Large scale genome sequencing and integrative analyses to define genomic predictors of recurrent pregnancy loss

In this proposal, we put forward our plan to recruit 1000 rigorously-phenotyped RPL trios including from diverse and underrepresented backgrounds across the US and to apply WGS and sophisticated variant detection and interpretation methods developed by our labs to identify pathogenic and likely pathogenic variants for RPL. We will then perform comprehensive integrative data analyses to define the genetic basis of unexplained RPL and map the genes and regions of the chromosome that are absolutely required for human development and a successful pregnancy. Our variant interpretation pipeline includes cutting edge approaches to map likely pathogenic noncoding and structural variants rarely assessed in any pregnancy loss study. We will also perform a pilot RNA-seq study to assess the utility of this approach for gene discovery in the pregnancy loss setting.