

1
Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
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
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Christina Zeitz and Isabelle Audo
Int. J. Mol. Sci. 2022, 23(2), 995; https://doi.org/10.3390/ijms23020995
Received: 11 December 2021 / Revised: 3 January 2022 / Accepted: 12 January 2022 / Published: 17 January 2022
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. View Full-Text
Keywords: inherited retinal degenerations; retinal dystrophy; genetic testing; next generation sequencing; whole exome sequencing; single gene sequencing; unresolved inherited retinal degenerations inherited retinal degenerations; retinal dystrophy; genetic testing; next generation sequencing; whole exome sequencing; single gene sequencing; unresolved inherited retinal degenerations
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MDPI and ACS Style

Stephenson, K.A.J.; Zhu, J.; Dockery, A.; Whelan, L.; Burke, T.; Turner, J.; O’Byrne, J.J.; Farrar, G.J.; Keegan, D.J. Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing. Int. J. Mol. Sci. 2022, 23, 995. https://doi.org/10.3390/ijms23020995

AMA Style

Stephenson KAJ, Zhu J, Dockery A, Whelan L, Burke T, Turner J, O’Byrne JJ, Farrar GJ, Keegan DJ. Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing. International Journal of Molecular Sciences. 2022; 23(2):995. https://doi.org/10.3390/ijms23020995

Chicago/Turabian Style

Stephenson, Kirk A.J., Julia Zhu, Adrian Dockery, Laura Whelan, Tomás Burke, Jacqueline Turner, James J. O’Byrne, G. J. Farrar, and David J. Keegan. 2022. "Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing" International Journal of Molecular Sciences 23, no. 2: 995. https://doi.org/10.3390/ijms23020995

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