Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.
OBJECTIVE
We examined the prevalence, genotype-phenotype correlation, and natural history of lamin A/C gene (LMNA) mutations in subjects with dilated cardiomyopathy (DCM).


BACKGROUND
Mutations in LMNA have been found in patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis, and clinical relevance of laminopathies in DCM are unknown.


BACKGROUND
A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNA using denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNA mutation carrier status and Kaplan-Meier survival analysis were performed.


RESULTS
Mutations in LMNA were detected in four families (8%), three with familial (R89L, 959delT, R377H) and one with sporadic DCM (S573L). There was significant phenotypic variability, but the presence of skeletal muscle involvement (p < 0.001), supraventricular arrhythmia (p = 0.003), conduction defects (p = 0.01), and "mildly" DCM (p = 0.006) were predictors of LMNA mutations. The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers.


CONCLUSIONS
Mutations in LMNA cause a severe and progressive DCM in a relevant proportion of patients. Mutation screening should be considered in patients with DCM, in particular when clinical predictors of LMNA mutation are present, regardless of family history.
Taylor
Matthew R G
MR
University of Colorado Cardiovascular Institute, Denver, Colorado 80010, USA.
Fain
Pamela R
PR
Sinagra
Gianfranco
G
Robinson
Misi L
ML
Robertson
Alastair D
AD
Carniel
Elisa
E
Di Lenarda
Andrea
A
Bohlmeyer
Teresa J
TJ
Ferguson
Debra A
DA
Brodsky
Gary L
GL
Boucek
Mark M
MM
Lascor
Jean
J
Moss
Andrew C
AC
Li
Wai Lun P
WL
Stetler
Gary L
GL
Muntoni
Francesco
F
Bristow
Michael R
MR
Mestroni
Luisa
L
D000595:Amino Acid Sequence; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D034881:Nuclear Lamina / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011336:Probability; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D015996:Survival Rate