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

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

Interventions

GENETIC

WES analysis

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.

GENETIC

whole-genome methylation analysis

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

Sponsors & Collaborators

• Istituto Auxologico Italiano

  collaborator OTHER

• University of Campania Luigi Vanvitelli

  collaborator OTHER

• Federico II University

  collaborator OTHER

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  lead OTHER

Principal Investigators

• Edgardo Somigliana, PhD · Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-05-19

Primary Completion

2025-12-31

Completion

2026-01-31

Countries

• Italy

Study Locations