The following specific aims are proposed:~Aim 1: Collect clinically well-characterized samples from trios (product of conception (POC), biological mother, and biological father) with unexplained RPL. Specifically, a cohort of 1,000 trios that are rigorously-phenotyped will be recruited, and for which couples' RPL is not attributable to known causes. The POC and parental blood samples will be collected. Establishing cell lines from the POC if technically feasible will be considered. If it is necessary for the purpose of determining the pathogenicity of sequence variants from the trio, collecting blood samples from other family members after consent will also be considered. The study team may also request DNA or POC tissues from a prior pregnancy loss(es) if available.~Aim 2: A whole genome sequencing (WGS) at the Yale Center for Genome Analysis (YCGA) will be performed and bioinformatic analyses to identify pathogenic variants in included trios will performed as well. Pathogenic variants will be comprehensively defined and fully annotated variant maps in all included trios to provide the substrate for subsequent novel gene discovery, and ultimately, the development of clinical diagnostic tests will be generated.
The overall goals of this proposal are to determine the genetic architecture of recurrent pregnancy loss (RPL) and to discover genomic predictors of RPL.