Phenotype-integrated reinterpretation of laboratory-reported ABCA4 gene sequencing results improves molecular diagnostic rate in Black/non-White patients and those with late-onset Stargardt macular dystrophy.

内容摘要

While diagnostic disparities by race and age of onset are reported in inherited retinal diseases, their impact on Stargardt disease (STGD)-a clinically and genetically heterogeneous macular dystrophy-remains unclear. We analyzed 246 STGD patients at a U.S. referral center (2003-2024) who completed genetic testing, comparing laboratory-reported results (lab-GT) with manual, phenotype-integrated reinterpretation (m-GT) of ABCA4 sequencing incorporating updated variant databases and genotype-phenotype correlation. Diagnostic yield and variant burden were assessed by race and age of onset. Positive/likely positive (P/LP) lab-GT was identified in 79% (195), with 78% (191) attributable to ABCA4 (ABCA4-positive lab-GT: 57% [141]). M-GT increased ABCA4-P/LP yield to 91% (224). Black participants had lower ABCA4-positive lab-GT than White participants (55% vs. 73%) and fewer pathogenic variants; on multivariable analysis, Black race (OR 0.34) and later age of onset (OR 0.95/year) independently predicted reduced molecular diagnosis. The disparity by race resolved with P/LP m-GT (89% vs. 90%); by age of onset, yield remained lower in late-onset cases (ABCA4-P/LP lab-GT: 86% early- [≤10 yrs], 83% intermediate- [11-44 yrs], 54% late-onset [≥45 yrs], improving to 97%, 94%, and 77% after m-GT). Posttest reinterpretation improves diagnostic yield, particularly for Black and late-onset STGD patients, underscoring the value of ancestry-informed interpretation, historical reanalysis, and genotype-phenotype correlation.