Role of Maternal Effect Genes and Epimutations in Beckwith-Wiedemann Syndrome and Adverse Reproductive Outcomes
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 208
- 试验地点
- 4
- 主要终点
- MEG Incidence
研究概览
简要总结
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.
详细描述
The first aim of the project is to define the incidence of Maternal-Effect Genes (MEGs) and specifically of SCMC pathogenic variants as a cause of differences in reproductive outcomes in the infertile female population and mothers of BWS children. To this aim, three cohorts of patients will be recruited: healthy women with offspring affected by BWS and peculiar reproductive history from our population of clinically and molecularly diagnosed BWS families (Cohort 1), 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 2), and women under 35, with RPL (Recurrent Pregnancy Loss defined as the loss of two or more pregnancies before 24 weeks of gestation) (Cohort 3).
To identify pathogenic variants, whole-exome sequencing (WES) will be performed as the first approach in all the recruited patients. WES analysis will be carried out following various steps. First, the investigators will analyze different subsets of genes, belonging to:
- Maternal effect genes as SCMC components and other related genes;
- 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;
- 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, the investigators 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.
The second aim of this project is to employ whole-genome methylation analysis to identify methylation changes in women with reproductive problems including those with offspring affected by BWS. Specific tasks will be:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
结局指标
主要结局
MEG Incidence
时间窗: 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
Incidence of MEGs, particularly pathogenetic variants of SCMC, in infertile female population and mothers of children affected by BWS
次要结局
- Compare DNA methylation(samples collected will be evaluated for whole-genome methylation within month 20)