Couple-Based Carrier Screening: How Gene and Variant Considerations Impact Outcomes

Abstract

Background/Objectives: The clinical utility of reproductive carrier screening varies based on the genes tested, variant reporting policies, and the screened patient population. This study aims to evaluate the outcomes of carrier screening among reproductive couples undergoing testing in a routine clinical setting. Methods: A total of 1595 couples, primarily referred by reproductive endocrinology and infertility specialists, underwent couple-based carrier screening across 390 genes. Carrier states were assessed on a couple basis and reported only if a couple were at risk of having affected offspring. At-risk conditions were classified by severity, as well as their likelihood of clinical impact based on the specific variants detected in each at-risk couple. Secondary findings with potential personal utility were also evaluated. Results: Among the screened couples, 4.2% were at risk of having a child with a genetic condition. When limited to high-clinical-impact results, the at-risk couple rate decreased to 1.0%, with 44% of these cases involving CFTR, SMN1, or FMR1. Secondary findings were identified in 1.7% of individuals. Conclusions: Carrier screening for only CFTR, SMN1, and FMR1 will miss more than half of at-risk couples, underscoring the importance of broader carrier screening. Specific variants and their combinations can influence the predicted clinical impact of at-risk conditions, marking a key advantage of couple-based reporting. Secondary findings were common, highlighting the importance of discussing these potential findings during pre-test counselling.

Keywords: carrier screening; cystic fibrosis; fragile X syndrome; infertility; spinal muscular atrophy.

Figure 1

At-risk couples. Core genes: CFTR, SMN1, FMR1, HBA1/HBA2, HBB; (a) example: FMR1 CGG repeats <65 have ≤5% risk of expansion to full mutation, even in the absence of AGG interruptions [23]; (b) example: at least one partner is a carrier of the CYP21A2 p.(Gln319*) variant and a whole-gene duplication, which are found in cis in 84% of carriers [24]; (c) examples: genotypes linked to BTD-related partial biotinidase deficiency or PAH-related mild hyperphenylalanaemia; (d) example: POLG-related disorders; (e) example: GAA-related Pompe disease and NPHS2-related steroid-resistant nephrotic syndrome; (f) example: SERPINA1 PI*ZZ homozygotes have a 2% risk of severe liver disease in childhood (GeneReviews—Alpha-1 Antitrypsin Deficiency); (g) examples: homozygotes for AGXT p.(Pro11Arg) and ACSF3 p.(Arg558Trp) have been observed in controls populations.