Genomic Predictors of Recurrent Pregnancy Loss
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- This is an observational study: the protocol does not assign a study treatment.
- Who it may be relevant to
- Registry conditions: Recurrent Pregnancy Loss. Basic parameters: 18 years — 50 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- United States
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Large Scale Genome Sequencing and Integrative Analyses to Define Genomic Predictors of Recurrent Pregnancy Loss
Overview
The overall goals of this proposal are to determine the genetic architecture of recurrent pregnancy loss (RPL) and to discover genomic predictors of RPL.
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.
Primary outcome measures
- Determine genetic etiology for Recurrent Pregnancy Loss [Time frame: 5 years]
Eligibility criteria
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
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: Yes
Study design
- Observational model
- Cohort
Study locations
United States · 10 centers
- University of Colorado — Aurora
- Yale University — New Haven
- Northwestern University — Chicago
- University of Chicago — Chicago
- Johns Hopkins University — Baltimore
- Wayne State University — Detroit
- Columbia University — New York
- Pennsylvania State University — Hershey
- … and 2 more centers
Identifiers
NCT: NCT05444283 · 2000029802 · 1R01HD105267-01