Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.
Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.
复制标题
伴有早期复极和短 QT 综合征的肥厚型心肌病家族中的新型三基因 CACNA1C/DES/MYPN 突变
DOI：
10.1186/s12967-017-1180-1
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发表时间：
2017-04-20
影响因子：
7.4
通讯作者：
Hu D
中科院分区：
文献类型：
--
作者：
Chen Y;Barajas-Martinez H;Zhu D;Wang X;Chen C;Zhuang R;Shi J;Wu X;Tao Y;Jin W;Wang X;Hu D
背景：早期复极(ER)型肥厚型心肌病(HCM)患者发生室性心律失常的风险较高，但其遗传背景尚未得到很好的研究。在此，我们报告了在一个伴有ER和短QT综合征(SQTS)的中国阻塞性肥厚性心肌病家系中发现的新的三基因突变。从外周血白细胞中提取DNA，用下一代方法进行基因筛查。结果：先证者为男性，52岁，下侧导联ER型心电图，房室传导阻滞，QTc356ms。他还患有严重的左心室肥厚和功能障碍。靶向测序发现了三种突变：DES的C.700G>；A/p.E234K，MYPN的C.2966G>；A/p.R989H，CACNA1C的C.5918G>；C/p.R1973P。在他患有ER和轻度心肌肥大的女儿身上也检测到了所有突变。与CACNA1C-WT(n=14)和CACNA1C-WT(n=14)相比，CACNA1C-R1973P突变导致IC值显著降低(68.4%，P<0.05)。计算机模拟显示，所有3个突变都是高度致病的。先证者接受了CRT-D(心脏再同步治疗)，降低了左室流出道梯度(左心室流出道梯度，前为124 mm Hg，后为27 mm Hg)，并恢复了左心功能(左心室射血分数，前为40%，后为63%)。结论：本研究揭示了一种新的CACNA1C突变，导致了合并SQTS的独特ER模式心电图的发生。提示罕见的三基因突变是肥厚型心肌炎患者临床表现复杂的致病底物。
Background:Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS).Methods:Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment.Results:The proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of ICacompared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post).Conclusions:The study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients.