Servicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
Servicio de Cardiología, Complejo Asistencial Universitario de Salamanca, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Centro de Referencia Nacional de Cardiopatías Familiares (CSUR), Salamanca, Spain.
Rev Esp Cardiol (Engl Ed). 2021 Sep;74(9):781-789. doi: 10.1016/j.rec.2020.06.019. Epub 2020 Sep 30.
HCN4 variants have been reported to cause combined sick sinus syndrome (SSS) and left ventricular noncompaction (LVNC) cardiomyopathy. This relationship has been proven in few cases and no previous patients have associated left atrial dilatation (LAD). Our objective was to study a familial disorder characterized by SSS, LAD, and hypertrabeculation/LVNC and to identify the underlying genetic and electrophysiological characteristics.
A family with SSS and LVNC underwent a clinical, genetic, and electrophysiological assessment. They were studied via electrocardiography, Holter recording, echocardiography, and exercise stress tests; cardiac magnetic resonance imaging was additionally performed in affected individuals. Genetic testing was undertaken with targeted next-generation sequencing, as well as a functional study of the candidate variant in Chinese hamster ovary cells.
Twelve members of the family had sinus bradycardia, associated with complete criteria of LVNC in 4 members and hypertrabeculation in 6 others, as well as LAD in 9 members. A HCN4 c.1123C>T;(p.R375C) variant was present in heterozygosis in all affected patients and absent in unaffected individuals. Electrophysiological analyses showed that the amplitude and densities of the HCN4 currents (I) generated by mutant p.R375C HCN4 channels were significantly lower than those generated by wild-type channels.
The combined phenotype of SSS, LAD, and LVNC is associated with the heritable HCN4 c.1123C>T;(p.R375C) variant. HCN4 variants should be included in the genetic diagnosis of LVNC cardiomyopathy and of patients with familial forms of SSS, as well as of individuals with sinus bradycardia and LAD.
已经有报道称 HCN4 变体可导致合并病态窦房结综合征（SSS）和左心室心肌致密化不全（LVNC）心肌病。这种关系已在少数病例中得到证实，以前没有患者伴有左心房扩张（LAD）。我们的目的是研究一种以 SSS、LAD 和心肌小梁化/LVNC 为特征的家族性疾病，并确定潜在的遗传和电生理特征。
一个有 SSS 和 LVNC 的家族接受了临床、遗传和电生理评估。通过心电图、动态心电图记录、超声心动图和运动应激试验进行研究；受影响的个体还进行了心脏磁共振成像检查。进行了靶向下一代测序的基因检测，以及在中国仓鼠卵巢细胞中对候选变异进行功能研究。
该家族的 12 名成员存在窦性心动过缓，其中 4 名符合 LVNC 的完整标准，6 名符合心肌小梁化，9 名符合 LAD。所有受影响的患者均存在 HCN4 c.1123C>T；(p.R375C)杂合变异，而未受影响的个体则不存在该变异。电生理分析表明，突变 p.R375C HCN4 通道产生的 HCN4 电流（I）的幅度和密度明显低于野生型通道产生的 I。
SSS、LAD 和 LVNC 的联合表型与可遗传的 HCN4 c.1123C>T；(p.R375C)变异有关。HCN4 变异应纳入 LVNC 心肌病以及家族性 SSS、窦性心动过缓和 LAD 患者的基因诊断中。
