Optimized PGT-M Strategy for Patients with No Proband

NCT06722313 | Enrolling By Invitation DMC

• 1 other identifier: JIAI E2023-12
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The clinical practice of PGT-M for monogenetic disease usually adopted a double-checking strategy, which detect the mutation by Sanger sequencing and meantime construct haplotypes using the DNA sample of the proband so as to avoid the risks of misdiagnosis due to recombination and allele drop out (ADO). When there is no affected parent or offspring to serve as the proband, embryo carriers identified through direct mutation detection can be preferentially taken as probands for subsequent linkage analysis. In cases where none of the embryos are detected as mutant carrier, single sperm or the second polar body (PB2) can be complementally collected in the work-up of haplotype establishment. Our study aims to develop an optimized strategy of haplotype construction using gametes or arrested embryos for PGT-M in pedigrees with single gene diseases and no proband in the setting of difficult cases, which takes into account the expected number of oocytes acquired and the gonadal mosaicism.

Conditions

De Novo Mutation; Preimplantation Genetic Testing; Without Proband

Keywords

preimplantation genetic testing; without proband; De Novo Mutation

Outcome Measures

Primary Outcomes (1)

• Consistence of the PGT-M with prenatal diagnosis with amniocentesis

  whether the PGT-M result of the embryos are consistent with the prenatal genetic testing result of amniocentesis

  16 weeks of gestation

Study Arms (1)

PGT-M

EXPERIMENTAL

The couples intended for PGT-M without proband were recruited from Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University between January 2023 and December 2024, and were included in the study if they were expected to have difficulties in the identification of an embryo as proband.

Diagnostic Test: Gametes (sperm or second polar bodies, MI eggs) or arrested embryos were reserved for identification of a proband

Interventions

Gametes (sperm or second polar bodies, MI eggs) or arrested embryos were reserved for identification of a proband DIAGNOSTIC_TEST

1. Targeted deep sequencing for mosaicism detection for patients with suspected gonadal mosaicism, eg. Repeated similar abortion due to the same variant while the couple were tested negative for the variant in the peripheral blood. 2. Ovarian stimulation, embryo culture, biopsy and vitrification as routinely used in the IVF clinical practice. 3. Gametes and arrested embryo preservation by the embryo laboratory during embryo culture. 4. Genetic testing, including multiple displacement amplification for WGA, variant sequencing in WGA products and Infinium Chip protocol for amplified DNA and haplotype analysis

Also known as: Targeted deep sequencing for mosaicism detection, Ovarian stimulation, embryo culture, biopsy and vitrification, Genetic testing

PGT-M

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The couples intended for PGT-M without proband were recruited from Shanghai JiAi Genetics and IVF Institute, Obstetrics and Gynecology Hospital of Fudan University between January 2023 and December 2024, and were included in the study if they were expected to have difficulties in the identification of an EAP, typically meeting one of the following criteria:
• the carrier of the pathogenic variant was without typical clinical symptoms or detected as gonadosomal mosaic;
• the asymptomatic parents, who had one or more children affected with the same disorder, did not possess the genomic alterations carried by the children as per Sanger sequencing or targeted deep sequencing;
• female partner with diminished ovarian reserve and therefore a low yield of embryos;
• the variants are X-linked and the karyotype of the variant carrier is 47, XXX or 47, XXY etc.

You may not qualify if:

• (1) Non-PGT-M families; (2) Pedigree of other proband samples can be obtained; (3) Patients seeking for PGT-M who strongly request no haplotype analysis in embryos and only require Sanger testing after being fully informed of the risk.

Sponsors & Collaborators

• ShangHai Ji Ai Genetics & IVF Institute: lead

Study Sites (1)

Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University

Shanghai, Shanghai Municipality, 200011, China

Location

Related Publications (4)

• Summerer A, Schafer E, Mautner VF, Messiaen L, Cooper DN, Kehrer-Sawatzki H. Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions. Hum Genet. 2019 Jan;138(1):73-81. doi: 10.1007/s00439-018-1961-5. Epub 2018 Nov 26.

  PMID: 30478644 BACKGROUND

• Xiao M, Shi H, Rao J, Xi Y, Zhang S, Wu J, Zhu S, Zhou J, Xu H, Lei C, Sun X. Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis. Front Med (Lausanne). 2022 Jun 17;9:936578. doi: 10.3389/fmed.2022.936578. eCollection 2022.

  PMID: 35783601 BACKGROUND

• Wilde AAM, Amin AS. Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy. JACC Clin Electrophysiol. 2018 May;4(5):569-579. doi: 10.1016/j.jacep.2018.03.006. Epub 2018 May 2.

  PMID: 29798782 BACKGROUND

• Wang Y, Zhai F, Guan S, Yan Z, Zhu X, Kuo Y, Wang N, Zhi X, Lian Y, Huang J, Jia J, Liu P, Li R, Qiao J, Yan L. A comprehensive PGT-M strategy for ADPKD patients with de novo PKD1 mutations using affected embryo or gametes as proband. J Assist Reprod Genet. 2021 Sep;38(9):2425-2434. doi: 10.1007/s10815-021-02188-z. Epub 2021 May 3.

  PMID: 33939064 BACKGROUND

MeSH Terms

Interventions

Sperm Count; Biopsy; Vitrification; Genetic Testing

Intervention Hierarchy (Ancestors)

Cell Count; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Semen Analysis; Investigative Techniques; Cell Physiological Phenomena; Cytodiagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Phase Transition; Physical Phenomena; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Yilun Sui, MD

  Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2024
• First Posted: December 9, 2024
• Study Start: January 1, 2023
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: December 9, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

CN (1)