Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

Abstract

Hearing impairment (HI) is characterized by extensive genetic heterogeneity. To determine the population-specific contribution of known autosomal recessive nonsyndromic (ARNS)HI genes and variants to HI etiology; pathogenic and likely pathogenic (PLP) ARNSHI variants were selected from ClinVar and the Deafness Variation Database and their frequencies were obtained from gnomAD for seven populations. ARNSHI prevalence due to PLP variants varies greatly by population ranging from 96.9 affected per 100,000 individuals for Ashkenazi Jews to 5.2 affected per 100,000 individuals for Africans/African Americans. For Europeans, Finns have the lowest prevalence due to ARNSHI PLP variants with 9.5 affected per 100,000 individuals. For East Asians, Latinos, non-Finish Europeans, and South Asians, ARNSHI prevalence due to PLP variants ranges from 17.1 to 33.7 affected per 100,000 individuals. ARNSHI variants that were previously reported in a single ancestry or family were observed in additional populations, e.g., USH1C p.(Q723*) reported in a Chinese family was the most prevalent pathogenic variant observed in gnomAD for African/African Americans. Variability between populations is due to how extensively ARNSHI has been studied, ARNSHI prevalence and ancestry specific ARNSHI variant architecture which is impacted by population history. Our study demonstrates that additional gene and variant discovery studies are necessary for all populations and particularly for individuals of African ancestry.

Fig. 1

Frequency per PLP ARNSHI variant in each gnomAD population. PLP variants are ordered by chromosome and position. Those with a frequency ≥2.0 × 10⁻³ in at least one population are labeled (see Supplementary Table S4 for additional information). Note that the Y-axis was adapted for each population due to the large variability in frequencies

Fig. 2

Frequent PLP ARNSHI variants for each gnomAD population. a Cumulative frequency of all PLP variants with a frequency of ≥2.0 × 10⁻³ in at least one gnomAD population (with exception of GJB2). Some variants are highly prevalent in a specific population, e.g., USH1C p.(Q723*) in AFR and LOXHD1 p.(R461*) in ASJ. b The relative (%) frequency for all PLP GJB2 variants with a frequency of ≥2.0 × 10⁻³ in at least one population