Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing
Citation:
Stephenson, K.A.J. and Zhu, J. and Dockery, A. and Whelan, L. and Burke, T. and Turner, J. and Oâ byrne, J.J. and Jane Farrar, G. and Keegan, D.J., 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, 2Download Item:
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.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
16/1A/4452
Author's Homepage:
http://people.tcd.ie/gjfarrar
Author: Farrar, Gwyneth
Type of material:
Journal ArticleCollections
Series/Report no:
International Journal of Molecular Sciences;23;
2;
Availability:
Full text availableKeywords:
inherited retinal degenerations (IRDs), panel-based next-generation sequencing (pNGS), autosomal recessive disease, Whole exome sequencing, Unresolved inherited retinal degenerations, Single gene sequencing, Retinal dystrophy, Next generation sequencing, Genetic testing, Inherited retinal degenerationsDOI:
http://dx.doi.org/10.3390/ijms23020995Metadata
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