Importance: The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. Objective: To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. Design, Setting, and Participants: Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. Main Outcomes and Measures: Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. Results: A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005). Conclusions and Relevance: This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.

Australian Inherited Retinal Disease Registry and DNA Bank Department of Medical Technology and Physics Sir Charles Gairdner Hospital Nedlands Western Australia Australia

Center for Biomedical Network Research on Rare Diseases Instituto de Salud Carlos 3 Madrid Spain

Centre for Ophthalmology and Visual Science The University of Western Australia Nedlands Western Australia Australia

Department of Epidemiology Erasmus Medical Center Rotterdam the Netherlands

Department of Genetics Instituto de Investigación Sanitaria Fundación Jiménez Díaz University Hospital Universidad Autónoma de Madrid Madrid Spain

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology Erasmus Medical Center Rotterdam the Netherlands

Department of Ophthalmology Radboud University Medical Center Nijmegen the Netherlands

Donders Institute for Brain Cognition and Behavior Radboud University Medical Center Nijmegen the Netherlands

Institute of Human Genetics University of Regensburg Regensburg Germany

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

University Lille Inserm CHU Lille U1172 LilNCog Lille Neuroscience and Cognition Lille France

University of Cape Town MRC Genomic and Precision Medicine Research Unit Division of Human Genetics Department of Pathology Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town South Africa

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