Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation
Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation
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DOI：
10.1016/j.healun.2015.12.014
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发表时间：
2016-05-01
影响因子：
8.9
通讯作者：
Garcia-Pavia, Pablo
中科院分区：
文献类型：
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作者：
Cuenca, Sofia;Ruiz-Cano, Maria J.;Garcia-Pavia, Pablo
背景：扩张型心肌病（DCM）是心脏移植（HTx）最常见的原因。在接受HTx治疗的患者中，DCM的遗传学基础尚不清楚。我们试图确定家族性扩张型心肌病HTx的遗传基础，并建立现代下一代测序（NGS）技术在此setting.METHODS产量：五十二个心脏移植患者由于家族性扩张型心肌病进行了NGS遗传评估与面板的126个基因相关的心脏疾病（59与DCM）。遗传变异最初被分类为致病性突变或不确定意义的变异（VUS）。最终的致病性状态由家族共分离研究确定。结果：最初，24个致病性突变被发现在21例（40%），25例（48%）携带19 VUS和6（12%）没有显示任何遗传变异。来自46个遗传变异家族中的36个家族的220名亲属的家族评价证实了14例患者的致病性，并允许将VUS重新分类为17例患者的致病性，3例为非致病性。在研究结束时，在38名患者（73%）中确定了导致DCM的突变，5名患者（10%）仅携带VUS。9例（17%）未发现遗传变异。结论：家族性扩张型心肌病患者接受HTx的遗传谱是异质性的，涉及多个基因。NGS技术加上详细的家族性研究允许在绝大多数家族性DCM病例中鉴定致病突变。详细的家族研究对于确定大量病例中潜在遗传缺陷的致病性仍然至关重要。(C)2016年国际心肺移植学会。All rights reserved.
BACKGROUND: Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.METHODS: Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.RESULTS: Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as nonpathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).CONCLUSIONS: The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.