Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.

肥厚型心肌病 (HCM) 通常会导致心力衰竭。肌节蛋白的突变是 HCM 最常见的原因，但在许多患者中，基因缺陷是未知的。在这里，我们报告了一名在出生后不久被诊断出患有 HCM 的年轻人。全外显子组测序揭示了FLNC的突变基因（c.7289C > T；p.Ala2430Val），该基因先前被证明会导致转染细胞中突变蛋白的聚集。这种突变患者的心肌组织以前没有被分析过，因此，潜在的病因尚不清楚。通过组织化学、免疫荧光染色、电子显微镜和蛋白质印迹分析详细分析了我们患者在 23 岁时在肌切除术中获得的心肌组织。心脏组织学显示肌原纤维肌病的典型病理，肌原纤维紊乱和异常蛋白聚集体，含有 BAG3、结蛋白、HSPB5 和细丝蛋白 C。对肌节和闰盘蛋白的分析显示间隙连接蛋白连接蛋白 43 和 Xin 阳性肌节病灶的表达局部降低我们病人的心肌细胞。此外，FLNC很可能与 HCM 相关，其特征是异常的闰盘、肌原纤维的混乱和含有类似于肌原纤维肌病的 Z 盘蛋白的聚集体，这支持了突变的病理效应。