Maternal Genes and Epimutations: Beckwith-Wiedemann Syndrome & Reproductive Risks

NCT06346418 | Recruiting DMC

• 1 other identifier: PNRR-MR1-2022-12376622
• Study Type: interventional
• Target: 208
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Beckwith-Wiedemann Syndrome

Outcome Measures

Primary Outcomes (1)

• MEG Incidence

  Incidence of MEGs, particularly pathogenetic variants of SCMC, in infertile female population and mothers of children affected by BWS

  WES at specific genes in all the cohorts and SNP-array will be performed following enrollment and will be finalized within month 17. The last part related to WGS on a selected subgroup of BWS mothers will be accomplished from 16 to month 20

Secondary Outcomes (1)

• Compare DNA methylation

  samples collected will be evaluated for whole-genome methylation within month 20

Study Arms (3)

healthy women with offspring affected by BWS

EXPERIMENTAL

healthy women with offspring affected by BWS and peculiar reproductive history from our population of clinically and molecularly diagnosed BWS families

Genetic: WES analysis; Genetic: whole-genome methylation analysis

women under 35 undergoing ART

EXPERIMENTAL

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

Genetic: WES analysis; Genetic: whole-genome methylation analysis

women under 35, with RPL

EXPERIMENTAL

women under 35, with RPL (defined as the loss of two or more pregnancies before 24 weeks of gestation)

Genetic: WES analysis; Genetic: whole-genome methylation analysis

Interventions

WES analysis GENETIC

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.

healthy women with offspring affected by BWS; women under 35 undergoing ART; women under 35, with RPL

whole-genome methylation analysis GENETIC

A whole-genome methylation analysis will be performed to identify methylation changes in women with reproductive problems including those with offspring affected by BWS

healthy women with offspring affected by BWS; women under 35 undergoing ART; women under 35, with RPL

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• Istituto Auxologico Italiano: collaborator
• University of Campania Luigi Vanvitelli: collaborator
• Federico II University: collaborator

Study Sites (2)

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

RECRUITING

Istituto Auxologico Italiano

Milan, 20145, Italy

RECRUITING

MeSH Terms

Conditions

Beckwith-Wiedemann Syndrome

Condition Hierarchy (Ancestors)

Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Imprinting Disorders

Study Officials

• Edgardo Somigliana, PhD

  Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Edgardo Somigliana, PhD

CONTACT

+390255034303; edgardo.somigliana@policlinico.mi.it

Marco Reschini, MSc

CONTACT

+390255034303; marco.reschini@policlinico.mi.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2024
• First Posted: April 4, 2024
• Study Start: May 19, 2023
• Primary Completion: December 1, 2025
• Study Completion: January 1, 2026
• Last Updated: May 2, 2025

Record last verified: 2025-01

Locations

IT (2)