Importance: Probing differences in disease prevalence between sexes is challenging, especially in mendelian diseases. Independent replication of any association study is warranted.
Objective: To evaluate whether the recently reported association between sex and mild ABCA4 alleles among patients with autosomal recessive Stargardt disease (STGD1) is reproducible.
Design, setting, and participants: Sequencing and clinical data from 644 unrelated patients with genetically confirmed STGD1 were analyzed in a cross-sectional study at the Department of Ophthalmology, Columbia University, New York, New York. Data were collected from June 1999 to October 2020.
Main outcomes and measures: Sex, best-corrected visual acuity, and age at onset among patients with STGD1 with and without mild ABCA4 alleles.
Results: A total of 644 patients with STGD1 with at least 2 pathogenic variants were included in the study. The mean (SD) age was 38.6 (17.2) years, and 352 participants (54.7%) were female. The proportion of women was slightly higher in the entire cohort and in most allele categories, although none of the differences were statistically significant. The proportion of women carrying the c.5603A>T p.(Asn1868Ile) allele was 7% (95% CI, -9 to 23) higher than in the subgroup not carrying any mild alleles (P = .32). The proportion of women carrying the c.5882G>A p.(Gly1961Glu) allele was 2% (95% CI, -12 to 15) higher than in the subgroup not carrying any mild alleles (P = .77). The difference between the total mild allele subcohort and the no mild allele subcohort was 3% (95% CI, -8 to 14; P = .48). Compared with patients in the no mild allele category, patients with mild alleles exhibited significantly delayed disease onset (mean [SD] age, 23.1 [11.6] for those with the c.5882G>A allele and 31.7 [13.5] years for those with the c.5603A>T allele vs 18.6 [11.8] years for those with no mild alleles; P < .001) and preserved visual acuity (5882G>A subgroup: mean [SD] logMAR, 0.65 [0.66]; 95% CI, 0.63-0.68; c.5603A>T subgroup: 0.64 [0.39]; 95% CI, 0.58-0.70; those with no mild alleles: 1.00 [0.57]; 95% CI, 0.96-1.03; P < .001).
Conclusions and relevance: This independent analysis of a larger cohort of individuals with Stargardt disease did not support the association between sex and certain mild ABCA4 alleles. While sex is undoubtedly an important variable in medicine, its putative association with clinical outcomes should be rigorously scrutinized.