肥厚型心肌病的基因型与表型分析

A research on the relationship of genotypes and phenotypes in hypertrophic cardiomyopathy

目的应用全外显子测序(WES)和三维斑点追踪超声心动图(3D-STE)技术探讨肥厚型心肌病(HCM)患者的基因型与表型间的关系。方法选取2018年6月至2019年1月复旦大学附属中山医院的HCM患者45例,并按心尖是否肥厚分为心尖肥厚型心肌病组(ApHCM组,20例)和非心尖肥厚型心肌病组(non-ApHCM组,25例)。采集HCM患者的静脉血进行WES测序。利用常规二维超声心动图测量室间隔厚度、左室后壁厚度、左室舒张末内径、左室收缩末内径、左室壁最大厚度和左室射血分数(LVEF),并采集标准心尖四腔心的全容积图像,应用3D-STE脱机分析,获得左心室整体纵向应变(GLS)、整体环向应变(GCS)、扭转和扭矩。并分析以上参数、基因突变与左室形态学的相关性。结果HCM患者携带基因突变的比例为73%,其中MYBPC3和MYH7基因的突变最多,分别占全部突变的18%和15%。ApHCM组和non-ApHCM组的基因检测结果均发现KCNEc.79C>T(p.Arg27Cys)和PRKAG2c.905G>A(p.Arg302Gln)突变。ApHCM组基因突变阳性的比例显著低于non-ApHCM组(60%对84%,P=0.041)。ApHCM组GLS显著大于non-ApHCM组(P=0.008)。突变阳性与突变阴性的HCM患者比较,GLS差异无统计学意义(P=0.068)。GLS与左室形态学(ApHCM和non-ApHCM)分类呈中等程度相关(r=0.364,P=0.012),而与是否携带基因突变无相关性(r=0.269,P=0.062)。结论HCM的遗传和表型间存在复杂多样的对应关系。ApHCM和non-ApHCM在基因突变和收缩功能上明显不同。GLS的大小与左室形态相关,而与基因突变无相关性。

Objective To explore the relationship between genotypes and phenotypes in hypertrophic cardiomyopathy(HCM)patients using whole exome sequencing(WES)and three-dimensional speckle-tracking echocardiography(3D-STE).Methods Twenty patients with apical HCM(ApHCM)and 25 patients with non-apical HCM(non-ApHCM)from June 2018 to January 2019 in Zhongshan Hospital of Fudan University were enrolled.All subjects underwent venous blood sampling and WES.Regular two-dimensional echocardiography was performed to acquire the following parameters:interventricular septum thickness,left ventricular posterior wall thickness,left ventricular end diastolic diameter,left ventricular end systolic diameter,the maximum thickness of left ventricular walls and left ventricular ejection fraction(LVEF).Full volume images were collected and then off-time analyzed with 3D-STE to acquire global longitudinal strain(GLS),global circumferential strain(GCS),twist and torsion.The relationships between above parameters,genotypes and phenotypes of left ventricle were analyzed.Results Mutations were found in 73%of HCM patients.The two most common genes MYBPC3 and MYH7 accounted for 18%and 15%of mutations respectively.KCNEc.79C>T(p.Arg27Cys)and PRKAG2c.905G>A(p.Arg302Gln)were detected in both ApHCM group and non-ApHCM group.In ApHCM group,60%of patients carried genetic mutations,which was significantly lower than non-ApHCM group(84%)(P=0.041).Compared with non-ApHCM group,GLS in ApHCM group was significantly higher(P=0.008).There was no statistical difference of GLS between patients with mutations and without mutations(P=0.068).GLS demonstrated a moderate correlation with morphologic types of HCM(ApHCM and non-ApHCM)(r=0.364,P=0.012).However,there was no correlation between GLS and the condition of mutations(r=0.269,P=0.062).Conclusions The relationship between genetics and phenotypic expression of HCM appears to be complex and heterogeneous.There are marked differences in gene mutations and systolic functions between ApHCM and non-ApHCM.The value of GLS correlates with the shape of left ventricle but not with genotypes.