(690) Determining ethnic disparities inherent to Tier 3 versus Tier 4 carrier screening

The American College of Medical Genetics and Genomics (ACMG) defines carrier screening tiers by carrier frequency, recommending Tier 3 for the general population, and Tier 4 for consanguineous couples or those with a family history of genetic disease. The objective is to evaluate ethnic disparities in carrier detection between Tier 3 and Tier 4 panels, and to assess the utility of Tier 4 screening in an ethnically diverse cohort.

Study Design:

This IRB-approved retrospective chart review included patients ≥ 18 years who opted for a carrier screening panel between 1/2020–4/2024. Self-reported ethnicity was mapped to WHO global regions. We determined how many carriers would have been missed if screening was limited to Tier 3 across ethnicities. Outcomes included prevalence of Tier 4-only gene carriers and the number needed to screen (NNS) to detect them, stratified by region.

Results:

Among 2,000 patients, 1,265 (65.7%) carried at least one Tier 4-only condition, with regional rates ranging from 45–100%, and most populations showing ≥ 60% prevalence (Figure 1). Highest Tier 4-only carrier rates included: Africa (76%), Caribbean (73%), Eastern Europe (71%), Western Europe (69%), and Southeast Asia (64%). NNS to detect one Tier 4-only variant ranged from 1.0 to 2.2, with greatest efficiency in Africa, Southeast Asia, and Eastern Europe. Carrier couples of Tier 4 conditions were identified in regions including the Mediterranean (n=10), Caribbean (n=9), and Eastern Europe (n=8). NNS to detect Tier 4-only carrier couples ranged from 7.3 to 58.1, with the lowest values in Eastern Europe (7.3), the Caribbean (7.3), and the Mediterranean (9.7) (Table 1).

Conclusion:

Tier 3 panels, which rely on carrier frequency thresholds largely derived from European populations, fail to identify carriers in underrepresented ethnic groups. Tier 4 provides greater carrier ascertainment across diverse populations and yields lower NNS, particularly in non-European groups. Our data supports the utility of Tier 4 carrier screening in ethnically diverse populations.