title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
abstract: BACKGROUND
  Potentially lethal and heritable cardiomyopathies and cardiac channelopathies are caused by heterogeneous autosomal dominant mutations in over 50 distinct genes, and multiple genes are responsible for a given disease. Clinical genetic tests are available for several of the inherited cardiac diseases and clinical investigations guide which test to order. This study describes a family with cardiac disease in which marked clinical diversity exists. In the absence of a unified clinical diagnosis, we used exome sequencing to identify a causal mutation.
  
  
  METHODS
  Clinical evaluation of family members was performed, including physical examination, electrocardiography, 2D transthoracic echocardiography and review of autopsy records. Exome sequencing was performed on a clinically affected individual and co-segregation studies and haplotype analysis were performed to further confirm pathogenicity.
  
  
  RESULTS
  Clinically affected members showed marked cardiac phenotype heterogeneity. While some individuals were asymptomatic, other presentations included left ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained death. Whole exome sequencing identified an Ala119Thr mutation in the alpha-actinin-2 (ACTN2) gene that segregated with disease. Haplotype analysis showed that this mutation segregated with an identical haplotype in a second, previously described family with clinically diverse cardiac disease, and is likely inherited from a common ancestor.
  
  
  CONCLUSIONS
  Mutations in the ACTN2 gene can be responsible for marked cardiac phenotype heterogeneity in families. The diverse mechanistic roles of ACTN2 in the cardiac Z-disc may explain this heterogeneous clinical presentation. Exome sequencing is a useful adjunct to cardiac genetic testing in families with mixed clinical presentations.
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, Sydney, NSW, 2042, Australia. r.bagnall@centenary.org.au.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia. r.bagnall@centenary.org.au.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, Sydney, NSW, 2042, Australia. l.molloy@centenary.org.au.|Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia. l.molloy@centenary.org.au.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Molloy
authors.affiliation: Department of Cardiology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia. Jon.Kalman@mh.org.au.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kalman
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, Sydney, NSW, 2042, Australia. c.semsarian@centenary.org.au.|Faculty of Medicine, University of Sydney, Sydney, NSW, Australia. c.semsarian@centenary.org.au.|Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. c.semsarian@centenary.org.au.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000185:Actinin / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution; D001315:Australia; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000473:pathology
chemical_list: C401401:ACTN2 protein, human; D000185:Actinin