Special subsets of electrocardiographically defined patients: Left bundle branch block, right bundle branch block, and atrial fibrillation

Hypertrophic cardiomyopathy (HCM) is the most common monogenic disease of the myocardium, with a 1:500 prevalence in the general population worldwide, although often misdiagnosed or neglected. HCM is defined by the presence of increased left ventricular (LV) wall thickness ≥15 mm by any imaging modality in one or more LV myocardial segments that is not solely explained by abnormal loading conditions and occurs in the absence of other detectable causes. A lower threshold for LV thickness (i.e., ≥13 mm) is adopted in first-degree relatives of patients with unequivocal disease. Clinical diagnosis is customarily made with two-dimensional echocardiography by detection of increased LV wall thickness, usually in the presence of a small LV cavity, after suspicion has been raised by the clinical profile or as a part of screening. In most patients, HCM is caused by mutations in genes encoding contractile proteins of the cardiac sarcomere, Z-disk, and intracellular calcium handling pathways. A minority of cases are caused by inherited metabolic and neuromuscular diseases, which are most common in pediatric cohorts, or so-called phenocopies such as amyloidosis or Fabry disease. In over one-third of patients, however, the genetic basis of the disease remains unresolved. To date, hundreds of different mutations have been associated with HCM (>90 % affecting myosin-binding protein C, beta-myosin heavy chain, and troponin T), and many families exhibit “private” mutations which have not been previously described. Adding to the genetic complexity of the disease is the fact that many of these variants, suspected to cause disease, do not meet the requirements for pathogenicity and are necessarily classified as “variants of unknown significance” (VUS). Despite over two decades of research in the field, attempts to correlate genotype with phenotype, disease severity, and outcome have yielded inconsistent and overall disappointing results, although some clinically relevant associations have been observed.