A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life
A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life
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DOI：
10.1136/jmedgenet-2014-102923
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发表时间：
2015-05-01
影响因子：
4
通讯作者：
Melacini, Paola
中科院分区：
文献类型：
--
作者：
Calore, Chiara;De Bortoli, Marzia;Melacini, Paola
背景在肥厚型心肌病(HCM)患者中，心肌肌球蛋白结合蛋白C(MYBPC3)基因突变占很大比例。方法对97例HCM先证者进行MYBPC3基因突变筛查，探讨MYBPC3基因突变的外显性及其对临床表现和预后的影响。在对14个家系的评估中，发现19个(19.5%)为创始人p.Pfs*27突变携带者，另有45个突变携带者。11例(38%)突变携带者的诊断年龄在30岁至40岁之间。疾病外显率不完全(64.4%)，与年龄有关，男性高于女性(85%对48%，p=0.009)。与无MYBPC3突变或携带其他MYBPC3突变的先证者相比，携带方正基因突变的先证者的非持续性室性心动过速(63%比22%，p=0.003；63%比23%，p=0.001)和植入性心律转复除颤器(58%比17%，p=0.001；58%比18%，p=0.005)的患病率最高。携带p.F305Pfs*27突变的先证者在出生后40年后因心脏性猝死(SCD)或流产而导致的生存率下降的发生率高于不携带MYBPC3突变的先证者(32%比15%，P=0.01)。结论p.F305Pfs*27突变携带者在30~40岁年龄段发病的概率较高，且男性发病风险较大。这种创始人突变与第四个十年后SCD/流产的SCD事件的增加有关。这些发现对肥厚型心肌炎患者的治疗和临床决策具有重要意义。
Background Mutations in the cardiac myosin binding protein C (MYBPC3) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis.Methods and results Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age-related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01).Conclusions p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life. These findings are of relevant importance for management and clinical decision-making in patients with HCM.