Genetics in Hypertrophic Cardiomyopathy: An Evolving Clinical Landscape.

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is characterised by unexplained increased wall thickness. Traditionally considered a monogenic disorder, emerging evidence highlights its complex genetic architecture. Genetic testing is now a cornerstone for diagnosis and family screening, although its prognostic and therapeutic impact at the individual level remains limited at present but is expected to grow as more comprehensive approaches are developed. Aimed at general cardiologists, this review summarises the benefits and limitations of current knowledge and genetic testing in HCM, and offers practical guidance on patient selection, interpretation of results, and integration into routine care. In this context, the challenge posed by variants of uncertain significance is discussed, and current and emerging strategies for their re-interpretation are outlined in brief. An updated overview is also provided of the genetic landscape, covering sarcomeric and non-sarcomeric genes, HCM phenocopies and new inheritance models, including oligogenic and polygenic mechanisms. Additionally, the potential of expanded genetic panels incorporating novel candidate genes and deep intronic and structural variants is highlighted. As gene therapy emerges as a future therapeutic option, precise molecular diagnosis will be essential for integrating genetic insights into routine clinical practice and advancing personalised care in HCM.