Work

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

Year: 2026

Type: article

Abstract: 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 Whites (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-[≤10yrs], 83% intermediate-[11-44yrs], 54% late-onset [≥45yrs], improving to 97%, 94%, and 77% after m-GT). Post-test 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.

Source: Ophthalmic Genetics

DOI: 10.1080/13816810.2026.2621864