Whole Genome Sequencing (WGS) on IVF Embryos and Individual Patients

NCT ID: NCT05739890

Last Updated: 2023-09-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Total Enrollment

100 participants

Study Classification

OBSERVATIONAL

Study Start Date

2023-06-01

Study Completion Date

2024-08-31

Brief Summary

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This research project aims to utilise recent advances in whole genome sequencing of preimplantation genetic diagnosis embryos to investigate the impact of paternal age on de novo mutation rates in IVF embryos. Embryos that are deemed unsuitable for transfer following preimplantation genetic testing for monogenic/single gene disorders (PGT-M) due to the detection of genetic abnormalities will be utilized for this study. These embryos will undergo re-biopsy, and both the biopsied samples as well as the remaining embryo tissue will be subject to whole genome sequencing. This will allow the assessment of de novo mutation rates based on the paternal age.

Detailed Description

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This project proposes a paired non-inferiority trial utilizing the retrospective testing of research embryos to establish the optimized parameters for amplified trophectoderm biopsy and whole genome sequencing compared to traditional preimplantation genetic testing for aneuploidy (PGT-A).

The primary outcome is the de novo mutation rate, which will be compared between embryos subjected to trophectoderm biopsy and whole genome sequencing versus reanalysis with Sanger sequencing. Trio testing will be performed for each embryo using DNA from the genetic parents in addition to embryo. The study will compare cases that include couples with at least one embryo deemed unsuitable for transfer. A paired study design will be used, with embryos from each couple split into two arms - one subjected to trophectoderm biopsy and whole genome sequencing, the other to reanalysis with targeted sequencing.

Biopsied trophectoderm samples and the remaining embryo tissues from the whole genome sequencing arm will undergo sequencing. Sequencing will also be performed on DNA samples from each genetic parent.

Derivation of de novo mutation rates is a key goal, as these provide insights into effects of paternal age and other factors on germline mutations in preimplantation embryos, increasing the knowledge of the risks associated with advanced paternal age. Secondary metrics will be investigated to supplement the analysis, including clean reads and clean bases indicating the amount of high-quality data for the source templates. Mapping rate, unique rate and duplicate rate, assessing data accuracy and quality. Comparison of multiple metrics will determine the optimized parameters for performing amplified trophectoderm biopsy and whole genome sequencing. This can then inform future research and clinical studies.

The de novo mutation rate will be derived by modelling the observed mutation rate as a function of parental ages, specifically the paternal age. Whole genome sequencing of embryo samples as well as both parents will identify raw numbers of de novo mutations. The paternal age coefficient for the de novo mutation rate will be calculated using a regression model with the number of de novo mutations as the dependent variable and paternal age as the key independent variable. Covariates like maternal age and sequencing quality metrics will also be included to account for potential confounding factors. The regression model will determine the increase in de novo mutations per year of paternal age, providing the paternal age coefficient. Comparing embryos from older and younger males will reveal differences in mutation rates. The overall model will establish the quantitative relationship between paternal age and de novo mutations in preimplantation embryos based on the study's whole genome sequencing data.

Conditions

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Fertility Issues Single-Gene Defects

Study Design

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Observational Model Type

COHORT

Study Time Perspective

OTHER

Study Groups

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Age >18yrs

The study will compare embryos from \>50 couples and their embryo samples flagged not suitable for transfer from deidentified couples with date of birth required.

Embryo genome sequencing

Intervention Type OTHER

This project proposes the testing of a cohort of research embryos to establish the key parameters for amplified trophectoderm biopsied embryos using minimum depth required for genome sequencing (\>depth of 30x per base).The remaining embryo tissue will be whole genome sequenced to validate the results of the biopsy.

Parents genome sequencing

Intervention Type OTHER

Analysis will be performed using trio testing of each embryo in addition to the DNA from the genetic parent to facilitate the derivation of de novo mutation rate.

Interventions

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Embryo genome sequencing

This project proposes the testing of a cohort of research embryos to establish the key parameters for amplified trophectoderm biopsied embryos using minimum depth required for genome sequencing (\>depth of 30x per base).The remaining embryo tissue will be whole genome sequenced to validate the results of the biopsy.

Intervention Type OTHER

Parents genome sequencing

Analysis will be performed using trio testing of each embryo in addition to the DNA from the genetic parent to facilitate the derivation of de novo mutation rate.

Intervention Type OTHER

Eligibility Criteria

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Exclusion Criteria

* Female patients with low ovarian reserve (\< 10 follicles or FSH\>10, AMH \<1).
Minimum Eligible Age

18 Years

Maximum Eligible Age

48 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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GenEmbryomics Pty. Ltd

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Nicholas Murphy, PhD

Role: PRINCIPAL_INVESTIGATOR

GenEmbryomics Pty. Ltd

Locations

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Neway Fertility

New York, New York, United States

Site Status NOT_YET_RECRUITING

ORM Fertility

Portland, Oregon, United States

Site Status NOT_YET_RECRUITING

Poma Fertility

Kirkland, Washington, United States

Site Status NOT_YET_RECRUITING

Preimplantation Genetic Testing Unit ART and Reproductive Genetics Unit, Memorial Sisli Hospital

Istanbul, Okmeydani-Sisli, Turkey (Türkiye)

Site Status RECRUITING

Countries

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United States Turkey (Türkiye)

Central Contacts

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Santiago Munné, PhD

Role: CONTACT

+1-646-2072897

Facility Contacts

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Semra Kahraman, M.D.

Role: primary

90 212 314 6666

Murat Cetinkaya, M.D., PhD

Role: backup

+90 533 266 42 24

Other Identifiers

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RP-GE_02

Identifier Type: -

Identifier Source: org_study_id

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