A Genetic Landscape of Euploid Miscarriages From Couples With Recurrent Pregnancy Loss Through Whole Exome Sequencing

This study aimed to identify candidate genes for recurrent pregnancy loss (RPL).

Trio-whole exome sequencing (WES) analysis was performed with blood samples and euploid miscarriage tissues from 55 couples.

Overall, 117 de novo protein-altering variants of 83 genes from 38 miscarriages were identified, with three alterations per embryo on average. A vast majority of the de novo variants were missense/indel and classified as variants of uncertain significance. The de novo variants preferentially hit the intolerant genes and impacted the functional pathways such as Pol II transcription, heart development, and p53 signaling. In search of recessive variants associated with embryo lethality, six autosomal and four X-chromosomal genes, which are functionally clustered into the pathways such as cilium assembly and regulation of cell morphogenesis, were prioritized for 12 family trios. Of the recessive variants, a large majority were missense and of uncertain significance. Notably, there were miscarriages having inherited biallelic variants and coincidental de novo variants. In perspective of maternal effect genes, homozygous or compound heterozygous missense variants of the MEI4 gene were identified.

Our findings reveal a significant heterogeneity and complexity in exomic variants contributing to RPL.