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

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 approximate to 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.

Automated summary

Inherited retinal degenerations (IRDs) are a common cause of blindness in the working age population. Genetic testing plays a crucial role in diagnosing IRDs, with first-tier panel-based next-generation sequencing having a high success rate. This study demonstrates the reassessment of patients with negative results from first-tier testing and the effectiveness of second-tier genetic testing methods. By utilizing appropriate genetic testing techniques, the overall resolution rate of previously unresolved cases was increased to 92%. First-tier testing remains the most cost-effective approach, and second-tier testing should be guided by clinical and genetic indications to achieve a genetic diagnosis in a cost-effective manner.