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

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the Joseph Albert Hekimian Fund (MSS), Andreas C. Dracopoulos Professorship (MSS), Andreas C. Dracopoulos and Daniel Finkelstein M.D. Rising Professorship in Ophthalmology (JJD), and Research to Prevent Blindness (unrestricted grant to the Wilmer Eye Institute). The sponsor or funding organization had no role in the design or conduct of this research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Johns Hopkins University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes