Genetic and phenotypic analysis of dilated cardiomyopathy with conduction system disease: demand for strategies in the management of presymptomatic lamin A/C mutant carriers.
BACKGROUND
One-third of cases of dilated cardiomyopathy (DCM) is of familial aetiology. Several genes have been reported to cause the autosomal dominant form of DCM.


OBJECTIVE
To analyze the lamin A/C gene (LMNA) in 31 unrelated patients with DCM and conduction system disease (CSD).


METHODS
Patients and family members underwent physical examination, ECG/Holter-ECG, echocardiography, and selective coronary angiography. Genetic analysis of all coding exons of LMNA was performed using PCR and sequencing.


RESULTS
Three different LMNA mutations (Arg377His, c.1397delA, c.424_425ins21nt) were identified in three families with autosomal dominant disease comprised of 39 individuals. 21 individuals were mutation carriers, of whom 12 were symptomatic. We observed a progressive and age-dependent form of DCM with CSD and arrhythmias. First, the patients developed a moderate left ventricular dilatation without symptoms. Later, systolic function declined progressively and the patients became symptomatic resulting in a high mortality due to sudden death and heart failure.


CONCLUSIONS
Genetic screening leads to the identification of symptomatic and asymptomatic mutant carriers. The latter at a young age should be regarded as "presymptomatic" because of the age-dependent disease manifestation. New guidelines are required for the management of these individuals.
Perrot
Andreas
A
Charité- Universitätsmedizin Berlin/Kardiologie am Campus Buch and Virchow-Klinikum, und Max-Delbrück-Centrum für Molekulare Medizin, Wiltbergstr. 50, 13125 Berlin, Germany. perrot@kvk-berlin.de
Sigusch
Holger H
HH
Nägele
Herbert
H
Genschel
Janine
J
Lehmkuhl
Hans
H
Hetzer
Roland
R
Geier
Christian
C
Leon Perez
Veronica
V
Reinhard
Dirk
D
Dietz
Rainer
R
Josef Osterziel
Karl
K
Schmidt
Hartmut H-J
HH
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D002648:Child; D018450:Disease Progression; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017433:Protein Structure, Secondary; D017422:Sequence Analysis, DNA
C494847:LMNA protein, human; D034904:Lamin Type A