Abstract
Purpose :
Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian retinal disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, is not completely understood. We hypothesized that a share of this complexity is influenced by variants in other, unlinked loci, i.e. trans-modifying genes.
Methods :
To identify the possible trans-modifiers, we performed exome sequencing in a large cohort of 583 confirmed and well characterized Stargardt/ABCA4 disease patients and compared variation in 285 genes that have been associated with simple or syndromic retinopathies, to cohorts of ethnically matched controls. We also compared the allele frequencies between three ABCA4 disease subgroups, defined by specific causal ABCA4 variants.
Results :
The strongest association was found with the frequent variant p.Ala96Ser in RGS9BP gene, minor allele frequency (MAF) 0.41 in the patient cohort vs. 0.32 in the control group, p=2.404E-07. In the late-onset ABCA4 disease subgroup, defined by the hypomorphic p.Asn1868Ile allele and including the c.4253+43G>A variant, the minor allele frequency for the PRPH2 haplotype-tagging p.Asp338Gly SNP was 0.14 vs. 0.25 in the remaining cohort, p=0.0027. In the disease subgroup, defined by the most frequent pathogenic ABCA4 variant in patients of European descent, p.Gly1961Glu, PITPNM3 variant p.Pro17Ser presented with increased MAF=0.17, compared to other patients, MAF=0.11; p=0.008. Moderately rare, likely functional, variants, with MAF<0.01 and CADD>20, were enriched in CEP290 in p.Gly1961Glu patient group, where 10.6% of 151 patients harbored a CEP290 variant compared to 3.5% in 342 patients with other ABCA4 pathogenic variants (p=0.0017).
Conclusions :
We identified three additional genes with possible modifying effect on ABCA4 disease. These findings should be replicated in other large ABCA4 disease cohorts and the specific trans-modifying effects of these variants/genes on the penetrance, expression and progression of ABCA4 disease have to be elucidated.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.