Ethnicity of pathogenic variants in the ABCA4 gene: analysis of allele frequency in the general population

Abstract

Purpose : To investigate the ethnicity of the prevalent variants in the ABCA4 gene utilizing the allele frequency in the general population.

Methods : 1193 ABCA4 variants detected in 4794 subjects on the Leiden Open Variation Database (LOVD version 3.0; https://www.lovd.nl/) were reviewed. 567 recurrent variants reported more than twice were selected for analysis. Assessment of pathogenicity was performed for each variant according to the previously published method (Fujinami et el. ProgStar report 8. 2019), and 226 pathogenic/likely pathogenic/disease-associated variants with available allele frequency were investigated. The allele frequency in six ethnic groups (African, Latino, Jewish, East Asian, European, South Asian) was surveyed on the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org/). Prevalent variants for each ethnic group were selected (allele frequency>0.02%, allele count>2), and enrichment in one ethnic group compared to another group was statistically examined (Fisher’s exact test). All prevalent variants were classified into two groups; Group 1 - variants statistically enriched (p<0.05) for an ethnic group, and Group 2 - variants shared among multiple ethnic groups.

Results : Sixty-four prevalent pathogenic ABCA4 variants were identified to be enriched in African (n=15), Latino (n=11), Jewish (n=7), East Asian (n=13), European (n=15), and South Asian (n=3) groups. 43 variants were included in Group 1; African (11/15, 73.3%), Latino (8/11, 72.7%), Jewish (6/7, 85.7%), East Asian (7/13, 53.8%), European (8/15, 53.3%), and South Asian (3/3, 100.0%). Twenty-one variants were in Group 2; African (4/15, 26.7%), Latino (3/11, 27.3%), Jewish (1/7, 14.3%), East Asian (6/13, 46.2%), European (7/15, 46.7%), and South Asian (0/3, 0.0%).

Conclusions : Around two thirds of prevalent pathogenic ABCA4 variants were specific for an ethnic group. The proportion of ethnicity specific variants was highest in South Asian and lowest in European groups; although the inherent selection bias in the process of identification of ABCA4 variants on the public database should be considered. These results help in the interpretation of detected variants, ethnicity-based genotype-phenotype correlation studies, as well as ethnicity-based counselling of patients.

This is a 2020 ARVO Annual Meeting abstract.