A feasibility study of a rare variant association test on inherited retinal diseases (IRDs)

Abstract

Purpose : IRDs, a group of monogenic conditions leading to progressive retinal degeneration and visual loss, are typical Mendelian traits. However, their missing heritability is ~30-50%, potentially due to limitations in detecting mutations with conventional methods. Rare variant association tests (RVATs) have the potential to identify pathogenic mutations using statistical methods that are not routinely applied. In this study, we performed the combined multivariate and collapsing (CMC) test (a type of RVAT) on patients with Stargardt disease and biallelic mutations in ABCA4, patients with all forms of IRDs, and controls, to show its applicability to the identification of novel disease genes.

Methods : Whole exome sequencing (WES) was performed on 26 Swiss patients with Stargardt disease, 194 genetically confirmed Swiss patients with IRDs, and 242 controls of European descent. After quality control, relatedness, and ancestry filtering, 12 patients with Stargardt disease, 143 IRD patients, and 199 unrelated controls passed the CMC test. After variant calling and annotation, variants were selected according to their population allele frequency (AF), type of alteration, and predicted damaging scores. Selected variants in each gene were collapsed into single scores. Odds ratios (OR) in all genes were calculated using a two-sided Fisher’s exact test with Bonferroni correction.

Results : As expected, ABCA4 was the gene with the highest enrichment of variantsin Stargardt patients at 0.1% AF (OR=Inf, p_uncorrected=1.70E-15, p_corrected=3.01E-12) (Table 1). In Swiss IRD patients, ABCA4, USH2A, RP1,and PRPH2 had enrichment at different AF thresholds (p_uncorrected<0.05). However, none of the genes in Swiss IRD patients were significantly enriched after Bonferroni correction due to the insufficient number of samples (Table 2).

Conclusions : This feasibility test shows enrichment of rare damaging variants in ABCA4, USH2A, RP1, and PRPH2 in all the patients analyzed. The effect of variant filtering on allele frequency and identical damaging properties was also clearly observed. In conclusion, this study demonstrates the potential applicability of RVATs in identifying IRD genes when a sufficiently large number of patients are analyzed.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Table 1. CMC test results in patients with Stargardt disease vs controls.

 

Table 2. CMC test results in all patients vs controls.