IGF2/H19-ICR1母源突变在先天生长过剩综合征遗传早现中机制及超声诊断特征的研究

"Congenital overgrowth syndrome", also known as "Beckwith-Wiedemann syndrome (BWS)" is a type of genetic disease that is harmful to the survival and development of the fetus and infants, also causing a high incidence of a variety of malignant tumors, the pathogenesis is not fully elucidated. The applicant's previous study confirmed the presence of “anticipation” at clinical phenotypes and molecular genetics aspects for familial BWS, and reported the epigenetic patterns and characteristics of BWS anticipation. However, there is still no research on the mechanism of familiar BWS anticipation. The applicant proposed that maternal NCBI37: 11: g. 2023019T > C blocks OCT4 binding to ICR1, promotes DNMTs expression, causes ICR1-GOM, inhibits CTCF, enhances IGF2 expression and silences H19, and DNA hypermethylation ratio is transmitted from generation to generation, finally causing anticipation of BWS. This project plans to confirm the above hypothesis in combination with the target mutant humanized BWS animal model. At the same time, the ultrasound platform based on series of the advanced real-time three-dimensional new imaging technology is applied to diagnose the BWS for different developmental stages in the offspring, and the standardized BWS ultrasonic diagnosis scoring system will be established. Furthermore, the relationships between the ultrasound imaging features and the BWS genetic anticipation degree will be explored. These will provide an important theoretical basis for the early diagnosis and follow-up of BWS genetic anticipation by ultrasonic medicine.

“先天生长过剩综合征”又称“Beckwith-Wiedemann syndrome（BWS）”，是对胎儿及婴幼儿生存发育危害重大的遗传疾病，且致多种恶性肿瘤的高发。前期，申请者证实了家族性BWS发病中存在临床及分子遗传学的子代“早现”现象，并发现其（表观）遗传异常表现模式，而BWS遗传早现的机制仍不清楚。申请者提出母源NCBI37:11:g.2023019T>C阻碍OCT4与ICR1结合，促进DNMTs表达，引起ICR1-GOM，抑制CTCF，使IGF2表达增强而H19沉默，且DNA高甲基化率在逐代传递中累积，引起早现。本项目将结合靶突变BWS动物模型证实上述假说。同时，应用以高级三维成像系列新技术为主的超声平台对各子代不同发育时期的BWS进行诊断，制定规范化BWS超声诊断评分系统，并获得超声影像特征与BWS遗传早现的对应关系，为实现超声医学对BWS遗传早现的早期诊断及随访提供重要依据。

先天生长过剩综合征（Beckwith-Wiedemann syndrome，BWS）是对生存发育危害重大的遗传疾病，并可致恶性肿瘤高发。本研究通过建立一个亚洲病例库，根据DNA甲基化模式、父源单倍体、Long-rang PCR、基因测序等实验结果，获取了相关（表观）遗传学数据，对其基本信息、孕产情况、临床表现、肿瘤、突变谱及与其他先天发育异常综合征的重叠等做了系统性分析。本研究发现亚裔家族性BWS中存在临床及分子遗传学的子代“早现”，阐述了其遗传模式，证实了母源NCBI37:11:g.2023019T>C突变可阻碍OCT4与ICR1结合，引起ICR1-GOM，抑制CTCF，使印记基因IGF2表达增强而H19沉默，且DNA高甲基化率在逐代传递中累积后引起早现，并同时应用Igf2/H19-icr1基因靶突变动物模型做出验证。此外，由于BWS中单卵双胞胎的发生率高于普通人群，既往认为此类双胎表型不一致，而分子遗传学结果通常发现是一致的，本研究揭露了部分单卵双胎的BWSp评分相同而分子遗传学却完全不同，并针对这些罕见而有趣的结果进一步提出了两种可能机制。同时，应用了以TrueVue为主的实时三维系列超声影像新技术，探讨了对相关畸形及肿物的诊断、评估和随访中采集、分析图像的标准化建议及应用价值，发现其较传统成像更具真实感，改善了后处理流程，提高了超声医生诊断信心，且高分辨率模拟外科视角的图像能帮助医生在术前加深对复杂畸形的理解，提高治疗成功率，为这些罕见先天畸形的临床及基础医学诊疗及遗传咨询提供了新的思路参考。本研究已发表标注该课题资助的论文12篇，其SCI论文10篇，中文2篇，在投SCI论文3篇。课题负责人参加国内外学术交流11次，其中国际会议4次，发言2次，国内7次，发言4次。获科研奖励4次，其中国际学术会议奖2项。参编书籍2部。申请发明专利1项。作为导师培养硕士研究生5人。