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

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


Aims: 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'.

Conclusion: 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.

MeSH terms

  • Adult
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / mortality
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / therapy
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / mortality
  • Cardiomyopathy, Dilated / physiopathology
  • Cardiomyopathy, Dilated / therapy
  • Codon, Nonsense*
  • Death, Sudden, Cardiac / etiology*
  • Death, Sudden, Cardiac / prevention & control
  • Defibrillators, Implantable
  • Disease Progression
  • Electric Countershock / instrumentation
  • Female
  • Genetic Predisposition to Disease
  • Heart Transplantation
  • Heredity
  • Humans
  • Lamin Type A / genetics*
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Prognosis
  • Risk Factors
  • Severity of Illness Index


  • Codon, Nonsense
  • LMNA protein, human
  • Lamin Type A

Supplementary concepts

  • Familial dilated cardiomyopathy