CAJ | 학술논문

目的探讨中国大样本队列肥厚型心肌病(HCM)患者的遗传学基础以及与不同基因型相关的表型严重性.方法对北京大学人民医院心脏中心2002至2011年连续收录的179例无血缘关系的HCM患者(男119例,女60例)直接测序分析β肌球蛋白重链(MYH7)、肌球蛋白结合蛋白C(MYBPC3)和心脏肌钙蛋白T(TNNT2)基因突变情况,并进行临床评估.结果共发现40例(22.3％)患者存在34种突变.79.4％ (27/34)的突变只出现1次,而仅MYH7的26位氨基酸可能为突变热点.突变基因分布情况为MYBPC3、MYH7和TNNT2分别占52.9％ (18/34)、35.3％ (12/34)和11.8％ (4/34).2.2％ (4/179)的患者存在双突变.基因型阳性(40例)与阴性患者(139例)的发病年龄[(35.4±17.6)岁比(47.6±17.1)岁,P＜0.001]、左心室壁厚度[(21.2±5.7)mm比(19.0±5.3)mm,P=0.031]、晕厥发生率(27.5％比10.8％,P=0.019)、HCM家族史(35.0％比9.4％,P＜0.001)和心脏性猝死家族史(25.0％比2.2％,P＜0.001)差异均有统计学意义;在6.5年的随访期间具有更明显的心功能恶化(24.2％比5.0％,P=0.002)和猝死风险(9.1％比0,P=0.009).MYBPC3与MYH7突变患者间临床参数和结局差异无统计学意义.本研究中的双突变患者具有恶性表型,而同一基因型(如MYH7-I736T、TNNT2-R92W)在不同患者中的表型严重程度不一.结论 MYBPC3是HCM患者中最多见的致病基因.尽管特定的基因或突变不能准确预测表型的严重性,但HCM患者如果存在肌小节基因突变,则提示更严重的结局.
목적 탐토중국대양본대렬비후형심기병(HCM)환자적유전학기출이급여불동기인형상관적표형엄중성.방법 대북경대학인민의원심장중심2002지2011년련속수록적179례무혈연관계적HCM환자(남119례,녀60례)직접측서분석β기구단백중련(MYH7)、기구단백결합단백C(MYBPC3)화심장기개단백T(TNNT2)기인돌변정황,병진행림상평고.결과 공발현40례(22.3％)환자존재34충돌변.79.4％ (27/34)적돌변지출현1차,이부MYH7적26위안기산가능위돌변열점.돌변기인분포정황위MYBPC3、MYH7화TNNT2분별점52.9％ (18/34)、35.3％ (12/34)화11.8％ (4/34).2.2％ (4/179)적환자존재쌍돌변.기인형양성(40례)여음성환자(139례)적발병년령[(35.4±17.6)세비(47.6±17.1)세,P＜0.001]、좌심실벽후도[(21.2±5.7)mm비(19.0±5.3)mm,P=0.031]、훈궐발생솔(27.5％비10.8％,P=0.019)、HCM가족사(35.0％비9.4％,P＜0.001)화심장성졸사가족사(25.0％비2.2％,P＜0.001)차이균유통계학의의;재6.5년적수방기간구유경명현적심공능악화(24.2％비5.0％,P=0.002)화졸사풍험(9.1％비0,P=0.009).MYBPC3여MYH7돌변환자간림상삼수화결국차이무통계학의의.본연구중적쌍돌변환자구유악성표형,이동일기인형(여MYH7-I736T、TNNT2-R92W)재불동환자중적표형엄중정도불일.결론 MYBPC3시HCM환자중최다견적치병기인.진관특정적기인혹돌변불능준학예측표형적엄중성,단HCM환자여과존재기소절기인돌변,칙제시경엄중적결국.
Objective To explore the genetic basis and phenotypic correlation with disease severity in a large cohort of Chinese patients with hypertrophic cardiomyopathy (HCM).Methods A total of 179 unrelated Chinese HCM patients admitted to our department from 2002 to 2011 were enrolled in this study.Direct gene sequencing of β-myosin heavy chain (MYH7),myosin binding protein-C (MYBPC3),and cardiac troponin T (TNNT2) were performed and clinical data were obtained in these patients.Results A total of 34 mutations were identified in 40 patients (22.3％),79.4％ (27/34) mutations occurred only once and a possible hot spot,A26 in MYH7,was found.Distribution of mutations was 52.9％ (18/34) (MYBPC3),35.3 ％ (12/34) (MYH7) and 11.8％ (4/34) (TNNT2) respectively.Double mutations were identified in 2.2％ (4/179) patients.Genotype-positive patients were associated with an earlier symptom onset,severer left ventricular hypertrophy,a higher incidence of syncope,and were more likely to have positive family history of HCM or sudden cardiac death (SCD),and were more likely to progress into heart failure(24.2％ vs.5.0％,P =0.002) and at a higher risk of SCD(9.1％ vs.0,P =0.009) during the 6.5-year follow-up.No statistical difference in any clinical parameters and outcomes was found between patients carrying MYBPC3 and MYH7 mutations.Double mutations were associated with malignant clinical progression in this cohort.Different phenotype severity could be seen in HCM patients with same genotype (e.g.MYH7-I736T,TNNT2-R92W).Conclusion MYBPC3 is the most predominant gene mutation in this HCM cohort.The presence of a sarcomere mutation in patients with HCM is associated with poor clinical outcome,although no specific genes or mutations can exactly predict the severity of clinical phenotypes.