Whole-Exome Sequencing in Recurrent Pregnancy Loss: Current Evidence and Future Directions in Saudi Arabia

Recurrent pregnancy loss or RPL is a controversial subject in reproductive medicine. Although we perform clinical tests and cytogenetic analyses, we are often left puzzled. Whole-exome sequencing (WES) is changing this trend, whose usage has helped discover inherited and new genetic changes related to miscarriage.

This review summarizes international experience of using WES in RPL diagnostics and genetics, particularly from Saudi Arabia and other consanguineous populations.

Based on PRISMA protocols, database searches were performed in PubMed, Scopus, Embase, and Web of Science for published studies (2013 to 2025). There were 24 studies in total of women or couples with RPL which is due two or more consecutive losses with WES. Afterward, we sought information on the study design, participants, how WES was performed, its diagnostic yield, the genes involved, and the clinical implications. Studies from Saudi Arabia were evaluated in more detail.

A diagnostic yield of 34.9% was observed across these studies. A total of 24 studies with 585 families and 5,000 pregnancy losses. increasing further in trio-based WES designs. More than 60 genes were found that not only are responsible but also likely to contribute to RPL. Maternal effects, cilia development, immune tolerance, and blood coagulation-endocrine functions. Most cases were of autosomal-recessive mode of inheritance, particularly in consanguineous groups from Saudi Arabia and South Asia. European populations, however, were shown to have a more abundant de novo variants. In Saudi Arabia, genomic research has contributed significantly toward identifying novel maternal-effect and early embryonic genes that highlight the necessity of population-specific genomic data.

WES is transforming the diagnosis of RPL by unveiling rare monogenic and oligogenic causes that would otherwise be missed by standard testing. The application of WES in reproductive health care facilitates counselling, PGTM and targeted carrier screening. These approaches can possibly improve outcomes and increase live births. The evidence from Saudi Arabia and other consanguineous populations suggests added advantages in the consanguineous context and points to ways that genomic medicine can aid reproductive choices. Future research should include functional validation of candidate variants, the use of AI-based tools for variant interpretation, and the establishment of global registries to promote equitable and population-informed genomics for future purposes.