Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy

J. Martijn Bos, Melissa L. Will, Bernard J. Gersh, Teresa M. Kruisselbrink, Steve R. Ommen, Michael John Ackerman

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Objectives: 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. Patients and 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 20mmor greater, a family history ofHCM, 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)727-737
Number of pages11
JournalMayo Clinic Proceedings
Volume89
Issue number6
DOIs
StatePublished - 2014

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Hypertrophic Cardiomyopathy
Phenotype
Genetic Testing
Genotype
Mutation
Hypertension
Myofibrils
Electronic Health Records
Sudden Cardiac Death
Genetic Counseling
Genes
Multivariate Analysis
Biomarkers

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. / Bos, J. Martijn; Will, Melissa L.; Gersh, Bernard J.; Kruisselbrink, Teresa M.; Ommen, Steve R.; Ackerman, Michael John.

In: Mayo Clinic Proceedings, Vol. 89, No. 6, 2014, p. 727-737.

Research output: Contribution to journalArticle

Bos, J. Martijn ; Will, Melissa L. ; Gersh, Bernard J. ; Kruisselbrink, Teresa M. ; Ommen, Steve R. ; Ackerman, Michael John. / Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. In: Mayo Clinic Proceedings. 2014 ; Vol. 89, No. 6. pp. 727-737.
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abstract = "Objectives: 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. Patients and 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 20mmor greater, a family history ofHCM, 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. Conclusion: 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.",
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AU - Ommen, Steve R.

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N2 - Objectives: 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. Patients and 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 20mmor greater, a family history ofHCM, 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. Conclusion: 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.

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