Familial forms of arrhythmias were described carefully several decades ago [e.g., 1–6] and were essential to elucidate the genetic basis of arrhythmias. These clinical observations are still important today, since in the era of human molecular genetics, these disorders have been subject to systematic gene investigations and identification. The rapid technological improvements of molecular genetic approaches – currently as whole-exome sequencing by NGS – and the detailed knowledge of the human genome [7, 8] have replaced genetic linkage and many candidate gene analyses (see Chap. 18). NGS certainly will speed up gene identification [9–13], as, for example, has been shown for familial forms of ventricular fibrillation due to a CALM1 gene mutation [14].

In the following sections, selected types of familial arrhythmias and their genetic bases are discussed. Two international consensus documents are available as guidelines for diagnosis and indications for genetic testing [15, 16].

LQTS is characterized by prolongation of the QT interval, typically measured in a baseline 12-lead or exercise ECG (recommended speed, 50 mm/s). These values have to be corrected for heart rate (by using Bazett’s formula to drive the corrected QTc value). A QTc of >450 ms (males) or >460 ms (females) is indicative for a LQTS but there is overlap with the normal population. The presence of interventricular conduction delay such as complete right or left bundle branch block may limit the use of the QT interval. The QT interval also can be affected by many drugs. In contrast to congenital LQTS, drug-induced QT prolongation (“acquired LQTS”) is often not genetic, and only in 10–15 % of case can the drug be considered to have unmasked “hidden LQTS” [17]. For many physicians, recognition of LQTS and accurate QT interval measurements are still difficult [18]. Due to cascade family investigations and systematic genetic testing, it now has become clear that there are many LQTS mutation carriers without symptoms [19]. These asymptomatic but LQTS mutation-positive patients still have congenital LQTS, even though the term “syndrome” might be misleading. The overall risk for cardiac events or arrest might be lower and mainly is determined by the degree of QT interval prolongation and exposure to risk or event-triggering factors [20, 21].

Since 1995, 13 genes have been associated with congenital LQTS. A significant portion of mutations (sensitivity approx. 35 %) can be identified in the KCNQ1 gene (subform LQT1; chromosome 11p15.5) encoding the α-subunit of the slowly activating, delayed outward rectifying K+ channel I_Ks (Kv7.1). These subunits form together with additional ß-subunits (e.g., KCNE1; LQT5) tetrameric channels. Mutations in KCNQ1 mainly result in decreased potassium outward current (“loss of function”). In addition to digenic inheritance [in 3–5 %, 22], other severe forms are the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS) with additional severe, bilateral sensorineural hearing loss. The second key gene for LQTS is the KCNH2 gene on chromosome 7q36.1 that encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel I_Kr (Kv11.1; human ether-a-go-go-related gene (hERG)) and plays an essential role in the final repolarization of the ventricular action potential as well as in drug-induced proarrhythmia [23]. “Loss-of-function” mutations in KCNH2 (sensitivity, 30 %) lead to LQT2, whereas opposite effects by a “gain of function” shorten the QT interval (so-called short QT syndrome, SQT1). Another LQTS subform, LQT3, is related to cardiac sodium channel defects by SCN5A gene (chromosome 3p22.2) mutations. The gene encodes the α-subunit from cardiac isoform of the voltage gated sodium channel (Nav1.5); the main electrophysiological mechanism is a “gain of function” (either due to abnormal channel gating or impaired trafficking) with pronounced inward sodium (I_Na) current, and mutations occur in 10–15 % of LQTS patients. In addition to the molecular and mechanistic differences in the major LQTS subforms, patients differ clinically by differences in the pharmacological response, phenotypic disease modification (e.g., repolarization pattern in surface ECG), and disease severity [e.g., 20, 21].

Concerning additional but mainly rare LQTS subforms (sensitivity <1 % or less), mutations in other ion channel genes or regulatory subunits have been found. These ion channel subunits are encoded by KCNE2 (K+; LQT6), KCNJ2 (K+; LQT7; Andersen-Tawil syndrome), KCNJ5 (K+; LQT13), and SCN4B (Na+; LQT10). Other genes for LQTS, sometimes based on a well-characterized single case report with a proven functional basis of the mutant, are ANK2 (ankyrin-B, LQT4), AKAP9 (A-kinase anchor protein; LQT11), CACNA1C (Ca2+; LQT8; also Timothy syndrome), CALM1 (calmodulin 1), CALM2 (calmodulin 2), CALM3 (calmodulin 3), CAV3 (caveolin 3; LQT9), and SNTA1 (syntrophin alpha 1; LQT12) (Tables 62.1 – 62.3).