Department of Cardiology and Angiology I, Heart Center University of Freiburg, Hugstetter Str. 55, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Europace. 2018 Dec 1;20(12):2003-2013. doi: 10.1093/europace/euy127.
Characterization of the cardiac phenotype associated with the novel LMNA nonsense mutation c.544C>T, p.Q182*, which we have identified in a large five-generation family.
A family tree was constructed. Clinical data [arrhythmia, syncope, sudden cardiac death (SCD), New York Heart Association (NYHA) class] were collected from living and deceased family members. DNA of 23 living family members was analysed for mutations in LMNA. Additionally, dilated cardiomyopathy multi-gene-panel testing and whole exome sequencing were performed in some family members to identify potential phenotype-modifiers. In this five-generation family (n = 65), 17 SCDs occurred at 49.3 ± 10.0 years. Furthermore, we identified eight additional mutation-carriers, seven symptomatic (44 ± 13 years), and one asymptomatic (44 years). First signs of disease [sinus bradycardia with atrioventricular (AV)-block I°] occurred at 36.5 ± 8.1 years. Paroxysmal atrial fibrillation (AF) (onset at 41.8 ± 5.7 years) rapidly progressed to permanent AF (46.2 ± 9.8 years). Subsequently, AV-conduction worsened, syncope, pacemaker-dependence, and non-sustained ventricular tachycardia (43.3 ± 8.2 years) followed. Ventricular arrhythmia caused SCD in patients without implantable cardioverter-defibrillator (ICD). Patients protected by ICD developed rapidly progressive heart failure (45.2 ± 10.6 years). A different phenotype was seen in a sub-family in three patients with early onset of rapidly decompensating heart failure and only minor prior arrhythmia-related symptoms. One patient received high-urgency heart transplantation (HTX) at 32 years, while two died prior to HTX. One of them developed lethal peripartum-associated heart failure. Possible disease-modifiers were identified in this 'heart failure sub-family'.
The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.
对我们在一个大型五代家族中发现的新型 LMNA 无义突变 c.544C>T，p.Q182*，进行心脏表型特征分析。
构建了一个家系。从在世和已故的家庭成员中收集临床数据[心律失常、晕厥、心源性猝死（SCD）、纽约心脏协会（NYHA）心功能分级]。对 23 名在世的家庭成员的 DNA 进行 LMNA 突变分析。此外，对一些家庭成员进行扩张型心肌病多基因panel 检测和全外显子组测序，以确定潜在的表型修饰因子。在这个五代家族（n=65）中，有 17 例 SCD 发生在 49.3±10.0 岁。此外，我们还发现了另外 8 名突变携带者，其中 7 名有症状（44±13 岁），1 名无症状（44 岁）。疾病的首发症状[窦性心动过缓伴房室（AV）阻滞 I°]发生在 36.5±8.1 岁。阵发性心房颤动（AF）（41.8±5.7 岁发病）迅速进展为永久性 AF（46.2±9.8 岁）。随后，AV 传导恶化，晕厥，需要起搏器，非持续性室性心动过速（43.3±8.2 岁）随之发生。无植入式心脏复律除颤器（ICD）的患者发生室性心律失常导致 SCD。由 ICD 保护的患者迅速发展为心力衰竭（45.2±10.6 岁）。在一个亚家族的 3 名患者中，观察到不同的表型，这些患者的心力衰竭起病较早，且仅有轻微的心律失常相关症状。一名患者在 32 岁时接受了紧急心脏移植（HTX），而两名患者在 HTX 前死亡。其中一名患者在围产期发生致命性心力衰竭。在这个“心力衰竭亚家族”中发现了可能的疾病修饰因子。
新型 LMNA 无义突变 c.544C>T 导致严重的心律失常表型，大多数患者的 SCD 发生率较高；在一个亚家族中，表现为快速进展性心力衰竭的明显不同的表型，提示需要早期考虑植入 ICD 和心脏移植。
