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Published on: August 8, 2022
Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy
Jodie Ingles1, Tanya Sarina, Laura Yeates
11] Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia [2] School of Medicine, University of Sydney, Sydney, Australia.
Insights
Family history significantly increases the likelihood of identifying genetic mutations in hypertrophic cardiomyopathy (HCM). This finding is crucial for genetic counseling and improving mutation detection rates in HCM patients.
Area of Science:
- Cardiovascular Genetics
- Genetic Diagnostics
- Hypertrophic Cardiomyopathy Research
Background:
- Genetic testing for hypertrophic cardiomyopathy (HCM) is available but faces challenges with low mutation detection rates and high costs.
- Identifying individuals with a higher probability of carrying a pathogenic mutation is essential for efficient genetic testing strategies.
Purpose of the Study:
- To identify clinical variables that predict the successful identification of pathogenic mutations in probands with hypertrophic cardiomyopathy (HCM).
- To enhance the diagnostic yield of genetic testing for HCM.
Main Methods:
- A 10-year retrospective study (2002-2011) of 265 unrelated probands meeting clinical diagnostic criteria for HCM across Australian cardiac genetic clinics.
- Collection of clinical, family history, and genotype data.
Main Results:
- A mutation detection rate of 52% was observed.
- Mutation detection was significantly higher in patients with a family history of HCM (72% vs. 29%) and sudden cardiac death (89% vs. 59%).
- Female gender, increased left-ventricular wall thickness, and family history of HCM or sudden cardiac death were associated with a higher chance of identifying a mutation.
Conclusions:
- Family history is a critical clinical predictor for positive genetic diagnoses in hypertrophic cardiomyopathy.
- These findings have direct clinical relevance for pretest genetic counseling and optimizing genetic testing strategies in HCM.
Purpose:
Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified.
Methods:
Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002-2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected.
Results:
A total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012).
Conclusion:
Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.
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