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目的探讨MYBPC3基因突变类型与肥厚型心肌病(HCM)患者临床表型及不良预后的关联。方法使用panel二代测序,检测529例HCM患者和307例健康对照的8个肌小节HCM致病基因。根据携带MYBPC3突变情况,将MYBPC3突变阳性患者分为3组:仅携带1个MYBPC3错义突变(错义组)、仅携带1个MYBPC3无义或剪切位点突变(截短组)或携带至少1个MYBPC3突变的多突变患者(多突变组)。比较3组患者间基线临床特征及临床结局的差异。结果本研究总计在93例(17.6%)患者中检测到64种MYBPC3致病突变。与未检出MYBPC3突变的患者相比,携带MYBPC3突变患者的家族史阳性的比例更高,左心室室壁厚度更大,出现异常Q波的患者比例更高。在携带MYBPC3突变患者中,多突变组最年轻,左心室室壁厚度更大。在4.7±3.2年随访期间内,MYBPC3突变患者全因死亡风险显著高于未检出MYBPC3突变患者(校正HR 2.00,95%CI 1.06-3.79,P=0.033),心血管死亡风险存在增加趋势(校正HR 1.80,95%CI 0.91-3.55,P=0.091)。在MYBPC3突变阳性患者中,多突变组的心血管死亡(校正后HR 30.4,95%CI 3.01-301.12,P=0.004)和全因死亡(校正后HR 25.2,95%CI 4.07-156.00,P=0.001)均显著升高,而截短突变组的心血管死亡和全因死亡则未见显著增加。尤其是携带MYBPC3复合突变的8例患者,在随访期间6(75%)例发生心血管死亡。结论 MYBPC3截短突变与HCM不良预后不存在相关性。携带多个突变的MYBPC3突变携带者,尤其是MYBPC3复合突变患者不良预后风险显著增。
Objective To investigate the relationship between the type of MYBPC3 mutation and the clinical phenotype and adverse prognosis of patients with hypertrophic cardiomyopathy (HCM). Methods Using panel second-generation sequencing, we detected HCM pathogenicity genes in 8 myotomes of 529 HCM patients and 307 healthy controls. MYBPC3 mutation-positive patients were divided into 3 groups according to their MYBPC3 mutation status: only 1 MYBPC3 missense mutation (missense group) was carried, only 1 MYBPC3 nonsense or cleavage site mutation (truncated group) or carrying Multiple mutants with at least 1 MYBPC3 mutation (multiple mutants). The baseline clinical characteristics and clinical outcomes between the three groups were compared. Results A total of 64 MYBPC3 causative mutations were detected in 93 (17.6%) patients in this study. Patients with MYBPC3 mutations had a higher prevalence of family history, greater left ventricular wall thickness, and a higher proportion of patients with abnormal Q waves compared with those without MYBPC3 mutations. In patients with MYBPC3 mutations, the multivessel group was the youngest with greater left ventricular wall thickness. During the median follow-up of 4.7 ± 3.2 years, the risk of all-cause mortality in patients with MYBPC3 mutation was significantly higher than that in patients with no MYBPC3 mutation (adjusted HR 2.00, 95% CI 1.06-3.79, P = 0.033) and an increased risk of cardiovascular death ( HR 1.80, 95% CI 0.91-3.55, P = 0.091). Among the MYBPC3 mutation-positive patients, cardiovascular death (adjusted HR 30.4, 95% CI 3.01-301.12, P = 0.004) and all-cause mortality (adjusted HR 25.2, 95% CI 4.07-156.00, P = 0.001) were significantly increased, while the truncated mutant group of cardiovascular death and all-cause mortality did not increase significantly. In particular, 8 of the patients with the MYBPC3 complex mutation had cardiovascular deaths during 6 (75%) follow-up visits. Conclusion There is no correlation between the truncated MYBPC3 mutation and the poor prognosis of HCM. Patients with multiple mutations in the MYBPC3 mutation carriers, especially in the MYBPC3 complex mutation patients, have a significantly increased risk of adverse outcomes.