A prolonged QT interval on ECG predisposes to Torsades de Pointes (TdP). The underlying ionic mechanism of QT prolongation in congenital long QT syndrome type 2 (LQTS2) involves:

• A Loss-of-function mutation in KCNQ1 gene encoding the slow delayed rectifier K+ channel (IKs)
• B Gain-of-function mutation in SCN5A gene encoding the cardiac Na+ channel, causing persistent late Na+ current
• C Gain-of-function mutation in CACNA1C gene encoding the L-type calcium channel (ICaL)
• D Loss-of-function mutation in KCNH2 (HERG) gene encoding the rapid delayed rectifier K+ channel (IKr) ✓

Explanation

LQTS2 is caused by loss-of-function mutations in the KCNH2 gene (also called HERG — human ether-a-go-go related gene), which encodes the alpha-subunit of the rapid delayed rectifier potassium channel (IKr). IKr is critical for phase 3 repolarization of the cardiac action potential. Reduced IKr prolongs repolarization, extending the QT interval and creating conditions for early afterdepolarizations (EADs) triggering TdP. LQTS1 is due to KCNQ1 mutations (IKs); LQTS3 is due to SCN5A gain-of-function (persistent INa); LQTS8 involves CACNA1C. IKr blockade by drugs (quinidine, erythromycin, haloperidol) causes acquired LQTS2-like QT prolongation.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.