A Paradigm Shift in Our Understanding of the Development of the Hypertrophic Cardiomyopathy Phenotype?

It has now been more than 2 decades since the seminal observation that hypertrophic cardiomyopathy (HCM) is caused by mutations encoding for the contractile proteins of the cardiac sarcomere.1 Over this relatively short period of time, our understanding of the molecular basis of this disease has grown enormously, including the identification now of >1400 individual mutations (in at least 11 different sarcomere genes) associated with HCM.2–8 This genetic heterogeneity is undoubtedly responsible for the diverse phenotypic expression and natural history observed within HCM.4,9,10 However, from a clinical perspective, perhaps the most important advance to have emerged from the current molecular era is automated DNA sequencing, which has led directly to the development of comprehensive genetic testing panels which identify mutations responsible for HCM.6–8Article see p 48 The powerful clinical application for genetic testing has provided the opportunity for family screening and diagnosis.6–8,11,12 If a disease-causing sarcomere mutation can be identified in the affected proband, relatives can then be genetically tested to determine whether they have the same mutation, and as a consequence whether they are at risk of developing disease. If such relatives do not carry the mutation there is virtually no future risk of developing HCM, and no further screening is necessary.5–8 This information can have a positive impact on HCM family members, lifting the substantial psychological burden often created by the possibility of transmitting a genetic heart disease, as well as the chance to eliminate the need for additional testing and the cost-burden associated with screening. However, it should be underscored that this strategy is predicated on the ability to identify a pathogenic mutation in the proband, a potential limitation because <50% of the time …