SCIENTIFIC BACKGROUND

CACNA1C, CACNA2D1, CACNB2, KCNH2, KCNJ2, KCNQ1

Scientific Background

Short QT syndrome (SQTS) is characterized by a shortened ventricular repolarization. In long-term ECG, a shortened frequency-corrected QT interval (QTc) of <340-350 ms and high or peaked T-waves can be detected, which greatly increases the risk of syncope, ventricular tachycardia and sudden cardiac death. Although cardiac arrest can occur in SQTS patients at any age, cardiac events are most common in the early years of life and in old age. The cumulative probability of suffering a cardiac arrest in the fifth decade of life is about 40%, which highlights the importance of early detection. The prevalence of SQTS in the Caucasian population is about 1:10,000.

 

In autosomal dominantly inherited SQTS, pathogenic variants in cardiac potassium channel genes (KCNQ1, KCNH2 and KCNJ2) can be detected in about 70% of the molecular genetically positive cases. These variants lead to increased potassium currents, which means that the normal heart rhythm can no longer be maintained. In rare cases, calcium channel genes (CACNA1C, CACNB2 and CACNA2D1) are affected resulting in a loss of function.

 

The diagnostic sensitivity of molecular genetic screening in SQTS is currently about 15-25%, as a result, genetic testing is only recommended where there is a positive family history.

 

The molecular classification and nomenclature (SQTS types 1-6) is based on the genes concerned:

 

  • KCNH2 (SQTS type 1; 45% of variants): encodes a cardiac voltage-dependent potassium channel. There is a high risk of cardiac events.
  • KCNQ1 (SQTS type 2; 17% of mutations): encodes a further K+ channel. There is a high risk of cardiac events.
  • KCNJ2 (SQTS type 3; 6% of variants): encodes a further K+ channel. There is a risk of cardiac events.
  • CACNA1C (SQTS type 4) encodes the α subunit of the cardiac voltage-dependent calcium channel Cav1.2.
  • CACNB2 (SQTS type 5) encodes the β subunit of the cardiac voltage-dependent calcium channel Cav1.2.
  • CACNA2D1 (SQTS type 6) encodes the α2-δ1 subunit of the cardiac voltage-dependent calcium channel Cav1.2.

 

The identification of carriers of pathogenic variants enables timely, possibly presymptomatic therapy. In previous studies, treatment with class Ia antiarrythmic drugs and the implantation of an ICD has been recommended. Furthermore, drugs of different classes can reduce the QT interval. All carriers should receive instructions for adjusting their lifestyle.

 

References

Mazzanti et al. 2017, J Cardiovasc Electrophysiol 28:1226 / Khera et al. 2016, Cardiol Rev 24 / Malik et al. 2016, Drug Saf 39:647 / Mazzanti et al. 2014, Cardiovasc Ther 12:499 / Maltret et al. 2014, Int J Cardiol 171:291 / Templin et al. 2011, Eur Heart J 32:1077 / Moreno‑Reviriego et Merino 2010, E-Journal of the ESC Council for Cardiology Practice Vol. 9 N°2 / Hedley et al. 2009, Hum Mutat 30:1486 / Barry et al. 2006, Circulation 113:1807

GENES

CACNA1C, CACNA2D1, CACNB2, KCNH2, KCNJ2, KCNQ1
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