The ethnic disparity in the diagnostic yield of high-throughput next-generation sequencing in inherited retinal diseases: a systematic review and meta-analysis.

Objective: Next-generation sequencing (NGS) is the state-of-the-art molecular diagnostics for genetic heterogenous inherited-retinal diseases (IRDs). However, the impact of ethnic discrepancy in NGS diagnostic yields for patients with IRD is unclear. Therefore, we performed a systemic review (SR) and meta-analysis (MA) to delineate this issue.

Methods: MEDLINE and PubMed databases were searched on 30 January 2024. Original studies published between 2013 and 2024 that reported the IRD diagnostic yield of panel-based sequencing was eligible for inclusion. The diagnostic yield is defined as the proportion of patients with a molecular diagnosis after high-throughput panel screening. Studies were stratified by IRD enrollment phenotype and patient ancestry.

Results: A total of 42 studies comprising 23,324 patients evaluated for diagnosis yield were included in the meta-analysis. The pooled diagnostic yield was 0.570 [0.530,0.610] across studies with IRD-related enrollment and 0.617 [0.568; 0.664] for those with IRD enrollment. The stratification of studies for ancestry produced a diagnostic yield of 0.629 [0.568; 0.688] in Europeans, and the diagnostic yield dropped to 0.549 [0.456; 0.641] for East Asians. There is a lack of available data for Latin American evidence meta-synthesis.

Conclusions: This review supports the existence of ethnic disparity in panel-based sequencing for IRDs. Specifically, a relatively lower diagnostic yield and a higher inconclusive diagnosis rate are present in East Asian populations compared to the European population. Consequently, our findings should prompt future reclassification of variants of unknown significance (VUS) in non-whites to improve the ethnic inequities of molecular diagnostic yields for IRDs.