title: Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy.
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.
authors.affiliation: Division of Cardiovascular Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Sharie B
authors.initials: SB
authors.lastname: Parks
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kushner
authors.forename: Deirdre
authors.initials: D
authors.lastname: Nauman
authors.forename: Donna
authors.initials: D
authors.lastname: Burgess
authors.forename: Susan
authors.initials: S
authors.lastname: Ludwigsen
authors.forename: Amanda
authors.initials: A
authors.lastname: Peterson
authors.forename: Duanxiang
authors.initials: D
authors.lastname: Li
authors.forename: Petra
authors.initials: P
authors.lastname: Jakobs
authors.forename: Michael
authors.initials: M
authors.lastname: Litt
authors.forename: Charles B
authors.initials: CB
authors.lastname: Porter
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rahko
authors.forename: Ray E
authors.initials: RE
authors.lastname: Hershberger
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D034881:Nuclear Lamina / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D034904:Lamin Type A