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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Evolution of genetic testing and gene therapy in hypertrophic cardiomyopathy
Katherine Chiswell1, Louisa Zaininger2, Christopher Semsarian3
1Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
Insights
Genetic testing for hypertrophic cardiomyopathy (HCM) improves diagnosis and family screening. Future gene therapies aim to cure this genetic heart disorder.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disorder.
- Disease-causing variants in sarcomere protein genes, notably MYBPC3 and MYH7, are responsible for 70-80% of HCM cases.
- Genetic insights have advanced precision medicine for HCM diagnosis and management.
Purpose of the Study:
- To review the current role of genetic testing in hypertrophic cardiomyopathy (HCM).
- To introduce novel mechanistic insights and potential gene therapy approaches for HCM.
- To highlight the impact of genetic discoveries on HCM diagnosis, prognosis, and treatment.
Main Methods:
- Review of studies on the genetic basis of HCM over the past 30 years.
- Analysis of the role of genetic testing in diagnosis, cascade testing, and reproductive decisions.
- Exploration of emerging genetic mechanisms and future gene therapy strategies.
Main Results:
- Genetic testing enables precise diagnosis and risk stratification in HCM patients.
- Identification of MYBPC3 and MYH7 variants as major contributors to HCM.
- Advances include understanding non-Mendelian and non-familial forms, and polygenic risk scores.
Conclusions:
- Genetic testing is crucial for personalized HCM management and family screening.
- Emerging genetic insights pave the way for innovative gene therapies, including gene replacement and editing.
- Future research focuses on curative approaches for hypertrophic cardiomyopathy through genetic interventions.
Abstract:
Studies over the last 30 years have identified hypertrophic cardiomyopathy (HCM) as predominantly an autosomal dominant disorder caused by disease-causing variants in genes encoding the sarcomere proteins critical for contractile function. The two most common disease genes implicated are the MYBPC3 and MYH7 genes, with disease-causing variants in these two genes accounting for 70-80% of all genotype-positive HCM patients. This increased knowledge of the genetic basis of HCM has heralded the era of precision medicine, with genetic testing leading to more improved and precise diagnosis, effective cascade genetic testing in at-risk family members, assistance with reproductive decisions, targeted therapeutics guided by both phenotype and genotype, and providing important insights into risk stratification and prognosis. Most recently, novel insights into genetic mechanisms have been elucidated, spanning non-Mendelian aetiologies, non-familial forms of HCM, and development of polygenic risk scores. These advances have laid the platform for exciting future endeavours such as newer gene therapy approaches in HCM, including gene replacement studies and genome editing approaches to ultimately cure disease. This brief review summarises the current role of genetic testing in HCM patients and families, and introduces some new mechanistic insights leading to the consideration of gene therapy approaches for HCM.
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