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  • Stargardt Disease More Likely in Women

    By Lynda Seminara
    Selected and Reviewed By: Neil M. Bressler, MD, and Deputy Editors
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    Journal Highlights

    JAMA Ophthalmology, October 2020

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    Autosomal-recessive Stargardt disease (STGD1) is the most common inherit­ed macular dystrophy, but the mecha­nisms underlying phenotypic variabil­ity and disease penetrance are poorly understood. Identifying patient factors that contribute to this often-blinding disease would improve counseling for patients and family members and pro­vide valuable management guidance. Runhart et al. studied genetic data for hundreds of patients with clinically suspected STGD1 and found a female preponderance among patients who carried a mild ABCA4 genotype.

    The main objective of the study was to explore the relationship between sex and incompletely penetrant ABCA4 alleles in STGD1. The authors collected data from two multicenter genetic studies and calculated the penetrance of reported mild ABCA4 variants by comparing allele frequencies between patients and the general population. Sex ratios were determined for patients with and without an ABCA4 allele who had incomplete penetrance.

    Altogether, 550 patients (mean age, 45.7 years) were evaluated. Of these, 311 (57%) were women. All five mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were found to have incomplete penetrance. The female-to-male ratio in the subset with c.5603A>T was 1.7:1. The proportion of women was higher in this subset than in those without a mild allele (difference of 13%; p = .02). The female-to-male ratio in the c.5882G>A subgroup was 2.1:1; again, the female preponderance was greater than for those without a mild allele (difference of 18%; p = .005).

    This study showed a sex imbalance among patients who carry a mild ABCA4 allele, which involves about 25% of all patients with STGD1. In light of this, STGD1 should be con­sidered a polygenic or multifactorial disease, said the authors, rather than a disease caused by ABCA4 gene muta­tions alone. This research augments the evidence of reduced penetrance for some common ABCA4 genotypes and emphasizes the potentially crucial role of sex in human health. Although the authors hypothesized that the factors linked to female preponderance could portend greater severity or earlier onset of the disease in women, this study did not indicate such consequences. Rather, the authors suspect that specific disease modifiers may play roles at certain stages of life, which may differ for men and women.

    The original article can be found here.