title: Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors.
abstract: BACKGROUND
  Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed.
  
  
  OBJECTIVE
  The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors.
  
  
  METHODS
  Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified.
  
  
  RESULTS
  Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, and 57 years) who experienced sudden cardiac arrest but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and 1 died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited 1 mutation independently from each of his parents with HCM)-that is, double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations-as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event.
  
  
  CONCLUSIONS
  These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, thereby predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors.
authors.affiliation: Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota 55407, USA. hcm.maron@mhif.org
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maron
authors.forename: Martin S
authors.initials: MS
authors.lastname: Maron
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018570:Risk Assessment; D012307:Risk Factors; D012518:Sarcomeres / Q000235:genetics*; D055815:Young Adult