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

Abstract

IMPORTANCEThe 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.

Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia

“…The second most common IRD diagnosis was Stargardt disease, contributing to 12% of IRD-related vision loss or blindness, which is higher than that reported in the Australian and Nowegian registries: 9-10% and 6-7% respectively (25,26). Interestingly, there was a female predominance, which has also been recently reported in those with mild or hypomorphic mutations (27). Although 76% of registrations related to Stargardt disease were in the working-age group, we found 10% were registered up to the age of 15 and 14% were registered at 65years or older, with a bimodal peak.…”

Stationary and Progressive Phenotypes Caused by the p.G90D Mutation in Rhodopsin Gene

“…Such an observation has not yet been reported for RHO retinopathy and is unexpected for an autosomal disease. Interestingly, gender disbalance was recently also reported in ABCA4-retinopathy, an autosomal recessive disease—where there were significantly more females with mild alleles in the patient cohort [ 44 ]. Another study, performed on rd10 mice (a model of autosomal recessive RP), reported an earlier onset of and faster rate of rod degeneration in female mice [ 45 ].…”

Stargardt disease: Multimodal imaging: A review

“…The concept of a unique late‐onset STGD1 phenotype was founded by the discovery of the c.5603A>T (p.Asn1868Ile) variant, previously considered benign, accounting for 80% of these single ABCA4 mutation cases 107 . Since 2017, this hypomorphic variant has been recognised as pathogenic in trans with a deleterious ABCA4 mutation and its non‐penetrance is enhanced by male gender 108 . Similarly to the c.5882G>A variant, patients with c.5603A>T manifest a distinct clinical phenotype.…”