Mutations in HCM are almost exclusively located in genes encoding sarcomeric proteins. The sarcomere represents the basal contractile unit of striated muscles, such as cardiac muscle, and is made up of thick and thin filaments. During contraction, the thin filaments slide past the thick filaments, shortening the sarcomere. In about 50–60 % of patients, a disease-causing (pathogenic) mutation can be detected [4, 7]. Main disease genes are myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) (Table 59.1) [4, 7–9]. Many countries or populations have specific so-called founder mutations. These mutations derive from a common ancestor and often comprise a large part of the detected mutations in that country or population.

No clear genotype-phenotype correlations are present in HCM, although older literature suggests this. Some correlations can be found in large cohorts; however, they cannot be used for prognosis or therapeutic options in the individual patient.

In contrast to HCM, mutations in DCM patients are found in a minority of cases and are often unique for the family. The recent discovery of the titin gene (TTN), the largest gene in the human genome in which mutations can be found in about 25 % of patients, has changed the mutation detection rate enormously [10]. Titin is highly expressed in the heart, where it regulates sarcomere contraction and signaling. Despite the fact that many variants in this gene are found, it is uncertain whether or not variants in TTN are pathogenic. This is partly because TTN missense variants are very common with 23 on average per individual in the Exome Variant Server database and because truncation variants are frequently also found in healthy control populations [11]. Other genes responsible for DCM encode proteins of the sarcomere, the nuclear envelope, the cytoskeleton, ion channels, desmosomes, and proteins involved in calcium homeostasis.

Genotype-phenotype correlations are present in DCM. DCM patients with a mutation in the LMNA (lamin A/C) gene almost all have conduction disease and are at higher risk of developing arrhythmic and thromboembolic events [12, 13]. Mutations in phospholamban (PLN) are associated with a higher risk of ventricular arrhythmias and severe heart failure [14].

Currently eight genes have been identified responsible for 60–65 % of all ARVC cases; five genes encode for components of the cardiac desmosome (plakoglobin (JUP), desmoplakin (DSP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2)) and three non-desmosomal proteins (transmembrane protein 43 (TMEM43), lamin A/C (LMNA), and PLN) (Table 59.1). The most frequently mutated gene is PKP2, with a detection rate up to of 40 % [15–18].