Rethinking Gene Inclusion Criteria in Expanded Carrier Screening

China’s First Multicenter Couple-Based ECS Study Beyond Carrier Frequency Cut-Offs

Expanded carrier screening has become an important tool for reproductive risk assessment, yet panel design and disease inclusion criteria remain highly variable. In China and many other regions, carrier frequency is still commonly used as a key criterion for selecting genes. However, fixed carrier frequency thresholds, such as the ACMG Tier 3 Screening recommendation (carrier frequency ≥ 1 in 200), may not fully reflect population-specific risks. This is particularly relevant for non-European populations, which remain underrepresented in many public variant databases. As a result, clinically meaningful reproductive risks and certain understudied diseases may be underestimated.

With continued advances in next-generation sequencing efficiency and cost-effectiveness, broader screening coverage is becoming increasingly feasible without substantially increasing testing costs. This creates an opportunity to develop expanded carrier screening strategies that are more comprehensive, population-specific, and clinically relevant.

A recent multicenter, couple-based study in China provides important evidence to support this direction. The study enrolled 2,010 couples from 30 hospitals across 24 cities and evaluated a large expanded carrier screening panel covering 1,736 genes, regardless of carrier frequency. Genes were selected based on autosomal recessive or X-linked inheritance recorded in OMIM, with gene–disease validity classified as “Strong” or “Definitive” according to ClinGen criteria. Included conditions were assessed as having moderate or severe clinical impact. Berry Genomics provided full-process technical support for the study.

Key Findings

1. Carrier Frequencies Are Highly Population-Specific

Among the 1,736 genes analyzed, compared with the ACMG Tier 3 screening recommendation (carrier frequency ≥ 1 in 200), the study identified 50 additional genes not included under that strategy, including GALC, ABCA4, SLC22A5, and SLC25A13. These findings suggest that international carrier frequency thresholds may underestimate certain disease risks in the Chinese population and highlight the importance of using Chinese population-specific data in ECS panel design.

2. Broader Screening Improves Rare Disease Prevention

The study identified 106 high-risk couples, corresponding to an overall high-risk couple rate of 5.3%. Importantly, if only common diseases (Gene carrier rate (GCR) ≥1 in 200 in this study) were included, 14 high-risk couples would have been missed. In addition, 53.3% of high-risk couples would still have been missed under the ACMG Tier 3 screening strategy. These findings suggest that relying heavily on carrier frequency cut-offs may limit the preventive value of ECS. A broader, severity-focused approach can help identify clinically meaningful reproductive risks that would otherwise remain undetected.

3. Couple-Based Screening Is More Efficient for Large Panels

In this study panel, the cumulative carrier rate was approximately 84%, indicating that most individuals carried at least one disease-associated variant. In routine practice, one partner is tested first, and the other is tested only if the first partner is identified as a carrier. However, when the carrier-positive rate is high, this routine approach can lead to frequent partner retesting, additional follow-up, and increased demand for genetic counseling. These findings suggest that for large ECS panels covering more than 1,000 genes, concurrent couple-based screening may be more practical. Testing both partners simultaneously allows reproductive risk to be assessed in a single workflow, reduces counseling burden, and helps minimize unnecessary concern caused by isolated carrier findings.

Overall, this study provides important Chinese population-based evidence for expanded carrier screening in the era of precision medicine. The results support a shift away from rigid carrier frequency thresholds toward a more comprehensive, population-specific ECS strategy focused on clinically relevant disorders. Such an approach may improve the detection of high-risk couples and better support informed reproductive decision-making. This study represents an important step toward establishing an ECS framework that reflects local population genetics, clinical needs, and public health priorities.

References:

Xiao B, Liu H, Sun Y, et al. Beyond carrier frequency: a preliminary multicenter study of simultaneous couple-based comprehensive carrier screening for common and rare genetic disorders. Genome Med. 2026;18(1):85. Published 2026 Apr 24. doi:10.1186/s13073-026-01628-8