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  Representation of women among individuals with mild variants in ABCA4-associated retinopathy: A meta-analysis

Cornelis, S. S., IntHout, J., Runhart, E. H., Grunewald, O., Lin, S., Corradi, Z., et al. (2024). Representation of women among individuals with mild variants in ABCA4-associated retinopathy: A meta-analysis. JAMA Ophthalmology, 142(5), 463-471. doi:10.1001/jamaophthalmol.2024.0660.

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Cornelis, Stéphanie S.1, Author
IntHout, Joanna1, Author
Runhart, Esmee H.2, Author
Grunewald, Olivier3, Author
Lin, Siying4, Author
Corradi, Zelia1, Author
Khan, Mubeen1, 5, Author           
Hitti-Malin, Rebekkah J.1, Author
Whelan, Laura6, Author
Farrar, G. Jane6, Author
Sharon, Dror7, Author
Van den Born, L. Ingeborgh2, Author
Arno, Gavin4, Author
Simcoe, Mark4, Author
Michaelides, Michel4, Author
Webster, Andrew R.4, Author
Roosing, Susanne1, Author
Mahroo, Omar A.4, Author
Dhaenens, Claire-Marie3, Author
Cremers, Frans P. M.1, Author
ABCA4 Study Group, Author               more..
1Radboud University Medical Center, Nijmegen, The Netherlands, ou_persistent22              
2The Rotterdam Eye Hospital, Rotterdam, The Netherlands, ou_persistent22              
3University of Lille, Lille, France, ou_persistent22              
4University College London, London, UK, ou_persistent22              
5Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society, ou_792549              
6Trinity College Dublin, Dublin, Ireland, ou_persistent22              
7The Hebrew University of Jerusalem, Jerusalem, Israel, ou_persistent22              


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 Abstract: Importance
Previous studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy.

To investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles.

Data Sources
Literature 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 Selection
Studies 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 Synthesis
Random-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 Measures
Proportion 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.

Women were significantly overrepresented in the mild variant group (proportion, 0.59; 95% CI, 0.56-0.62; P < .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 Relevance
This 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.


Language(s): eng - English
 Dates: 2024-04-112024
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1001/jamaophthalmol.2024.0660
 Degree: -



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Title: JAMA Ophthalmology
Source Genre: Journal
Publ. Info: -
Pages: - Volume / Issue: 142 (5) Sequence Number: - Start / End Page: 463 - 471 Identifier: ISSN: 2168-6165