Monogenic Findings in Early Pregnancy Loss: Whole-Exome Sequencing Study of Euploid Products of Conception

Early pregnancy loss (EPL), particularly when recurrent, represents a profoundly distressing experience for affected couples. Although chromosomal abnormalities are the most common cause of EPL, a substantial proportion of cases, especially those involving euploid embryos, remain unexplained. In this study, we investigated the potential contribution of rare monogenic variants to euploid EPL using whole-exome sequencing (WES).

WES was performed on 66 euploid products of conceptions (POCs) from EPLs occurring before 12 gestational weeks. A molecular diagnosis with a high level of confidence, defined as the presence of pathogenic or likely pathogenic (P/LP) variant(s) consistent with the expected mode of inheritance, was established in 13/66 POCs (19.7%). These included one large 21q22.12-q22.3 duplication encompassing DYRK1A and RUNX1. P/LP small variants were detected in CPLANE1, DHCR7, DSG2, DVL1, F5, NF1, RBM8A, SLC6A1, and VWF, representing genes with variable degrees of prior association with developmental phenotypes and, in some cases, limited or no evidence for embryonic lethality.

In an additional 9/66 POCs (13.6%), findings were suggestive but not conclusive for a monogenic contribution. These included four cases with compound heterozygosity involving a pathogenic variant and a variant of uncertain significance (VUS) in autosomal recessive genes (GBA1, PAH, PKHD1, and RPGRIP1L), as well as five cases harboring single heterozygous VUS in autosomal dominant genes (MYH3, PRDM6, SCN5A, TBX18, and TSC1). The pathogenic relevance of these variants remains uncertain, particularly in the absence of functional validation.

The implicated genes were clustered in biological categories: 1) genes plausibly associated with prenatal or early embryonic lethality, 2) genes causing severe congenital disorders not typically considered embryonically lethal, and 3) genes linked to later-onset or susceptibility phenotypes. These observations are consistent with a spectrum model in which highly deleterious variants may act as primary drivers of embryonic demise, whereas variants with reduced penetrance, later-onset associations or uncertain significance may contribute in a multifactorial context, potentially interacting with additional genetic, maternal or environmental factors.

In conclusion, our findings suggest that monogenic variants may contribute to a subset of euploid EPL cases, although the strength of evidence varies considerably across detected variants. The integration of WES into the evaluation of recurrent euploid pregnancy loss holds promise but should be interpreted with caution. Further studies incorporating functional analyses, larger cohorts, and parental data are needed to clarify causality and to define the clinical utility of such approaches in genetic counseling, recurrence-risk assessment, and reproductive planning.