Variants in ciliary genes are an important genetic cause of recurrent pregnancy loss: A hypotheses

Genetic factor is an important aspect of the etiology of recurrent pregnancy loss (RPL). Primary cilium is a cell surface and hair-like sensory structure that plays a crucial role during embryonic development. We hypothesize that the recessive variants of ciliary genes in couples could be an important genetic cause of RPL. Our rationales are as follows: first, hundreds of genes encode structural or regulatory proteins within the cilia to maintain their normal morphology and function, and a deficiency in any of these genes may affect early embryo development; second, ciliary genes are predominant among the candidate genes identified using whole exome sequencing (WES) of family trios with RPL in existing studies; third, knockout mouse models of ciliary genes showed various defects in embryonic cilia that may cause pregnancy loss. To test the hypothesis, WES based on a cohort of couples with RPL and their euploid miscarriages can be performed to identify potential pathogenic variants of ciliary genes to validate the disease-gene associations. An enrichment of ciliary gene among the candidate genes is expected by Gene ontology analysis. Furthermore, immunofluorescence staining of paraffin-fixed placenta tissues from miscarriages carrying clinically relevant variants can be used to visualize the defects in embryonic cilia to establish a genotype-phenotype correlation. Findings from this proposed study may promote establishment of a ciliary gene panel associated with RPL, which will facilitate the precision medicine of RPL, such as preimplantation genetic screening for patients with recurrent implantation failure.