Clinical trial NCT06722313: Optimized PGT-M Strategy for Patients with No Proband
Official title: Optimized PGT-M Strategy Using Gametes or Arrested Embryos from Patients with No Proband
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: De Novo Mutation
Preimplantation Genetic Testing
Without Proband
Keywords: preimplantation genetic testing
without proband
De Novo Mutation
Lead sponsor: ShangHai Ji Ai Genetics & IVF Institute
Sponsor class: OTHER
First posted: 2024-12-09
Enrollment: 5
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.


Eligibility criteria: Inclusion Criteria:

* 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:

  1. the carrier of the pathogenic variant was without typical clinical symptoms or detected as gonadosomal mosaic;
  2. 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;
  3. female partner with diminished ovarian reserve and therefore a low yield of embryos;
  4. the variants are X-linked and the karyotype of the variant carrier is 47, XXX or 47, XXY etc.

Exclusion Criteria:

* (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.

Primary outcomes:
measure: Consistence of the PGT-M with prenatal diagnosis with amniocentesis
timeFrame: 16 weeks of gestation
Secondary outcomes:
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
state: Shanghai
Study officials:
affiliation: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
name: Yilun Sui, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.