Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, characterized by unexplained left ventricular hypertrophy.
• Traditionally viewed as monogenic, HCM exhibits a complex genetic architecture with emerging evidence.
• Genetic testing is crucial for diagnosis and family screening, though its prognostic and therapeutic utility is evolving.

Purpose of the Study:

• To review the benefits and limitations of current genetic knowledge and testing in HCM for general cardiologists.
• To provide practical guidance on patient selection, result interpretation, and integrating genetic testing into clinical practice.
• To discuss challenges with variants of uncertain significance and outline re-interpretation strategies.

Main Methods:

• Review of current literature on hypertrophic cardiomyopathy genetics.
• Analysis of genetic testing approaches, including expanded panels and novel variant detection.
• Discussion of evolving genetic landscape, including non-sarcomeric genes and complex inheritance patterns.

Main Results:

• HCM genetics are complex, involving sarcomeric and non-sarcomeric genes, phenocopies, and oligogenic/polygenic models.
• Challenges exist in interpreting variants of uncertain significance, with ongoing re-interpretation strategies.
• Expanded genetic panels offer potential for identifying novel candidate genes and structural variants.

Conclusions:

• Precise molecular diagnosis through advanced genetic testing is essential for personalized care in HCM.
• Gene therapy holds future therapeutic promise, contingent on accurate genetic insights.
• Integrating genetic findings into routine clinical practice will advance personalized medicine for HCM patients.