期刊
JAMA OPHTHALMOLOGY
卷 138, 期 10, 页码 1035-1042出版社
AMER MEDICAL ASSOC
DOI: 10.1001/jamaophthalmol.2020.2990
关键词
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资金
- Federal Ministry of Education and Research
- Spanish National Organization of the Blind [SVV/260367/2017]
- Instituto de Salud Carlos III from the Spanish Ministry of Health [06/07/0036, PT13/0010/0012, I16/P00425]
- regional government of Madrid [B2017/BMD-3721]
- European Regional Development Fund
- RetinaUK [GR591]
- Fighting Blindness Ireland [FB18CRE]
- program of Horizon 2020, Marie Sklodowska-Curie Innovative Training Network StarT (European Training Network to Diagnose, Understand and Treat Stargardt Disease, a Frequent Inherited Blinding Disorder)
- Foundation Fighting Blindness USA [PPA-0517-0717-RAD]
- Rotterdamse Stichting Blindenbelangen
- Stichting Blindenhulp
- Stichting tot Verbetering van het Lot der Blinden
- Landelijke Stichting voor Blinden en Slechtzienden
- Macula Degeneratie fonds
- Stichting Blinden-Penning
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Conchita Rabago Foundation
- UNCE [204064]
- Ministry of Health of the Czech Republic [NU20-07-00182]
- Groupement de Cooperation Sanitaire Interregional G4 qui reunit les Centres Hospitaliers Universitaires Amiens, Caen, Lille, et Rouen
- Fondation Stargardt France
- PROGRES Q26 of the Charles University
- RAREGenomics-CM
IMPORTANCE The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P=.02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P=.005). CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.
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