Abstract
Recurrent pregnancy loss (RPL) affects ~5% of women, yet the genetic basis of euploid losses remains unclear. We performed genome sequencing in 118 families with unexplained euploid RPL, most without fetal anomalies. We identified genomic variants in 30 families (25.4%) across 28 genes. Thirteen genes were previously linked to perinatal lethality, while fifteen were novel. Inherited variants accounted for 83.3% (25/30) of families, including two due to parental germline mosaicism, seven heterozygous variants transmitted from affected or asymptomatic parents, five cases with hemizygous variants, and 11 with biallelic variants. Four additional families (3.4%) had biparental ultra-rare variants in genes not yet associated with any human disease but with plausible roles in prenatal lethality. Transcriptomic analyses implicated roles in hematopoiesis, cardiovascular development, inflammation, and fluid homeostasis. We identified monogenic basis in a quarter of unexplained euploid RPL cases and expanded our understanding of early human lethality, recurrence risk, and inheritance patterns.