High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics.
BACKGROUND
Among the most frequently encountered mutations in dilated cardiomyopathy (DCM) are those in the lamin A/C (LMNA) gene. Our goal was to analyze the LMNA gene in patients with DCM and/or conduction disease referred to the cardiogenetics outpatient clinic and to evaluate the prevalence of LMNA mutations and their clinical expression.


RESULTS
The LMNA gene was screened in 61 index patients. Eleven mutations (including 6 novel) were identified, mainly in the subgroup of familial DCM with cardiac conduction disease (3/10 index patients) and in patients with DCM and Emery-Dreifuss, Limb-Girdle, or unclassified forms of muscular dystrophy (7/8 index patients). In addition, a mutation was identified in 1 of 4 families with only cardiac conduction disease. We did not identify any large deletions or duplications. Genotype-phenotype relationships revealed a high rate of sudden death and cardiac transplants in carriers of the p.N195K mutation. Our study confirmed that the p.R225X mutation leads to cardiac conduction disease with late or no development of DCM, underscoring the importance of this mutation in putative familial "lone conduction disease." Nearly one third of LMNA mutation carriers had experienced a thromboembolic event.


CONCLUSIONS
This study highlights the role of LMNA mutations in DCM and related disorders. A severe phenotype in p.N195K mutation carriers and preferential cardiac conduction disease in p.R225X carriers was encountered. Because of the clinical variability, including the development of associated symptoms in time, LMNA screening should be considered in patients with DCM or familial lone conduction disease.
van Tintelen
J Peter
JP
Department of Genetics, University Medical Center Groningen, University of Groningen, The Netherlands. p.van.tintelen@medgen.umcg.nl
Hofstra
Robert M W
RM
Katerberg
Hilga
H
Rossenbacker
Tom
T
Wiesfeld
Ans C P
AC
du Marchie Sarvaas
Gideon J
GJ
Wilde
Arthur A M
AA
van Langen
Irene M
IM
Nannenberg
Eline A
EA
van der Kooi
Anneke J
AJ
Kraak
Marian
M
van Gelder
Isabelle C
IC
van Veldhuisen
Dirk Jan
DJ
Vos
Yvonne
Y
van den Berg
Maarten P
MP
D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
D034904:Lamin Type A