Trio Analysis of Recurrent Pregnancy Loss Integrated Bioinformatics Genomics Study (TRIOS)

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PROJECT SUMMARY Recurrent pregnancy loss (RPL) affects up to 5% of families, yet nearly half of cases remain unexplained after evaluation by current testing recommendations. Unexplained euploid RPL is particularly frustrating for families and providers because there is no clear explanation nor proven therapy to mitigate risk of recurrence. As clinical presentations, subsequent pregnancy outcomes, and underlying etiologies vary widely, this complex disorder requires a precision health approach. TRIOS, the parent grant, investigates genetic causes of unexplained recurrent pregnancy loss. Genome sequencing holds immense promise for discovery of genetic variants that are lethal in humans; however, despite genetic diversity among humankind, it is well-documented that genetic studies of human disease have historically failed to capture this variation. Repeated underrepresentation of individuals of non-European ancestry has not only severely limited the understanding of genetic disease in humans, but has also led to significant ancestry-based health inequities. Conversely, increased diversity in genomic research has been shown to simultaneously increase genetic discovery and reduce health disparities. For this reason, concerted efforts to increase racial and ethnic diversity in genetic research is necessary for discovery and characterization of all disease-causing genetic variants, as well as providing equitable and personalized care to all. This supplemental proposal aims to explore and implement novel community outreach, recruitment, and enrollment methods to reduce barriers and increase minority engagement in the genetic research described in our parent grant. We will engage community physicians and front-line community healthcare workers through unstructured focus groups to better understand the threats and opportunities in enrolling their patients in research studies. Financial and transportation barriers will be minimized by facilitating enrollment and collection of samples by mail. Additionally, we will ensure research materials are accessible in Spanish, and bilingual staff are available to support families throughout all study phases. When found, we will provide actionable genetic test results to enrollees, providing personalized and direct benefit from participation in our research. Importantly, this proposed supplement will provide valuable insights into best practices for expanding geographic, socio-economic, and ancestral diversity in reproductive and genetic research. We are uniquely positioned to achieve the aims of this study due to the diverse population of Northern California, our affiliation with a far-reaching healthcare system, and a research team experienced in community-engaged research efforts. The proposed supplement is anticipated to enhance and enrich our recruitment of diverse populations for our parent grant examining genetic causes of RPL through genome sequencing, multi-omics analysis, and applied machine learning methodologies. This work will ultimately advance our understanding of RPL, inform human biology, decrease disparities, and allow for tailored diagnostics, recurrence risks, and novel therapeutics for this devastating and complex disorder.