Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy
Authors: Cornelis Stéphanie S. , IntHout Joanna , Runhart Esmee H. , Grunewald Olivier , Lin Siying , Corradi Zelia , Khan Mubeen , Hitti-Malin Rebekkah J. , Whelan Laura , Farrar G. Jane , Sharon Dror , van den Born L. Ingeborgh , Arno Gavin , Simcoe Mark , Michaelides Michel , Webster Andrew R. , Roosing Susanne , Mahroo Omar A. , Dhaenens Claire-Marie , Cremers Frans P. M. ,   Study Group, AlTalbishi Ala'a , Ayuso Carmen , Banfi Sandro , Banin Eyal , Ben-Yosef Tamar , Bolz Hanno J. , Dockery Adrian , Downes Susan , Fakin Ana , Gorin Michael B. , Heon Elise , Hoyng Carel B. , Inglehearn Chris F. , Karali Marianthi , Kämpjärvi Kati , Klaver Caroline C.W. , Liskova Petra , Oldak Monika , Plomp Astrid S. , Sajovic Jana , Stöhr Heidi , Szaflik Jacek P. , Thiadens Alberta A.H.J. , Tracewska Anna M. , Vajter Marie , Verheij Joke B.G.M. , Weber Bernhard H.F. 
Published: April 2024

ImportancePrevious studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy.ObjectiveTo investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles.Data SourcesLiterature data, data from 2 European centers, and a new study. Data from a Radboudumc database and from the Rotterdam Eye Hospital were used for exploratory hypothesis testing.Study SelectionStudies investigating the sex ratio in individuals with ABCA4-AR and data from centers that collected ABCA4 variant and sex data. The literature search was performed on February 1, 2023; data from the centers were from before 2023.Data Extraction and SynthesisRandom-effects meta-analyses were conducted to test whether the proportions of women among individuals with ABCA4-associated retinopathy with mild and nonmild variants differed from 0.5, including subgroup analyses for mild alleles. Sensitivity analyses were performed excluding data with possibly incomplete variant identification. χ2 Tests were conducted to compare the proportions of women in adult-onset autosomal non–ABCA4-associated retinopathy and adult-onset ABCA4-associated retinopathy and to investigate if women with suspected ABCA4-associated retinopathy are more likely to obtain a genetic diagnosis. Data analyses were performed from March to October 2023.Main Outcomes and MeasuresProportion of women per ABCA4-associated retinopathy group. The exploratory testing included sex ratio comparisons for individuals with ABCA4-associated retinopathy vs those with other autosomal retinopathies and for individuals with ABCA4-associated retinopathy who underwent genetic testing vs those who did not.ResultsWomen were significantly overrepresented in the mild variant group (proportion, 0.59; 95% CI, 0.56-0.62; P &amp;lt; .001) but not in the nonmild variant group (proportion, 0.50; 95% CI, 0.46-0.54; P = .89). Sensitivity analyses confirmed these results. Subgroup analyses on mild variants showed differences in the proportions of women. Furthermore, in the Radboudumc database, the proportion of adult women among individuals with ABCA4-associated retinopathy (652/1154 = 0.56) was 0.10 (95% CI, 0.05-0.15) higher than among individuals with other retinopathies (280/602 = 0.47).Conclusions and RelevanceThis meta-analysis supports the likelihood that sex is a modifier in developing ABCA4-associated retinopathy for individuals with a mild ABCA4 allele. This finding may be relevant for prognosis predictions and recurrence risks for individuals with ABCA4-associated retinopathy. Future studies should further investigate whether the overrepresentation of women is caused by differences in the disease mechanism, by differences in health care–seeking behavior, or by health care discrimination between women and men with ABCA4-AR.