Noonan综合征相关拷贝数变异及其致病机理研究

Noonan syndrome (NS) is a clinically homogeneous but genetically heterogeneousdisorder.The prevalence is estimated to be 1/1,500-1/2,000 in live births. The clinical phenotypes are variable, which includes some cardinal features: distinctive facial dysmorphism, congenital heart defects and short stature. Based on the molecular pathogenesis, Noonan syndrome has been described as a disorder of dysregulated RAS-MAPK signaling pathway or RASopathies. Nine genes including PTPN11, SOS1, RAF1, KRAS, BRAF, NRAS, MEK1, SHOC2 and CBL have been identified in 70-75% of affected cases. However, chromosome structural changes such as copy number variations (CNVs) are rarely found in underlying NS. Recently, we identified two duplications and one deletion containing the critical genes of RAS-MAPK signaling pathway (PTPN11, RAF1 and SHOC2) with high resolution SNP array. By constructing the biological model of zebrafish gene abnormal-expression for genetic research, we try to explore the function pathogenic mechanism of rare copy number variation. This study aims to launch a systematic research on the mutations and CNVs in NS patients, and to understand how the rare copy number variations can cause Noonan syndrome.

Noonan综合征是一种具有较高遗传异质性的常染色体显性遗传疾病，是婴幼儿中仅次于21-三体的常见综合征，新生儿中发病率高达1/1500-1/2000。其临床表型复杂，主要表现为特殊面容、先天性心脏病和身材矮小。Noonan综合征分子本质上是一类RAS-MAPK信号通路疾病。迄今，已明确通路中PTPN11、SOS1、RAF1、KRAS、BRAF, NRAS, MEK1, SHOC2及 CBL等9个基因突变可激活RAS-MAPK信号通路导致Noonan综合征，但仍有15-30% 患者致病原因不明。最近本研究小组通过SNP-array芯片技术发现包含核心基因PTPN11和RAF1的重复及SHOC2的微缺失等拷贝数变异均可导致Noonan综合征。同时拟通过构建斑马鱼相关基因表达异常的生物模型进行遗传研究，进而探讨拷贝数变异的致病机理。

本研究重点是Noonan综合征相关拷贝数变异及其致病机理的研究。通过不断收集临床Noonan综合征病例的临床资料及外周血标本，对所有病例进行遗传分析。经过基因测序发现了PTPN11，RAF1及SOS1的已知基因的已知突变；SNP—array及芯片技术发现包含核心基因PTPN11和RAF1的重复及SHOC2的微缺失等拷贝数变异均可导致Noonan综合征，其中SHOC2的微缺失导致Noonan综合征是国际上首个报道。同时搭建了海外斑马鱼实验室平台，尝试通过斑马鱼来构建相关基因表达异常的生物模型进行遗传研究。. 本研究紧密结合临床，在国内较早开展 Noonan综合征患者基因突变检测；本课题在世界范围内也是较早应用高分辨SNP array芯片技术研究 Noonan综合征相关拷贝数变异。尝试通过构建模式生物模型发现拷贝数变异导致 Noonan综合征。. 主要结果已经发表在Molecular Cytogenet上，“Rare copy number variations containing genes involved in rasopathies： deletion of shoc2 and duplication of ptpn11. Mol Cytogenet,”（2014；7卷, p 28）。