Clinical Investigation
Genetics
Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy

https://doi.org/10.1016/j.ahj.2008.01.026Get rights and content

Background

Lamin A/C mutations are a well-established cause of dilated cardiomyopathy (DCM), although their frequency has not been examined in a large cohort of patients. We sought to examine the frequency of mutations in LMNA, the gene encoding lamin A/C, in patients with idiopathic (IDC) or familial dilated cardiomyopathy (FDC).

Methods

Clinical cardiovascular data, family histories, and blood samples were collected from 324 unrelated IDC probands, of whom 187 had FDC. DNA samples were sequenced for nucleotide alterations in LMNA. Likely protein-altering mutations were followed up by evaluating additional family members, when possible.

Results

We identified 18 protein-altering LMNA variants in 19 probands or 5.9% of all cases (7.5% of FDC; 3.6% of IDC). Of the 18 alterations, 11 were missense (one present in 2 kindreds), 3 were nonsense, 3 were insertion/deletions, and 1 was a splice site alteration. Conduction system disease and DCM were common in carriers of LMNA variants. Unexpectedly, in 6 of the 19 kindreds with a protein-altering LMNA variant (32%), at least one affected family member was negative for the LMNA variant.

Conclusions

Lamin A/C variants were observed with a frequency of 5.9% in probands with DCM. The novel observation of FDC pedigrees in which not all affected individuals carry the putative disease-causing LMNA mutation suggests that some protein-altering LMNA variants are not causative or that some proportion of FDC may be because of multiple causative factors. These findings warrant increased caution in FDC research and molecular diagnostics.

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)

  • H. Morita et al.

    Genetic causes of human heart failure

    J Clin Invest

    (2005)
  • D. Fatkin et al.

    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

    (1999)
  • G. Brodsky et al.

    Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement

    Circ

    (2000)
  • Cited by (0)

    This work was supported by National Institutes of Health awards RO1- HL58626 (Dr Hershberger) and 5 M01 RR000334.

    View full text