Expanded Carrier Screening: Current Evidence and Future Directions in the Era of Population Genomics

Expanded carrier screening (ECS) has emerged as a cornerstone of reproductive genetics, enabling the identification of couples at risk of transmitting autosomal recessive and X-linked disorders. Advances in next-generation sequencing and the increasing adoption of exome- and genome-based strategies have greatly expanded its clinical scope. However, despite existing national and international recommendations, substantial heterogeneity remains in gene panel composition, inclusion criteria, and interpretation frameworks. A key novelty of the current genomic era is the availability of large, publicly accessible human genome datasets encompassing broader ancestral diversity. These resources are transforming our understanding of variant frequencies and disease penetrance across populations, supporting the development of evidence-based and ancestry-informed gene panels. In parallel, recent studies investigating the genetic contribution of pathogenic variants to euploid pregnancy losses are opening new perspectives for ECS. Incorporating genes associated with lethal conditions in utero may enhance the predictive power of screening and deepen our understanding of reproductive outcomes, while also demanding careful consideration of clinical validity and counseling implications. This mini-review synthesizes current evidence on ECS, examines ongoing interpretive and implementation challenges, and discusses how population-scale genomic resources and emerging data on reproductive lethality are shaping the next generation of evidence-based carrier screening.