Genomic Predictors of Recurrent Pregnancy Loss (GPRPL)

Large Scale Genome Sequencing and Integrative Analyses to Define Genomic Predictors of Recurrent Pregnancy Loss

The overall goals of this proposal are to determine the genetic architecture of recurrent pregnancy loss (RPL) and to discover genomic predictors of RPL.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Pregnancy Loss

Detailed Description

The following specific aims are proposed:

Aim 1: Collect clinically well-characterized samples from two distinct cohorts of participants with unexplained recurrent pregnancy loss (RPL).

• Cohort A will consist of trios (product of conception (POC), biological mother, and biological father) with unexplained RPL. Specifically, a cohort of up to 500 rigorously phenotyped trios will be recruited, for which couples' RPL is not attributable to known causes. POC tissues and parental DNA samples (blood or saliva) will be collected. If necessary for the purpose of determining the pathogenicity of sequence variants identified in the trio, collecting DNA samples from other family members after consent will also be considered. The study team may also request DNA or POC tissues from prior pregnancy loss(es) if available.
• Cohort B will consist of up to 100 women with a history of three or more pregnancy losses, with or without a liveborn child, and no known etiology. For these participants, DNA samples (blood or saliva) will be collected from the mothers. If high-impact variants are identified, DNA samples from parents or siblings may be collected for segregation analysis after consent.

Aim 2: Whole genome sequencing (WGS) will be performed at the Yale Center for Genome Analysis (YCGA), along with bioinformatic analyses to identify pathogenic variants in both cohorts. For Cohort A, analyses will focus on pathogenic variants identified in RPL trios, and for Cohort B, analyses will focus on variants associated with maternal effect genes in the mothers. Pathogenic variants will be comprehensively defined, and fully annotated variant maps will be generated for all included samples to provide the substrate for subsequent novel gene discovery and, ultimately, the development of clinical diagnostic tests.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Yong-Hui Jiang, MD, PhD; Phone Number: 2037852429; Email: yong-hui.jiang@yale.edu
• Study Contact Backup: Name: Heping Zhang, PhD; Phone Number: 12037855185; Email: heping.zhang@yale.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
      • Principal Investigator: Nanette Santoro, MD
      • Contact: Asma Giornazi, MS; Phone Number: 720-276-8941; Email: asma.giornazi@ucdenver.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Yale University
      • Principal Investigator: Hugh Taylor, MD
      • Principal Investigator: Yong-Hui Jiang, MD, PhD
      • Contact: Yong-Hui Jiang, MD, PhD; Phone Number: 203-785-2429; Email: yong-hui.jiang@yale.edu
      • Sub-Investigator: Heping Zhang, PhD
      • Contact: Mar T Giner-Calabuig, PhD; Phone Number: 203-737-2212; Email: mar.giner-calabuig@yale.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Principal Investigator: Emily Jungheim, MD
      • Contact: Riley Bonaccorsi; Phone Number: 312-694-6678; Email: riley.bonaccorsi@nm.org
    • Chicago, Illinois, United States, 60611
      • Active, not recruiting
      • University of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • Johns Hopkins University
      • Principal Investigator: James Segars, MD
      • Contact: Samya El Sayed, MD; Phone Number: 443-473-2674; Email: selsaye4@jh.edu
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Wayne State University
      • Contact: Michelle Yoscovits; Phone Number: 313-577-8016; Email: mbrossoi@med.wayne.edu
      • Principal Investigator: Stephen Krawetz, PhD
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
      • Contact: Jessica Giordano, CGC; Phone Number: 516-521-5604; Email: jlg2197@cumc.columbia.edu
      • Contact: Alexandra Tinfow, CGC; Phone Number: 917-838-2196; Email: at3452@cumc.columbia.edu
      • Principal Investigator: Uma Reddy, MD, MPH
      • Principal Investigator: Samuel Z Williams, MD, PhD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Recruiting
      • Pennsylvania State University
      • Contact: Robinn Moyer; Phone Number: 717-531-6272; Email: Rmoyer3@pennstatehealth.psu.ed
      • Principal Investigator: Sarah Horvath, MD
  • Texas
    • Austin, Texas, United States, 78712
      • Recruiting
      • University of Texas at Austin
      • Contact: Brooke Lasher; Phone Number: 404-441-3186; Email: brooke.lasher@austin.utexas.edu
      • Contact: Elizabeth Davis, RN; Phone Number: 512-495-2103; Email: elizabethrose.davis@austin.utexas.edu
      • Principal Investigator: Winifred Mak, MD, PhD
    • San Antonio, Texas, United States, 78299
      • Recruiting
      • University of Texas at San Antonio
      • Principal Investigator: Winifred Mak, MD, PhD
      • Contact: Susie Reyes, RN; Phone Number: 210-450-5384; Email: reyessr@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Couples who have had two or more previous pregnancy losses and have undiagnosed cause of recurrent pregnancy loss.

Description

Cohort A - Fetal Intolerome Cohort

Inclusion Criteria:

• Women with loss of a current singleton pregnancy at < 20 0/7 weeks gestation, documented by ultrasonography or histopathological examination
• History of one or more prior pregnancy losses
• Euploid current pregnancy confirmed by karyotype, microarray, or STORK (Short-read Transpore Rapid Karyotyping) sequencing Note: A limited number of aneuploid losses will be included as part of the pilot phase

Exclusion Criteria:

• History of parental karyotype abnormalities
• History of antiphospholipid antibody syndrome
• Evidence of uncontrolled diabetes
• Evidence of uncontrolled thyroid disease
• History of autoimmune disease related to pregnancy loss (e.g., systemic lupus erythematosus, rheumatoid arthritis)
• History of uterine anomalies
• History of cervical insufficiency

Cohort B - Maternal Effect Gene Cohort

Inclusion Criteria:

- Women with a history of three or more pregnancy losses of unknown cause, with or without a liveborn child

Exclusion Criteria:

- Known etiology for pregnancy loss

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine genetic etiology for Recurrent Pregnancy Loss	The WGS tool will be used to analyze the POC sample and parental blood samples to determine the clinical reportable genetic cause for RPL	5 years

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Johns Hopkins University; University of Colorado, Denver; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Northwestern University; University of Chicago; Wayne State University; Columbia University; Penn State University; University of Utah; The University of Texas Health Science Center at San Antonio; University of Texas at Austin

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: June 29, 2022
• First Submitted That Met QC Criteria: June 29, 2022
• First Posted (Actual): July 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Pregnancy Complications; Death; Recurrence; Abortion, Spontaneous; Fetal Death; Abortion, Habitual
• Other Study ID Numbers: 2000029802; 1R01HD105267-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No