Hypertrophic Cardiomyopathy in the Era of Precision Medicine: Redefining Diagnosis, Therapeutics and Risk
TL;DR
Findings reinforce the concept of HCM as a spectrum of diseases rather than a single genetic entity, setting the stage for more individualised approaches to diagnosis, counselling and management.
Abstract
clinical monitoring. Patients with sarcomeric variants generally have worse prognosis than those without, including earlier disease onset and higher rates of sudden cardiac death, heart failure and arrhythmias. 3 Historically, HCM was regarded as a monogenic disorder caused by pathogenic variants in sarcomeric genes. While MYH7 and MYBPC3 continue to account for the majority of genetically confirmed cases, contemporary research has revealed a more complex and heterogeneous genetic architecture. Recent gene re-evaluations and variant reclassifications have highlighted the role of non-sarcomeric genes, including FHOD3 , ALPK3 , CSRP3 and TRIM63 , as contributors to HCM phenotypes. 3 Common genetic variants play a substantial role in HCM susceptibility and disease expression, with genome-wide association studies identifying 70 susceptibility loci associated with HCM risk. Polygenic risk scores derived from these common variants significantly modify disease penetrance, severity and outcomes, particularly in pathogenic variant carriers where penetrance differs. 3 These findings have important implications for clinical practice; they reinforce the concept of HCM as a spectrum of diseases rather than a single genetic entity, setting the stage for more individualised approaches to diagnosis, counselling and management.