Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss

Abstract

Understanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children’s hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.

Racial and ethnic disparities in genetic testing for hearing loss: a systematic review and synthesis

“…While CGT is one of the strongest tools in the clinical evaluation of SNHL, it must be equivalently accessible and informative across all populations, lest it exacerbate existing disparities. Several studies have found that Hispanic and Black populations are currently less served by genetic testing, with higher numbers of VUSs and poorer diagnostic rates (Yan et al 2016;Florentine et al 2021). In an attempt to understand and address the source of this disparity in genetic testing, we reviewed the distribution of studies on genetic testing in hearing loss.…”

“…This search identified studies in which either WES, multiple-gene testing (including CGT), or single-gene testing for common genes involved in hearing loss, excluding GJB2, was performed. We assembled this list of individual genes by examining a database of pediatric patients with SNHL who underwent CGT at UCSF (Florentine et al 2021). Each of the 41 genes included was possibly causative for hearing loss in two or more patients within a racially and ethnically diverse cohort.…”

“…There is growing acknowledgement of disparities in genetic testing in hearing loss based on race and ethnicity. Multiple groups have found that the rate of molecular diagnosis as well as the spectrum of genes implicated by CGT for SNHL varies widely by racial/ethnic group, with Asians and Whites having higher diagnostic rates compared with Blacks and Hispanics (Sloan-Heggen et al 2016;Yan et al 2016;Florentine et al 2021) While it is possible that true differences exist between these groups in the incidence of genetic hearing loss, it is also possible that the decreased diagnostic efficacy of genetic testing among Blacks and…”

“…Therefore, underrepresentation of groups in genetic studies, and the resultant underrepresentation in the knowledge base upon which variant classification is performed, may constrain diagnostic power for these groups. Indeed, the proportion of known deafness-causing variants is greater in Whites and Asians, whereas the rate of variants of unknown significance (VUSs) is high among people of African or Central American descent (Yan et al 2016;Florentine et al 2021). Conversely, targeted ascertainment of specific populations can have deleterious effects on knowledge and clinical management for both targeted and non-targeted populations (Carmeli 2004).…”

Outcomes of Gene Panel Testing for Sensorineural Hearing Loss in a Diverse Patient Cohort

“…26 The diagnostic yield for HL gene panel testing has been reported to range from 12.7% to 64.3%. [27][28][29][30][31][32][33][34][35][36][37][38][39][40] These rates have been based on research studies with largely homogenous study populations. Most had participants of European or East Asian origin; only 3 studies 28,39,41 included people of African origin.…”