Genetics of Long QT and Short QT Syndromes

Abstract

Long QT syndrome (LQTS) is the best described inheritable arrhythmogenic disorder. It is characterised by a increased duration of cardiac action potential secondary either to mutations that produce a loss‐of‐function of potassium channels responsible for cardiac repolarisation or to gain‐of‐function alterations of sodium channels responsible for cardiac depolarisation. Seventeen genes have been associated with LQTS. The first three genotypes discovered (LQT1–LQT3) account for 95% of genotype‐positive cases. Genetic analysis allows to identify the pathogenic genetic defect in 80% of patients and plays a crucial role in the diagnosis, risk stratification and treatment.

Conversely, short QT syndrome (SQTS) is the latest described inheritable arrhythmogenic disease, and its genetic basis has been poorly clarified. It is characterised by an abnormal shortening of the cardiac repolarisation, which may result either from gain‐of‐function mutations of potassium channels responsible for cardiac repolarisation or from a diminished function of voltage‐dependent‐L‐type calcium channels responsible for cardiac depolarisation. The five genetic forms of the disease identified account for only 20% of SQTS patients. Therefore, genetic analysis portends a limited contribution to the diagnosis and management of SQTS patients.

Key Concepts

  • Long QT syndrome (LQTS) is the best described monogenic inherited arrhythmogenic disorder, with 17 disease‐related genes described to date. The first three genotypes discovered represent about 75% of all LQTS cases.
  • The common pathophysiological substrate of LQTS variants is represented by a prolongation of cardiac repolarisation that can be secondary either to loss‐of‐function defects of potassium channels responsible for cardiac repolarisation or to gain‐of‐function alterations of sodium channels responsible for cardiac depolarisation.
  • Genetic analysis allows to identify the pathogenic defect in 80% of LQTS patients and therefore plays a crucial role in the diagnosis, risk stratification and therapeutic approach of LQTS patients.
  • Short QT syndrome (SQTS) is the latest described inherited arrhythmogenic disorder, and its genetic basis has been scarcely understood. To date, five genetic forms of the disease have been identified.
  • Genetic analysis allows to identify the pathogenic defect in only 20% of SQTS affected individuals.
  • The pathophysiological substrate of SQTS resides in an abnormal shortening of cardiac repolarisation, which can be secondary to gain‐of‐function mutations harboured in potassium channels or to loss‐of‐function defects of voltage‐dependent L‐type calcium channels.
  • Due to the lack of genotype–phenotype correlation information to this date and due to the low yield of genetic testing, in SQTS genetic analysis does not help in risk stratification and clinical management of affected individuals.

Keywords: channelopathies; long QT syndrome; short QT syndrome; sudden cardiac death; Torsades de Pointes; genetics; mexiletine

Figure 1. Examples of electrocardiograms of patients with Long QT Syndrome and Short QT Syndrome. (a) The electrocardiogram of a patient with Long QT Syndrome type 3 (LQT3). Note the typical sinus bradycardia and the broad‐based T wave with late onset. RR: 1500 ms; QT: 720 ms; QTc: 588 ms. (b) ECG example of an asymptomatic Short QT type Syndrome type 3 (SQT3) patient. RR: 850 ms; QT: 310 ms; QTc: 336 ms.
Figure 2. Basal ECG of a 20‐year‐old patient with Andersen–Tawil syndrome. The trace shows the typical prominent U waves (see the asterisk) and frequent ventricular ectopic beats.
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Further Reading

Bohnen MS, Peng G, Robey SH, et al. (2017) Molecular pathophysiology of congenital long QT syndrome. Physiological Reviews 97 (1): 89–134.

Priori SG, Napolitano C, Schwartz PJ, et al. (2000) The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation 102 (9): 945–947.

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Maragna, Riccardo, Mazzanti, Andrea, and Priori, Silvia G(Sep 2017) Genetics of Long QT and Short QT Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024386]