Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 63
- 试验地点
- 1
- 主要终点
- Epigenetic signature associated with pathogenic variations in the CHD7 gene (CHARGE Syndrome)
研究概览
简要总结
It is necessary to define reference DNA Methylation Episignatures from fetal DNA. The hypotheses are:
- It is possible to define reference DNA Methylation Episignatures from fetal DNA extracted from amniotic fluid or frozen tissues collected during the postmortem examination
- Fetal DNA Methylation Episignatures may be different to postanal DNA Methylation Episignatures defined on DNA extracted from blood
详细描述
Congenital anomalies (CA) complicate 3 to 5% of pregnancies and may be associated with genetic disorders. Diagnosis of genetic diseases is a major medical challenge, especially during pregnancy.
Over the past two decades, next-generation sequencing (NGS) has revolutionized our ability to identify the genetic condition associated with CA. During pregnancy, prenatal exome sequencing identified an additional diagnosis in around 30% of fetuses with CA when standard chromosomal investigations (karyotype and chromosomal microarray analysis, CMA) fail to provide a diagnosis.
Despite these major advances, around 40% of rare diseases remain unsolved, including 10-15% of patients harboring variants of uncertain significance (VUS).
After birth, additional functional analyses ("multi-OMICS"), including genome-wide DNA methylation studies, may be offered to reclassify VUS.
DNA methylation anomalies play an important role in pathologies (developmental disorders and oncology).
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 0 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Patient Inclusion Criteria:
- •Fetuses with a postmortem examination as part of the etiological diagnosis of developmental abnormality within the Genomic Medicine of Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from lung and amniotic fluid is available
- •OR a child cared for in the Genomic Medicine for Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from whole blood is available
- •with pathogenic or probably pathogenic variation in a gene following CHD7, KMT2D, HYLS1, TCTN3 or FLVCR2
- •whose parents have consented to molecular genetic testing as part of diagnosis and research
- •Negative Controls :
- •Fetuses with a postmortem examination as part of the etiological diagnosis of developmental abnormality within the Genomic Medicine of Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from lung and amniotic fluid are available
- •OR a child cared for in the Genomic Medicine for Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from whole blood is available
- •does not have pathogenic or probably pathogenic variation in a gene following CHD7, KMT2D, HYLS1, TCTN3 or FLVCR2
- •whose parents have consented to molecular genetic testing as part of diagnosis and research
- •For everyone:
- •For living participants: Non-objection by holders of parental authority to the reuse of clinical data and biological samples collected and stored in the context of care (consent of care).
- •For deceased participants:
- •Consent of the holders of parental authority to the use of the samples kept for research purposes, signed as part of the treatment
- •No mention of opposition to the reuse of clinical data from the treatment in the patient's medical record
排除标准
- •Refusal of postmortem examination in case of fetal loss
- •Parents' refusal of molecular investigations
结局指标
主要结局
Epigenetic signature associated with pathogenic variations in the CHD7 gene (CHARGE Syndrome)
时间窗: 12 months
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
Epigenetic signature associated with pathogenic variations in the KMT2D gene (KABUKI syndrome)
时间窗: 12 months
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
次要结局
- Identification of a new epigenetic signature in foetal pathologies(12 months)
- Statistical prediction parameter for each epigenetic signature(12 months)
- Differential methylation between fetal and postnatal epigenetic signature(12 months)
- Differential methylation between tissue and amniotic fluid epigenetic signatures(12 months)