Maternal Genes and Epimutations: Beckwith-Wiedemann Syndrome & Reproductive Risks
Role of Maternal Effect Genes and Epimutations in Beckwith-Wiedemann Syndrome and Adverse Reproductive Outcomes
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
208 participants
May 19, 2023
INTERVENTIONAL
Conditions
Summary
Pathogenic variants in subcortical maternal complex (SCMC) have been identified not only in mothers of Beckwith-Wiedemann syndrome (BWS) babies but also in women with reproductive disturbances such as failed pregnancy attempts and recurrent pregnancy loss. Based on the higher incidence of BWS in children born from Assisted Reproductive Technology (ART), this project aims to investigate incidence and molecular mechanism of pathogenic variants of SCMC in women with reproductive disorders. Study objectives will be (i) assess the incidence of these variants as a cause of differences in reproductive outcomes in the infertile female population and mothers of children with BWS; (ii) identify methylation changes in women with reproductive problems including those with offspring affected by BWS; (iii) determine the molecular causes underlying female infertility and imprinting disorder associated with damaging SCMC gene variants by employing a mouse model.
Eligibility
Inclusion Criteria3
- Cohort 1: healthy women with offspring affected by BWS and peculiar reproductive history from our population of clinically and molecularly diagnosed BWS families;
- Cohort 2: women under 35 undergoing ART for infertility (defined as failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourses) and unable to obtain a live birth after three completed cycles or after the transfer of at least 6 blastocysts;
- Cohort 3: women under 35, with RPL (defined as the loss of two or more pregnancies before 24 weeks of gestation).
Exclusion Criteria2
- presence of conventional and molecular karyotype alterations
- occurrence of known causes that can lead to decreased fertility or recurrent abortions: disorders of the ovaries, such as polycystic ovarian syndrome and other follicular disorders, disorders of the endocrine system causing imbalances of reproductive hormones levels, autoimmune conditions, male infertility, uterine or tubal dysfunctions and malformations, thrombophilic or noncorrected thyroid dysfunctions.
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Interventions
Whole-exome sequencing will be performed as the first approach in all the recruited patients. First, we will analyze different subsets of genes, belonging to: 1. Maternal effect genes as SCMC components and other related genes; 2. Genes essential in the maturation of the oocyte and zygote progression through the early phases of the embryogenesis or highly expressed at different stages of oocyte maturation; 3. Genes with known and potential roles in the establishment and control of genomic imprinting and involved in DNA methylation reactions. Subsequently, variants with a high pathogenicity score will be analyzed, to identify any genes that may be associated with the phenomenon, but do not belong to the previously described categories of genes. Finally, we will conduct a whole genome sequencing (WGS) analysis on a selected subgroup of BWS mothers with peculiar clinical histories and negative WES analysis, to explore all the noncoding and regulatory regions not targeted by WES.
A whole-genome methylation analysis will be performed to identify methylation changes in women with reproductive problems including those with offspring affected by BWS
Locations(2)
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NCT06346418