Abstract
Purpose :
ABCA4 has high variant carrier frequency. c.5603A>T, (p.Asn1868Ile) is a well-known hypomorphic ABCA4 variant, which typically confers a milder phenotype and late disease onset. It is present in 6.6% of alleles in the non-Finnish European database (Genome Aggregation Database - GnomAD) and in a significant proportion of patients with ABCA4 retinopathy. It is our purpose to report its prevalence in our cohort of patients with genetically confirmed ABCA4 retinopathy, and to describe the phenotype in those patients for whom clinical information was available.
Methods :
We included patients with molecularly confirmed ABCA4 retinopathy, who had been seen in the Ophthalmic Genetics clinic at a single centre from 1991 to 2022. Patients seen elsewhere but who underwent genetic testing in our centre during this period and were subsequently found to harbour biallelic disease-causing ABCA4 variants were also included in this study.
Results :
A total of 646 families in our cohort have been molecularly confirmed to have biallelic, disease-causing ABCA4 variants. Thirty unrelated probands were found to harbour the c.5603A>T, (p.Asn1868Ile) variant; 16 patients (53%) carried 2 different mutations, one being the aforementioned variant, 12 (40%) carried 3, and 2 (6%) carried 4. Segregation was available for 9 patients, 4 of whom presented with 3 complex alleles including c.5603A>T, (p.Asn1868Ile). Phenotype-genotype correlation was available for 6 females and 2 males, who showed variable clinical features ranging from scattered macular flecks to severe cone-rod dystrophy.
Conclusions :
c.5603A>T, (p.Asn1868Ile) was found in 4.6% of families genetically characterised with ABCA4 retinopathy in our cohort. Although it has been reported to exhibit a typically milder phenotype, clinical features may vary depending on the trans-acting allele, as reflected on our cohort. Over-representation of women carrying mild ABCA4 alleles has previously been reported, but our cohort offers insufficient data to strongly support sex-related risk factors for ABCA4 retinopathy. However, genetic or environmental modifiers may play a role in the clinical variability of patients carrying not only c.5603A>T, (p.Asn1868Ile), but other ABCA4 variants.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.