Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France.
NeuroMyoGen Institute, CNRS UMR 5310 - INSERM U1217, Université de Lyon 1, Lyon, France.
Clin Genet. 2017 Dec;92(6):616-623. doi: 10.1111/cge.13043. Epub 2017 May 18.
Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. More than 40 genes have been reported to cause DCM. To provide new insights into the pathophysiology of dilated cardiomyopathy, a next-generation sequencing (NGS) workflow based on a panel of 48 cardiomyopathies-causing genes was used to analyze a cohort of 222 DCM patients. Truncating variants were detected on 63 unrelated DCM cases (28.4%). Most of them were identified, as expected, on TTN (29 DCM probands), but truncating variants were also identified on myofibrillar myopathies causing genes in 17 DCM patients (7.7% of the DCM cohort): 10 variations on FLNC and 7 variations on BAG3 . This study confirms that truncating variants on myofibrillar myopathies causing genes are frequently associated with dilated cardiomyopathies and also suggest that FLNC mutations could be considered as a common cause of dilated cardiomyopathy. Molecular approaches that would allow to detect systematically truncating variants in FLNC and BAG3 into genetic testing should significantly increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy.
扩张型心肌病 (DCM) 是心力衰竭的主要原因之一，具有较高的发病率和死亡率。已有超过 40 种基因被报道可导致 DCM。为了深入了解扩张型心肌病的病理生理学，本研究采用了一种基于 48 个心肌病致病基因的下一代测序 (NGS) 工作流程，对 222 例 DCM 患者的队列进行了分析。在 63 例无亲缘关系的 DCM 病例中检测到截断变异 (28.4%)。其中大多数（29 例 DCM 先证者）如预期的那样在 TTN 上发现，但是在 17 例 DCM 患者（DCM 队列的 7.7%）的肌原纤维肌病致病基因上也发现了截断变异：FLNC 上有 10 个变异，BAG3 上有 7 个变异。本研究证实，肌原纤维肌病致病基因上的截断变异与扩张型心肌病密切相关，同时还表明 FLNC 突变可被视为扩张型心肌病的常见病因。如果能将 FLNC 和 BAG3 中的截断变异系统地纳入基因检测，分子方法将显著提高检测的灵敏度，从而使许多扩张型心肌病患者能够更早地诊断和接受治疗。
