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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic
J Martijn Bos1, Melissa L Will1, Bernard J Gersh2
1Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
Insights
Genetic testing for hypertrophic cardiomyopathy (HCM) identified mutations in 34% of patients. A new clinical score helps predict the likelihood of finding these HCM genetic mutations.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Epidemiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disease.
- Accurate genetic diagnosis is crucial for risk stratification and family screening.
- Previous studies have explored genotype-phenotype correlations in smaller HCM cohorts.
Purpose of the Study:
- To determine the prevalence and spectrum of mutations in the largest hypertrophic cardiomyopathy (HCM) cohort.
- To establish genotype-phenotype relationships in HCM.
- To develop a clinically applicable score for predicting positive HCM genetic test results.
Main Methods:
- Conducted genetic testing for 9 HCM-associated myofilament genes in 1053 unrelated HCM patients.
- Phenotyping was performed through comprehensive review of electronic medical records.
- Statistical analyses identified clinical and echocardiographic predictors of positive genetic test results.
Main Results:
- Overall, 34% of patients (359/1053) had a positive genetic test result for HCM mutations.
- Key predictors of positive genetic testing included specific echocardiographic patterns, younger age at diagnosis, increased left ventricular wall thickness, and family history.
- A phenotype-derived score accurately predicted the probability of mutation-positive HCM, ranging from 6% to 80%.
Conclusions:
- The largest HCM cohort to date shows a 34% yield for genetic testing.
- Simple clinical and echocardiographic markers effectively predict the likelihood of mutation-positive HCM.
- The Mayo HCM Genotype Predictor score offers a valuable tool for genetic counseling and guiding genetic testing decisions.
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 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.
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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