Table1_Case Report: A Chinese Family of Hypertrophic Cardiomyopathy Caused by a Novel Splicing Mutation in the FLNC Gene.doc

Hypertrophic cardiomyopathy (HCM) is a type of primary cardiomyopathy with genetic etiology, and it carries a high risk of diastolic dysfunction, heart failure, and malignant arrhythmias. We reported the first familial HCM in China, caused by a novel FLNC splicing mutation. We performed duo exome sequencing (ES) to examine the genome of the proband and his mother. For 10 days, a 15-year-old boy was presented to our hospital due to non–exercise-associated chest tightness and asthma. He was diagnosed with HCM [end-diastolic interventricular septal thickness was about 18 mm by transthoracic echocardiography (TTE)]. His mother and sister performed TTE to screen familial cardiomyopathy, which revealed hypertrophic cardiomyopathy only in the proband’s mother. In ES of the mother–son duo, we identified a novel heterozygous mutation of the FLNC gene (chr7:128492808, NM_001127487, c.5905+2T>C, rs1808874360) as the candidate cause of autosomal dominant HCM. Sanger sequencing confirmed this novel mutation in the proband and his mother but absent in the proband’s sister. The potential impact of the novel mutation was predicted by MutationTaster, dbscSNV_ADA_SCORE, dbscSNV_RF_SCORE, CADD_phred, PhyloP20way_mammalian, PhyloP100way_vertebrate, SiPhy_29way_logOdds, and GERP++_RS software. After the administration of furosemide, spironolactone, and metoprolol, the proband’s heart function was improved, and symptoms were alleviated. We presented the first familial HCM caused by a novel FLNC splicing mutation via exome sequencing in China. Therefore, it is necessary that familial screening for patients with HCM should be performed for the early detection of HCM intervention in malignant cardiac events in advance and block genes.

肥厚型心肌病（Hypertrophic cardiomyopathy, HCM）是一类具有遗传病因的原发性心肌病，常伴随舒张功能障碍、心力衰竭及恶性心律失常的高发病风险。本研究报道了国内首例由新型FLNC剪接突变导致的家族性肥厚型心肌病。研究对象为一名15岁男性患儿，因非运动相关性胸闷、气喘就诊我院，病程10天。经胸超声心动图（transthoracic echocardiography, TTE）检查显示其舒张末期室间隔厚度约18mm，确诊为肥厚型心肌病。其母亲与妹妹接受TTE筛查家族性心肌病，结果仅先证者的母亲确诊肥厚型心肌病。对母子二人开展二人外显子组测序（duo exome sequencing, ES），鉴定出FLNC基因的新型杂合突变（chr7:128492808, NM_001127487, c.5905+2T>C, rs1808874360），该突变被认为是常染色体显性遗传性肥厚型心肌病的候选致病因素。桑格测序（Sanger sequencing）证实先证者及其母亲携带该新型突变，而先证者的妹妹未携带该突变。本研究通过MutationTaster、dbscSNV_ADA_SCORE、dbscSNV_RF_SCORE、CADD_phred、PhyloP20way_mammalian、PhyloP100way_vertebrate、SiPhy_29way_logOdds及GERP++_RS多款软件，预测了该新型突变的潜在致病影响。患儿接受呋塞米、螺内酯及美托洛尔治疗后，心功能得到改善，临床症状得以缓解。本研究通过外显子组测序报道了国内首例由新型FLNC剪接突变导致的家族性肥厚型心肌病。因此，对肥厚型心肌病患者开展家族筛查，有助于早期发现疾病、提前干预恶性心脏事件并阻断致病基因的传递。