心脏肌钙蛋白Ⅰ基因Arg162位点不同突变基因型与肥厚型心肌病临床表型研究

Phenotype of Hypertrophic Cardiomyopathy with Arg162Trp and Arg162Gln Mutations in Cardiac Troponin Ⅰ Gene in Unrelated Chinese Patients

目的通过分析携带心脏肌钙蛋白I基因(TNNI3)Arg162位点不同错义突变的肥厚型心肌病患者的临床表现,探索该位点不同突变基因型与临床表型的关系。方法共收集4例携带TNNI3基因Arg162位点突变的非亲缘关系的中国肥厚型心肌病患者及307例正常对照,采用panel二代测序对肌小节基因TNNI3、MYH7、MYBPC3、TNNT2、MYL2、MYL3、TPM1和ACTC1进行检测,对发现的突变进行Sanger测序验证,对患者进行临床评估,分析基因型及临床表型。结果 4例肥厚型心肌病患者携带2种不同的TNNI3基因Arg162位点错义突变,其中2例携带Arg162Trp突变的患者发病年龄在65岁及以上,以非对称性的室间隔增厚为主,1例有晕厥史及猝死家族史,随访出现心力衰竭并植入永久起搏器治疗,另1例伴有左室流出道梗阻;其余2例携带Arg162Gln突变的患者发病年龄均为35岁前,且均表现为心尖肥厚为主,临床表型较轻。结论 TNNI3基因Arg162位点2种不同错义突变所致肥厚型心肌病的临床表型变异较大,患者可出现心律失常、心力衰竭等不良事件,而Arg162Gln突变携带者趋于表现为心尖肥厚型心肌病,可能提示预后较为良好。

Objective To compare the clinical expressions of hypertrophic cardiomyopathy patients with two different types of Arg162 mutations in cardiac troponin I gene（TNNI3）. Methods Four unrelated Chinese HCM patients with Arg162 mutations in TNNI3 gene and 307 healthy controls were enrolled after panel sequenced for sarcomere encoding genes including TNNI3, MYH7, MYBPC3, TNNT2, MYL2, MYL3, TPM1 and ACTC1 by next generation sequencing（NGS）. Clinical evaluations and genetic assessments were performed afterward. Results Of the four patients, two types of missense mutations of Arg162 in TNNI3 gene were identified（2 with Arg162 Trp, 2 with Arg162 Gln）. These mutations were not detected in 307 healthy controls. Both of the two patients harbored Arg162 Trp mutation manifested with asymmetric left ventricular hypertrophy with late onset（age at onset over 65 years old）. One of them with symptom of syncope and a positive family history of HCM/sudden death, experienced heart failure and received permanent pacemaker implantation during follow up, the other patient manifested with left ventricular outflow tract obstruction（LVOTO）. While both of the two patients harbored Arg162 Gln mutation presented with apical hypertrophy with early onset（age at onset less than 35 years old）, manifested milder phenotype. Conclusions Phenotypes of patients carrying different mutations of Arg162 in TNNI3 gene were heterogeneous, and could lead to adverse event such as heart failure and arrhythmia. Patients harbored Arg162 Gln mutation tended to present with apical hypertrophic cardiomyopathy, might potentially indicate better prognosis.