Beyond carrier frequency: a preliminary multicenter study of simultaneous couple-based comprehensive carrier screening for common and rare genetic disorders.

backgroundCurrently, the American College of Medical Genetics and Genomics (ACMG) carrier screening (CS) guidelines do not recommend routinely screening for conditions with carrier frequencies ≤ 1:200. Advances in DNA sequencing and declining costs, alongside growing awareness, make it increasingly feasible to expand CS to cover a broader spectrum of conditions. We aimed to design a CS panel regardless of carrier frequency to evaluate its utility in less common disease.

methodsWe developed a large CS panel through gene curation, phenotypic severity evaluation, independent of carrier frequency. A cohort of 2010 couples across 24 Chinese cities underwent couple-based simultaneous screening. Gene carrier rate (GCR) was calculated, with subsequent assessment of at-risk couple rate (ACR) across varying GCR thresholds.

resultsThe results obtained from testing 1736 genes were presented. Among 2010 couples undergoing CS, 106 were identified as having an increased risk of offspring with at least one genetic condition. The initial ACR is 5.3% (106/2010). After excluding couples not carrying high-risk CFTR variants based on the ACMG-recommended 100-variant panel for CFTR, the adjusted ACR was 5.2% (105/2010). Furthermore, after excluding GJB2: c.109 G > A and HFE, the adjusted ACR decreased to 2.2% (45/2,010). Fifty genes with a GCR ≥ 1/200 were identified through individual carrier analysis that were absent from the ACMG Tier 3 list. Setting a GCR ≥ 1/200 threshold would fail to detect 14 high-risk couples associated with 16 rare conditions: two couples carried pathogenic variants linked to two rare conditions each. Notably, 53.3% of identified high-risk couples would remain undetected under ACMG Tier 3-recommended conditions, with the majority of missed conditions representing rare yet severe disorders. The simultaneous couple-screening model maintained manageable ACR while resolving all reproductive concerns in a single phase, thereby reducing genetic counseling demands compared to sequential approaches. This methodology also minimized false-positive interpretations through integrated variant analysis.

conclusionsThis study obtained preliminary Chinese population-specific GCR for both common and rare recessive conditions, providing a foundation for future CS panel optimization. Couples at risk of having a child with rare conditions are often undetectable using conventional CS paradigms that set GCR levels at ≥ 1/200 thresholds, emphasizing the need to expand beyond ACMG Tier 3 standards to address rare severe genetic disorders. For large CS panels, simultaneous couple-based screening is an effective strategy.