The Impact of Specific ABCA4 Variants on Retinal Function Using Regression Analysis of Electroretinography Data in a Large Patient Cohort

Abstract

Purpose : ABCA4-retinopathy is the most common monogenic inherited retinal disease but current prognostic capability is limited by genetic heterogeneity with more than 1000 possible variants, for which combinations due to recessive inheritance result in a number of genotypes of at least n(n+1) / 2. Full-field electroretinography (ERG) is used clinically in the diagnosis and prognosis of ABCA4-retinopathy by measuring the activity of retinal cell populations in response to light stimuli. This study investigates whether regression analysis of genetic variants with ERG data can be used to derive coefficients relating to severity from a uniquely large single-centre patient cohort.

Methods : In this retrospective cohort study, multiple ISCEV-standard ERG parameters were labelled (DA 10, LA 3, and LA 30Hz ERGs) from 495 patients with confirmed ABCA4-retinopathy and compound heterozygous or homozygous pathogenic ABCA4 variants. ERG trace labelling was automated through custom peak-finding algorithms on additionally bandpass-filtered traces and labelled values normalised for ElasticNet regression analysis against the ABCA4 variant background of the cohort. ElasticNet is an extended regression method to deal with a large number of potentially correlated features.

Results : The analysis generated beta coefficients associated with individual variants. Within the 50 most frequent variants in the cohort, higher coefficient values were observed to be associated with previously identified milder variants including c.5882G>A p.(G1961E), c.5603A>T p.(N1868I) and c.4253+43G>A and lower coefficients with nonsense mutations and the severe intronic variant c.5461-10T>C. Many variants had intermediate coefficients consistent with partial function of the resultant protein. The resultant models had an average r² value of 0.726, and results were consistent for the derived coefficients across the measured ERG features DA 10 a-wave and b-wave, LA 3 a-wave and b-wave and LA 30Hz peak amplitude (avg. r=0825. (range 0.724-0.931)).

Conclusions : This analysis provides a novel quantification of the impact of specific ABCA4 variants on retinal function in a data-driven regression analysis based on clinical ERG recordings; the findings were consistent with previously described genotype-phenotype correlations.

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