Clinical InvestigationGeneticsLamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy
Section snippets
Patient population
Informed consent was obtained from all subjects for this institutional review board–approved project. The study included 324 unrelated IDC probands and used methods of clinical categorization previously described.10 For this study, families with confirmed and probable familial disease10 were classified as FDC; those with a negative family history or possible FDC10 were classified as IDC. In FDC cases, the patient and at least one first- or second-degree relative had confirmed IDC, defined as
Molecular analysis of the FDC cohort
The entire coding region of LMNA (Figure 1) was sequenced in 324 unrelated IDC probands (187 with FDC). We identified 18 (3 previously published by our group6, 7) protein-altering variants in 19 (5.9%) of the 324 subjects (Table I), all of whom were white. Fourteen of 187 FDC probands carried an LMNA variant (7.5%) compared to 5 of 137 IDC cases (3.6%). There were 11 missense (one identified twice), 3 nonsense, 2 insertion, 1 splice site, and 1 deletion variant (Table I). Seventeen variants in
Discussion
In 324 unrelated patients with IDC or FDC, we identified 19 with protein-altering LMNA nucleotide variants (5.9%) of which 3 were previously published by our group.6, 7 We were interested in the relative risk of lamin A/C cardiomyopathy in patients with FDC versus those with apparent nonfamilial IDC. Notably, 14 (7.5%) of 187 FDC probands carried LMNA mutations compared to 5 (3.6%) of 137 IDC cases. In addition to dilated cardiomyopathy, 18 (95%) of the 19 probands also had conduction system
Conclusion
The incidence of LMNA mutations in FDC is approximately 7.5% compared to 3.6% in IDC. This is the first description of FDC pedigrees in which apparently pathogenic LMNA mutations are identified but which do not account for all cases of IDC in the family, suggesting that more than one factor may be responsible for FDC in some kindreds. Collectively, these findings suggest a more complex basis of genetic dilated cardiomyopathy than previously appreciated. We urge caution in the interpretation of
References (27)
- et al.
Clinical and genetic issues in familial dilated cardiomyopathy
J Am Coll Cardiol
(2005) - et al.
Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease
J Card Fail
(2001) - et al.
A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation
Am Heart J
(2002) - et al.
Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect–related disease
J Am Coll Cardiol
(2002) - et al.
Clinical characteristics of 304 kindreds evaluated for familial dilated cardiomyopathy
J Cardiac Failure
(2006) - et al.
Natural history of dilated cardiomyopathy due to lamin A/C gene mutations
J Am Coll Cardiol
(2003) - et al.
High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics
Am Heart J
(2007) Genomic sequence, splicing, and gene annotation
Am J Hum Genet
(2000)- et al.
Molecular and cellular mechanisms of cardiac arrhythmias
Cell
(2001) - et al.
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy
J Am Coll Cardiol
(2004)
Genetic causes of human heart failure
J Clin Invest
Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease
N Engl J Med
Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement
Circ
Cited by (191)
Mapping and Ablation of Ventricular Tachycardia in Inherited Left Ventricular Cardiomyopathies
2024, JACC: Clinical ElectrophysiologyLMNA Cardiomyopathy: Important Considerations for the Heart Failure Clinician
2023, Journal of Cardiac FailureThe Genetic Evaluation of Dilated Cardiomyopathy
2023, Structural HeartEmerging Targeted Therapies for Inherited Cardiomyopathies and Arrhythmias
2023, Cardiac Electrophysiology ClinicsGenetic Abnormalities of the Sinoatrial Node and Atrioventricular Conduction
2023, Cardiology ClinicsFirst human implant of the cardiac contractility modulation in patient with dilated cardiomyopathy–related laminopathy
2023, HeartRhythm Case Reports
This work was supported by National Institutes of Health awards RO1- HL58626 (Dr Hershberger) and 5 M01 RR000334.