ABCA4-alleles bearing two rare cis-variants comprise a significant proportion of those found in affected patients.

Abstract

Purpose : Biallelic pathogenic variants in the ABCA4 gene cause a significant proportion of inherited retinal disease worldwide. High allelic heterogeneity partly explains the wide variability in visual outcomes in affected patients. Understanding the pathogenicity of individual alleles is confounded by the co-occurrence on one chromosome of two or more rare variants. Such ‘complex alleles’, due to linkage disequilibrium, often occur in many unrelated probands. Here we explore this phenomenon in a large cohort of molecularly solved and phased probands.

Methods : Patients with genetically confirmed ABCA4-retinopathy seen at a single centre were included. We sought those with 3 or more rare variants; either variants with proven pathogenicity or else rare missense variants, including those scored individually as variants of uncertain pathogenicity (VUP). The reported complex alleles that comprise c.5603A>T, p.(Asn1868Ile) (allele frequency 4%) are the subject of a separate study and not included here.

Results : The full cohort comprised 925 patients. Of these, 106 patients (11.4%) carried 3 protein altering rare variants, and 12 (1.3%) carried 4, such alleles comprising 7% of all disease-associated chromosomes, occurring in 118/925 probands. The most common was c.[1622T>C;3113C>T] (p.[Leu541Pro;Ala1038Val]) accounting for 39 alleles in 36 probands. The allele c.[634C>T;5882G>A] (p.[Arg212Cys;Gly1961Glu]) occurred on 10 alleles of 10 patients of African descent, c.[4222T>C;4918C>T] (p.[Trp1408Arg;Arg1640Trp]) and c.[2588G>C;1715G>A] (p.[Gly863Ala;Arg572Gln]) occurred in 9 and 6 alleles in European patients, respectively, and did not include c.5603T.

Conclusions : Our results show that a significant proportion of patients have complex alleles in which two or more disease-associated variants may be found together. The reporting of such alleles, will help in the scoring of genotypes by clinical labs, reducing those instances in which two variants might be assumed to be in trans, particularly when relatives are unavailable for phasing. The modification of some variants by others occurring in cis will become evident with increasing phased genotypic data from affected patients.

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