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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and
Susan Christian1, Allison Cirino2,3, Brittany Hansen4
1Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada smc12@ualberta.ca.
Insights
Genetic testing for hypertrophic cardiomyopathy (HCM) is effective, with higher detection rates in children and adults with a family history. Genotype-positive individuals experience earlier onset and higher disease penetrance.
Area of Science:
- Cardiovascular Genetics
- Genetic Medicine
- Molecular Cardiology
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disease.
- Genetic testing plays a crucial role in diagnosing HCM and identifying at-risk relatives.
Purpose of the Study:
- To systematically review and quantify the diagnostic validity and clinical utility of genetic testing for HCM.
- To assess detection rates, genotype-phenotype correlations, and disease penetrance in HCM patients and families.
Main Methods:
- A comprehensive systematic search of major biomedical databases (PubMed, Embase, CINAHL, Cochrane) was conducted.
- Included studies were assessed for quality using the Newcastle-Ottawa tool, with prespecified subgroup and sensitivity analyses.
Main Results:
- Genetic testing detected pathogenic variants in 56% of pediatric and 42% of adult HCM cases; detection was higher in adults with a family history (59%).
- Improved variant interpretation standards reduced adult detection rates, highlighting the importance of classification methods.
- Genotype-positive individuals exhibited earlier age-of-onset and higher disease penetrance (62% overall in adults).
Conclusions:
- This systematic review provides a collective quantification of genetic testing utility in HCM, addressing key clinical questions.
- Findings highlight significant differences in detection rates and penetrance based on age, family history, and variant classification.
- The study identifies critical areas for future research in HCM genetics and clinical management.
Objective:
This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.
Methods:
A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool.
Results:
A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003).
Conclusions:
This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.
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