title: Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.
abstract: OBJECTIVE
  This study describes a genome-wide linkage analysis of a large family with clinically heterogeneous hypertrophic cardiomyopathy (HCM).
  
  
  BACKGROUND
  Familial HCM is a disorder characterized by genetic heterogeneity. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that other genes may be involved.
  
  
  METHODS
  Clinical evaluation, including clinical history, physical examination, electrocardiography, and 2-dimensional echocardiography, was performed, and blood was collected from family members (n = 23) for deoxyribonucleic acid analysis. The family was genotyped with markers from the 10-cM AB PRISM Human Linkage mapping set (Applied Biosystems, Foster City, California), and 2-point linkage analysis was performed.
  
  
  RESULTS
  Affected family members showed marked clinical diversity, ranging from asymptomatic individuals to those with syncope, heart failure, and premature sudden death. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the marker D1S2850 (logarithm of odds ratio = 2.82, theta = 0). A missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified that segregated with disease in the family. An additional 297 HCM probands were screened for mutations in the ACTN2 gene using high-resolution melt analysis. Three causative ACTN2 mutations, Thr495Met, Glu583Ala, and Glu628Gly, were identified in an additional 4 families (total 1.7%) with HCM.
  
  
  CONCLUSIONS
  This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disk proteins account for a small but significant proportion of genotyped HCM families.
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Chiu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.forename: Jodie
authors.initials: J
authors.lastname: Ingles
authors.forename: Laura
authors.initials: L
authors.lastname: Yeates
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Donald
authors.forename: Mika
authors.initials: M
authors.lastname: Jormakka
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Lind
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000185:Actinin / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics*; D002648:Child; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D014463:Ultrasonography
chemical_list: C401401:ACTN2 protein, human; D000185:Actinin