title: Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  To determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result.
  
  
  METHODS
  Between April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4 ± 19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records.
  
  
  RESULTS
  Overall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present.
  
  
  CONCLUSIONS
  In this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Will
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
authors.affiliation: Division of Laboratory Genetics, Mayo Clinic, Rochester, MN.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Kruisselbrink
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN. Electronic address: ackerman.michael@mayo.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000328:Adult; D000367:Age Factors; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D004452:Echocardiography; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D009210:Myofibrils / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D012372:ROC Curve; D012518:Sarcomeres / Q000235:genetics
chemical_list: D005819:Genetic Markers