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

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Aim 1: We will collect samples from of clinically well-characterized trios (products of conception (POC), biological mother, and biological father) with a history of unexplained RPL. Specially, we will recruit a cohort of 1,000 RPL trios that are rigorously-phenotyped and not attributable to known causes of RPL. For each RPL trio, POC tissues and parental blood samples (from both biological parents) will be collected. We will consider establishing cell lines from POC if technically feasible. If it is necessary for the purpose of determining the pathogenicity of genomic variants detected via whole genome sequencing (WGS), we will consider collecting blood samples from other family members after obtaining consent. The study team may also request DNA or POC tissues from prior pregnancy losses if available. Aim 2: We will perform WGS at the Yale Center for Genome Analysis (YCGA) and other bioinformatic analyses to identify pathogenic variants in RPL trios. We will comprehensively define pathogenic variants and generate fully annotated variant maps for all RPL trios to provide the substrate for subsequent novel gene discovery, and ultimately, for the development of clinical diagnostic tests.


Child to Adult


Women with loss of a current singleton pregnancy at < 20 0/7 weeks gestation (documented by ultrasonography or histopathological examination) and two or more prior pregnancy losses.

Subject inclusion criteria: Women with loss of a current singleton pregnancy at < 20 0/7 weeks gestation (documented by ultrasonography or histopathological examination) and two or more prior pregnancy losses. Current qualifying pregnancy losses will have undergone a complete clinical evaluation with negative results (or results that do not explain the history of RPL) as follows: • Karyotype and/or microarray for the POC without a pathogenic/likely pathogenic finding(s) • Parental karyotypes (with/without microarray) without a pathogenic/likely pathogenic finding(s) • Pathologic exam of the fetal and placenta (14-20 weeks of gestation) • Lupus anticoagulant test negative • Anticardiolipin IgG < 40 GPL AND IgM < 40 MPL; OR both < 99th percentile • Anti β2 glycoprotein IgG and IgM < 99th percentile • TSH within normal limits (per the local lab’s reference range) • HgbA1C < 6.5 • Hysterosalpingogram or sonohysterogram without uterine anomalies Other family members (such as siblings of the POC, siblings of the biological parents (aunts/uncles of the POC), and grandparents of the POC) may also be considered for inclusion if required for interpretation. These additional family members would only be asked to submit a one-time blood sample. Subject exclusion criteria: The presence of a known etiology for pregnancy loss (e.g., fetal aneuploidy, parental chromosome translocations that are unbalanced or result in an unbalanced translocation in the POC, immunologic disorders, uncontrolled diabetes, uncontrolled thyroid disease, cervical insufficiency, uterine anomalies, and/or or any confirmed genetic condition of either parent that is well-documented to cause pregnancy loss) will be considered exclusion criteria. In addition, individuals using a donor egg(s) or donor sperm will be excluded.

Type of Study



Outpatient CTRC
SGF Colorado - Colorado Springs
SGF Colorado - Denver

Principal Investigator
Photograph of Nanette Santoro,  MD

Nanette Santoro, MD

Study ID

Protocol Number: 21-3533


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