title: Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Mutations in the gene that encode cardiac troponin T (cTnT) account for approximately 15% of cases of familial hypertrophic cardiomyopathy (HCM). These mutations are associated with a particularly severe form of HCM characterized by a high incidence of sudden death and a poor overall prognosis, despite subclinical or mild left ventricular hypertrophy.
  
  
  RESULTS
  We evaluated a family with HCM and multiple occurrences of sudden death in children. DNA samples were isolated from peripheral blood or paraffin-embedded tissue, and all protein-encoding exons of the cTnT gene were sequenced. A mutation was identified in exon 11 and is predicted to substitute a phenylalanine-for-serine mutation at residue 179 (Ser(179)Phe) in cTnT. Both parents and 3 of 4 surviving and clinically unaffected children were heterozygous for this mutation; another clinically unaffected child did not carry the mutation. Genetic analysis of DNA from a child who died suddenly at age 17 years demonstrated he was homozygous for this mutation. A review of his echocardiogram revealed profound left and right ventricular hypertrophy.
  
  
  CONCLUSIONS
  An homozygous Ser(179)Phe mutation in cTnT causes a severe form of HCM characterized by striking morphological abnormalities and juvenile lethality. In contrast, the natural history of the heterozygous mutation is benign. These studies emphasize the relevance of genetic diagnosis in hypertrophic cardiomyopathy and provide a new perspective on the clinical consequences of troponin T mutations.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: C Y
authors.initials: CY
authors.lastname: Ho
authors.forename: H M
authors.initials: HM
authors.lastname: Lever
authors.forename: R
authors.initials: R
authors.lastname: DeSanctis
authors.forename: C F
authors.initials: CF
authors.lastname: Farver
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D005260:Female; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D020107:Troponin T / Q000235:genetics*
chemical_list: D020107:Troponin T