Noonan综合征合并肥厚型心肌病患儿基因突变与临床表型分析

Gene mutation and clinical phenotype analysis of patients with Noonan syndrome and hypertrophic cardiomyopathy

目的分析Noonan综合征合并肥厚型心肌病患儿的基因突变与临床表型。方法以北京安贞医院小儿心脏中心收治的5例确诊Noonan综合征合并肥厚型心肌病患儿为研究对象，进行基因突变检测，确定突变位点及结构域，分析突变基因与肥厚型心肌病临床表型的关系。结果5例患儿的3个基因突变位点（12号染色体PTPN11基因，1号染色体RIT1基因及3号染色体RAF1基因）与肥厚型心肌病相关。2例患儿基因检测发现与肥厚型心肌病相关的已知基因突变MYPN、MYH6及MYBPC3。2例患儿基因突变均为RAF1，c.770C〉T，但临床表现不同，其中1例患儿除有特殊面容及智商较低外，肺动脉瓣狭窄极轻，心室肌肥厚亦不严重。 结论Noonan综合征表现明显的遗传异质性，同一基因位点突变，临床表现多样。PTPN11、RAF1及RIT1基因位于特定结构域的突变位点与伴肥厚型心肌病的Noonan综合征密切相关。

ObjectiveTo analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy.MethodDetermined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database.ResultThree mutant genes （PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3） in five cases all had been reported to be related to hypertrophic cardiomyopathy. The reported hypertrophic cardiomyopathy relevant genes MYPN, MYH6 and MYBP3 had also been found in case 1 and 2. Patients with same gene mutation had different clinical manifestations. Both case 4 and 5 had RAF1 mutation （c.770C〉T）. However, case 4 had special face, low IQ, mild pulmonary artery stenosis, and only mild ventricular hypertrophy.ConclusionNoonan syndrome is a genetic heterogeneity disease. Our study identified specific gene mutations that could result in Noonan syndrome with hypertrophic cardiomyopathy through molecular biology methods. The results emphasize the importance of gene detection in the management of Noonan syndrome.