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Original Investigation
August 20, 2020

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease

Author Affiliations
  • 1Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
  • 2Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
  • 3Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
  • 4Department of Genetics, Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain
  • 5Center for Biomedical Network Research on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
  • 6Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Western Australia, Australia
  • 7Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
  • 8Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
  • 9Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
  • 10University 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
  • 11Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • 12Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 13Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
  • 14University Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, Lille, France
JAMA Ophthalmol. 2020;138(10):1035-1042. doi:10.1001/jamaophthalmol.2020.2990
Key Points

Question  Are mild ABCA4 alleles associated with the patient’s sex in Stargardt disease?

Findings  In this cross-sectional study of 550 patients with genetically confirmed Stargardt disease, a female predilection was observed among patients who carried a mild ABCA4 genotype compared with patients who harbored (moderately) severe ABCA4 genotypes.

Meaning  This study found that, in the 25% of patients with Stargardt disease who carried a combination of a mild and a severe allele, sex may play a modifying role in the disease.


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.

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