Female Sex Likely Modifies Development of ABCA4-Associated Retinopathy

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A notable overrepresentation of women was observed among individuals with ABCA4-associated retinopathy carrying a mild variant with reduced penetrance.

Sex is likely a modifying factor in the development of ABCA4-associated retinopathy among individuals carrying a mild reduced penetrant (mild_rp) ABCA4 variant, according to a recent meta-analysis.1

Recruiting individuals with an ABCA4-associated retinopathy diagnosis from centers in the United States and Europe, the analysis found the proportion of women was significantly higher than 0.5 among individuals with a mild_rp ABCA4 variant than a non-mild variant.

“This finding may be relevant for prognosis predictions and recurrence risks for individuals with ABCA4-associated retinopathy,” wrote the investigative team, led by Frans P.M. Cremers, PhD, department of human genetics, Radboud University Medical Center.

Stargardt disease is an inherited retinal degeneration caused by biallelic pathogenic variants in ABCA4, with clinical manifestations ranging from macular degeneration to fundus flecks. Those with early- or late-onset retinopathy may not present all clinical hallmarks, leading to the entire disease spectrum described as an ABCA4-associated retinopathy.

A 2020 analysis found that the ratio of women to men with biallelic ABCA4 variants who carry a noncomplex mild reduced penetrant is higher than that in patients carrying 2 non-mild variants.3 Unable to replicate these findings, a later study reported more women across both cohorts.4

These data point to more women being affected by ABCA4-associated retinopathy than men and the difference being larger in individuals with a mild_rp ABCA4 variant.1 The current meta-analysis was performed with these published data and 3 novel datasets to evaluate sex as a modifying factor among individuals with ABCA4-associated retinopathy carrying ≥1 mild allele or non-mild alleles.

Investigators performed a literature search in February 2023, with data collected from centers existing before 2023. Random-effects meta-analyses were subdivided into main, exploratory, and sensitivity analyses for mild_rp and non-mild groups. In each analysis, the proportions of women were compared with 0.5, and P values were considered statistically significant if smaller than .025.

Moreover, tests were used to compare the proportions of women in adult-onset non–ABCA4-associated retinopathy and if women with suspected ABCA4-associated retinopathy were more likely to obtain a genetic diagnosis. Analysis was performed from March to October 2023.

Approximately 2,000 individuals were identified from the study populations, including 18 individuals with 2 mild_rp non-complex variants. Meta-analysis on the proportion of women in the mild_rp group showed women were significantly overrepresented in the mild variant group (mean proportion, 0.59; 95% CI, 0.56 - 0.62; P <.001), but not the non-mild variant group (mean proportion, 0.50; 95% CI, 0.46 - 0.54; P = .89).

Sensitivity analyses revealed similar results in the mild_rp (mean proportion, 0.61; 95% CI, 0.56 - 0.65) and non-mild (mean proportion, 0.51; 95% CI, 0.48 - 0.54) cohorts, suggesting the robustness of the primary findings.

Cremers and colleagues indicated individuals with ABCA4-associated retinopathy caused by mild_rp variants often exhibit a later onset of the disease. Thus, the overrepresentation of women could be due to a difference in obtaining a diagnosis based on differences in healthcare-seeking behavior.

To investigate this sex ratio–diagnosis hypothesis further, investigators consulted a genetic IRD database from the Radboudumc for the number of women and men who were genetically diagnosed with an autosomal form of retinopathy and sent in genetic material for testing after their 18th birthday.

According to these data, the proportion of adult women (652 of 1154; 56%) among individuals with ABCA4-associated retinopathy was 0.10 higher (95% CI, 0.05 - 0.15) than the proportion of women (280 of 602; 47%) among individuals with retinopathy caused by variants in another autosomal gene.

Cremers and colleagues indicated the reported overrepresentation of women may be specific for ABCA4-associated retinopathy and may not be reliant on sex-specific healthcare-seeking behavior. However, a discrepancy may exist between seeking care and receiving a diagnosis.

“A sex difference in the disease mechanism would mean that women are at an approximately 1.4-fold increased risk of developing ABCA4-AR compared with men when they carry a mild_rp variant. This effect could be incorporated in earlier described risk estimates used for genetic counseling,” they wrote.


  1. Cornelis SS, IntHout J, Runhart EH, et al. Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy: A Meta-Analysis. JAMA Ophthalmol. Published online April 11, 2024. doi:10.1001/jamaophthalmol.2024.0660
  2. Cremers FPM, Lee W, Collin RWJ, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res. 2020;79:100861. doi:10.1016/j.preteyeres.2020.100861
  3. Runhart EH, Khan M, Cornelis SS, et al. Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease [published correction appears in JAMA Ophthalmol. 2021 Feb 25;:null]. JAMA Ophthalmol. 2020;138(10):1035-1042. doi:10.1001/jamaophthalmol.2020.2990
  4. Lee W, Zernant J, Nagasaki T, Allikmets R. Reevaluating the Association of Sex With ABCA4 Alleles in Patients With Stargardt Disease. JAMA Ophthalmol. 2021;139(6):654-657. doi:10.1001/jamaophthalmol.2021.0460