PMID- 29947763
OWN - NLM
STAT- MEDLINE
DCOM- 20190916
LR  - 20190916
IS  - 1532-2092 (Electronic)
IS  - 1099-5129 (Linking)
VI  - 20
IP  - 12
DP  - 2018 Dec 1
TI  - A novel LMNA nonsense mutation causes two distinct phenotypes of cardiomyopathy 
      with high risk of sudden cardiac death in a large five-generation family.
PG  - 2003-2013
LID - 10.1093/europace/euy127 [doi]
AB  - 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 degrees ] 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.
FAU - Glocklhofer, Christina R
AU  - Glocklhofer CR
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Steinfurt, Johannes
AU  - Steinfurt J
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Franke, Gerlind
AU  - Franke G
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Hoppmann, Anselm
AU  - Hoppmann A
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
AD  - Institute of Genetic Epidemiology, Medical Center University of Freiburg, 
      Freiburg, Germany.
AD  - Genetics and Experimental Bioinformatics, Faculty of Biology, University of 
      Freiburg, Freiburg, Germany.
FAU - Glantschnig, Theresa
AU  - Glantschnig T
AD  - Division of Cardiology, Medical University of Graz, Graz, Austria.
FAU - Perez-Feliz, Stefanie
AU  - Perez-Feliz S
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Alter, Svenja
AU  - Alter S
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
AD  - Institute of Human Genetics, Medical Center University of Freiburg, Freiburg, 
      Germany.
FAU - Fischer, Judith
AU  - Fischer J
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
AD  - Institute of Human Genetics, Medical Center University of Freiburg, Freiburg, 
      Germany.
FAU - Brunner, Michael
AU  - Brunner M
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Rainer, Peter P
AU  - Rainer PP
AD  - Division of Cardiology, Medical University of Graz, Graz, Austria.
FAU - Kottgen, Anna
AU  - Kottgen A
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
AD  - Institute of Genetic Epidemiology, Medical Center University of Freiburg, 
      Freiburg, Germany.
FAU - Bode, Christoph
AU  - Bode C
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
FAU - Odening, Katja E
AU  - Odening KE
AD  - Department of Cardiology and Angiology I, Heart Center University of Freiburg, 
      Hugstetter Str. 55, Freiburg, Germany.
AD  - Faculty of Medicine, University of Freiburg, Freiburg, Germany.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Europace
JT  - Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal 
      of the working groups on cardiac pacing, arrhythmias, and cardiac cellular 
      electrophysiology of the European Society of Cardiology
JID - 100883649
RN  - 0 (Codon, Nonsense)
RN  - 0 (LMNA protein, human)
RN  - 0 (Lamin Type A)
RN  - Familial dilated cardiomyopathy
SB  - IM
MH  - Adult
MH  - Arrhythmias, Cardiac/*genetics/mortality/physiopathology/therapy
MH  - Cardiomyopathy, Dilated/*genetics/mortality/physiopathology/therapy
MH  - *Codon, Nonsense
MH  - Death, Sudden, Cardiac/*etiology/prevention & control
MH  - Defibrillators, Implantable
MH  - Disease Progression
MH  - Electric Countershock/instrumentation
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Heart Transplantation
MH  - Heredity
MH  - Humans
MH  - Lamin Type A/*genetics
MH  - Male
MH  - Middle Aged
MH  - Pedigree
MH  - Phenotype
MH  - Prognosis
MH  - Risk Factors
MH  - Severity of Illness Index
EDAT- 2018/06/28 06:00
MHDA- 2019/09/17 06:00
CRDT- 2018/06/28 06:00
PHST- 2018/02/09 00:00 [received]
PHST- 2018/05/09 00:00 [accepted]
PHST- 2018/06/28 06:00 [pubmed]
PHST- 2019/09/17 06:00 [medline]
PHST- 2018/06/28 06:00 [entrez]
AID - 5045549 [pii]
AID - 10.1093/europace/euy127 [doi]
PST - ppublish
SO  - Europace. 2018 Dec 1;20(12):2003-2013. doi: 10.1093/europace/euy127.