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

Abstract

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.

Figure 1.. Comparison of Sex Distribution Among Patients With and Without a Mild ABCA4 Allele

A, More women than men carried the mild allele c.5882G>A (54:25) or c.5603A>T (79:46), whereas the female to male ratio among patients not carrying a mild allele was exactly 1 (142:142). B, In Stargardt disease (STGD1) caused by the mild allele c.5882G>A or c.5603A>T, the proportion of women (68% and 63%, respectively) was significantly higher than in STGD1 not caused by a mild ABCA4 allele (13% [95% CI, 3%-23%; P = .02] vs 18% [95% CI, 6%-30%; P = .005]). ^aP < .03.

Figure 2.. Age at Onset by Sex and Carriers of ABCA4 Allele

Horizontal lines and error bars represent the median with the interquartile range. No difference in age at onset was observed between men and women in any of the 3 subgroups (ie, biallelic patients not carrying a known mild allele, patients carrying the c.5882G>A allele, and patients carrying the c.5603A>T allele).

Figure 3.. Sex and Other Modifying Factors Associated With Risk for Stargardt Disease (STGD1)

Shown is a modification of the previously proposed ABCA4 disease model that associated genotypes with phenotypes on the basis of the residual activity of the ABCA4 protein.^,, In individuals heterozygous for 1 severe variant, ABCA4 activity was reduced to 50%, which does not lead to STGD1. In a previous in vitro study, individually tested variants were considered mild if the percentage of wild-type messenger RNA, which we extrapolated to the residual protein activity, was 60% to 80%. Therefore, a combination of a severe and a mild allele leads to a total residual activity of approximately 30% to 40% and results in classic STGD1 (mild/severe bar). Because the expression of a mild, low-penetrant allele was variable, its combination with a severe variant could result either in generally late-onset STGD1 or in a normal phenotype (Mild, low penetrant/severe bar). Only in this latter category of individuals might sex and other genetic, epigenetic, and nongenetic modifiers alter the risk for developing STGD1.