High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics
High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics
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DOI：
10.1016/j.ahj.2007.07.038
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发表时间：
2007-12-01
影响因子：
4.8
通讯作者：
van den Berg, Maarten P.
中科院分区：
文献类型：
--
作者：
van Tintelen, J. Peter;Hofstra, Robert M. W.;van den Berg, Maarten P.
扩张型心肌病（DCM）中最常见的突变是纤层蛋白A/C （LMNA）基因的突变。我们的目的是分析在心脏遗传学门诊就诊的DCM和/或传导疾病患者的LMNA基因，并评估LMNA突变的患病率及其临床表达。方法与结果对61例指标患者进行了LMNA基因筛选。发现了11个突变（包括6个新突变），主要发生在家族性DCM合并心传导疾病亚组（3/10指数患者）和DCM合并emry - dreifuss、Limb-Girdle或未分类的肌营养不良患者（7/8指数患者）。此外，在仅有心脏传导疾病的4个家族中，有1个家族发现了突变。我们没有发现任何大的删除或重复。基因型-表型关系揭示了p.N 195K突变携带者的猝死率和心脏移植率高。我们的研究证实，p.R225X突变导致心脏传导疾病，并导致DCM晚期或不发生DCM，强调了该突变在假定的家族性“单传导疾病”中的重要性。近三分之一的LMNA突变携带者经历过血栓栓塞事件。结论本研究强调了LMNA突变在DCM及相关疾病中的作用。在p.N 195K突变携带者中发现了严重的表型，在p.R225X携带者中发现了优先的心脏传导疾病。由于临床的可变性，包括相关症状的及时出现，DCM或家族性单传导疾病患者应考虑进行LMNA筛查。
Background Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression.Methods and Results The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications.Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N 195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event.Conclusions This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N 195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction disease.