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Europace. 2018 Dec 1;20(12):2003-2013. doi: 10.1093/europace/euy127.

A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy with high risk of sudden cardiac death in a large five-generation family.

Author information

Department of Cardiology and Angiology I, Heart Center University of Freiburg, Hugstetter Str. 55, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Genetic Epidemiology, Medical Center University of Freiburg, Freiburg, Germany.
Genetics and Experimental Bioinformatics, Faculty of Biology, University of Freiburg, Freiburg, Germany.
Division of Cardiology, Medical University of Graz, Graz, Austria.
Institute of Human Genetics, Medical Center University of Freiburg, Freiburg, Germany.



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.

Methods and results:

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.


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