Study Highlights Sex Differences in Stargardt Disease

Sex may play a modifying role in the 25% of patients with Stargardt disease who carried a combination of a mild and a severe allele, according to results of a cross-sectional study published in JAMA Ophthalmology.

Stargardt disease is an inherited disorder of the retina that typically causes vision problems during childhood and adolescence, the National Eye Institute states. It can also lead to atrophic-appearing macular lesions and variable loss of best-corrected visual acuity.

However, “the mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1)…are poorly understood.” Identifying unknown disease modifiers may improve patient and family counseling and provide valuable information for disease management, authors said.

To calculate penetrance of reported mild ABCA4 variants, researchers compared allele frequencies in the general population with genotyping data in a patient population. Data were gleaned from the Genome Aggregation Databases and ABCA4 Leiden Open Variation Database, respectively, for a total study population of 550. Data were also collected on sex, age, and age at disease onset, defined as the onset of initial symptoms of STGD1 reported by the patient.

Mean (SD) participant age was 45.7 (18) years and 311 (57%) were female. Mild alleles were frequently identified in 266 (48%) participants, often in women (169 of 266 [64%]) and c.5603A>T was found to be the most frequent variant in this cohort (present in 125 [23%] of patients).

Additional findings include:

• 5 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)
• Among the patients who harbored any of the 6 other mild alleles (c.4253+43G>A, c.5714+5G>A, c.6089G>A, c.3113C>T, c.769-784C>T, and c.2588G>C), the overall women-to-men ratio was 1.4 to 1

In a genetically predefined patient group, those who harbored ABCA4 alleles with potential incomplete penetrance were predominantly women, researchers wrote. However, the results do not indicate that female patients are expected to have more severe cases of STGD1.

“This observation corroborated the evidence of reduced penetrance in STGD1 and pointed to the existence of sex-related modifiers of the expression of reduced penetrant ABCA4 alleles.”

Future studies ought to be carried out to elucidate the cause of sex differences in STGD1 and findings warrant consideration of sex as a variable in future clinical trials involving the disease or treatment.

“This cross-sectional study demonstrated a female predilection in STGD1 among all patients who were carrying either of the 2 most frequent and mild ABCA4 alleles compared with patients who were not carrying a putative mild ABCA4 allele,” researchers concluded.

Reference:

Runhart EH, Khan M, Cornelis SS, Association of sex with frequent and mild ABCA4 alleles in Stargardt disease. JAMA Ophthalmol. Published online August 20, 2020. doi:10.1001/jamaophthalmol.2020.2990