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

Sharie B. Parks, Jessica Kushner, Deirdre Nauman, Donna Burgess, Susan Ludwigsen, Amanda Peterson, Duanxiang Li, Petra Jakobs, Michael Litt, Charles B. Porter, Peter S. Rahko, Ray E. Hershberger

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)161-169
Number of pages9
JournalAmerican Heart Journal
Volume156
Issue number1
DOIs
StatePublished - Jul 2008

Fingerprint

Lamin Type A
Dilated Cardiomyopathy
Mutation
Proteins
Molecular Pathology
Mutation Rate
Pedigree
Familial dilated cardiomyopathy
Nucleotides
Observation
DNA
Research
Genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Parks, S. B., Kushner, J., Nauman, D., Burgess, D., Ludwigsen, S., Peterson, A., ... Hershberger, R. E. (2008). Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. American Heart Journal, 156(1), 161-169. https://doi.org/10.1016/j.ahj.2008.01.026

Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. / Parks, Sharie B.; Kushner, Jessica; Nauman, Deirdre; Burgess, Donna; Ludwigsen, Susan; Peterson, Amanda; Li, Duanxiang; Jakobs, Petra; Litt, Michael; Porter, Charles B.; Rahko, Peter S.; Hershberger, Ray E.

In: American Heart Journal, Vol. 156, No. 1, 07.2008, p. 161-169.

Research output: Contribution to journalArticle

Parks, SB, Kushner, J, Nauman, D, Burgess, D, Ludwigsen, S, Peterson, A, Li, D, Jakobs, P, Litt, M, Porter, CB, Rahko, PS & Hershberger, RE 2008, 'Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy', American Heart Journal, vol. 156, no. 1, pp. 161-169. https://doi.org/10.1016/j.ahj.2008.01.026
Parks, Sharie B. ; Kushner, Jessica ; Nauman, Deirdre ; Burgess, Donna ; Ludwigsen, Susan ; Peterson, Amanda ; Li, Duanxiang ; Jakobs, Petra ; Litt, Michael ; Porter, Charles B. ; Rahko, Peter S. ; Hershberger, Ray E. / Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. In: American Heart Journal. 2008 ; Vol. 156, No. 1. pp. 161-169.
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abstract = "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.",
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AU - Kushner, Jessica

AU - Nauman, Deirdre

AU - Burgess, Donna

AU - Ludwigsen, Susan

AU - Peterson, Amanda

AU - Li, Duanxiang

AU - Jakobs, Petra

AU - Litt, Michael

AU - Porter, Charles B.

AU - Rahko, Peter S.

AU - Hershberger, Ray E.

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N2 - 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.

AB - 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.

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