Exploring the p.Gly863Ala variant in ABCA4: the complex allele with p.Asn1868Ile is enriched in ABCA4-retinopathy patients compared to the general population

Abstract

Purpose : The p.Gly863Ala missense variant in ABCA4 is associated with ABCA4-retinopathy (Stargardt disease). It has been previously noted that this variant often occurs in cis with another missense variant, p.Asn1868Ile. The purpose of this study was to assess the co-segregation of these variants in a large population-based cohort (UK Biobank) and a single centre ABCA4-retinopathy patient cohort.

Methods : Whole exome sequencing data was available for 37586 participants of European ancestry in the UK Biobank for the population-based cohort. The haplotypic structure of this ABCA4 region was determined from pairwise linkage disequilibrium calculations. The patient cohort included 96 ABCA4-retinopathy patients carrying p.Gly863Ala variant recruited at Moorfields Eye Hospital.

Results : In the UK Biobank cohort 924 participants carried the p.Gly863Ala variant. Only 265 (29%) of these participants also carried the p.Asn1868Ile variant. Haplotypic analysis identified three haplotypes containing the p.Gly863Ala variant, with the p.Asn1868Ile present on one. ICD10 codes indicated that six participants carrying the p.Gly863Ala variant had been diagnosed with retinal disease that may be ABCA4-retinopathy (degeneration of macula and posterior pole), two of whom were also carrying the p.Asn1868Ile variant. In the patient cohort that had received a diagnosis with p.Gly863Ala as one allele, 63/96 had data available for p.Asn1868Ile genotype and 53/63 (84%) also carried the p.Asn1868Ile variant. Therefore, the odds ratio for ABCA4 retinopathy for carriers of both variants compared to p.Gly863Ala only is 9.8 (95% CI: 5.3-17.9, p=6.7x10^-14).

Conclusions : There is a significant (p=6.7x10^-14) association of the p.[Gly863Ala;Asn1868Ile] allele in ABCA4-retinopathy cases compared to the p.Gly863Ala variant alone. Thus, the p.Gly863Ala variant is present on several haplotypes with a haplotype carrying both this variant and the p.Asn1868Ile variant being highly enriched in disease. This suggests that a modifying effect of the haplotype may exist (possibly due to the p.Asn1868Ile variant that has recently been shown to act as a low penetrant pathogenic allele in its own right). Further investigation is needed to determine additional factors that may influence the penetrance of disease in carriers of p.Gly863Ala, such as cis modifiers and the severity of trans alleles.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.