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Chapter 80: Genetics of Channelopathies and Clinical Implications

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A 28-year-old woman is seen in consult after a near drowning episode. Both her presenting EKG and her baseline EKG today reveal a QTc of 490 ms. Which of the following genetic mutations paired with its responsible ion channel is most likely responsible for this patient’s channelopathy?

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A. KCNH2 / IKr

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B. KCNQ1 / IKs

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C. KCNQ1 / INa

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D. KCNH2 / IKs

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E. KCNJ2 / IK1

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The answer is B. (Hurst’s The Heart, 14th Edition, Chap. 80) The patient most likely has long QT syndrome type 1 (LQTS1), for which the classic trigger is strenuous swimming. The gene mutation associated with LQTS1 is KCNQ1, which is the gene of the IKs current (slow component of the delayed rectifier current) (option B). IKs is mostly active during phase 3 of the action potential, but its role in the control of repolarization becomes more evident during adrenergic stimulation since the current is mainly activated by catecholamines. Thus, the consequences of KCNQ1 mutations, leading to reduced IKs, become more evident during increased sympathetic tone (eg, exercise, acute emotions) with a failure to shorten the action potential (ie, QT interval). LQTS2 is due to loss of function mutations in the KCNH2 gene, which encodes for the α-subunit (pore-forming protein) of the IKr (rapid component of the delayed rectifier) channel, which participates in the control of cardiac repolarization during phase 3 (option A). Exposure to loud noises in LQTS2 patients should be avoided. LQTS3 is due to gain of function mutations in SCN5A that induce an increase of the late component of INa, leaving the peak (fast) component of the current unaffected or only mildly altered (option C: SCN5A / INa is the correct pairing). Option D: KCNH2 / IKr is the correct pairing. A mutation in KCNJ2 would lead to LQTS7, also known as Andersen–Tawil syndrome (option E).1 The gene encodes for the cardiac inward rectifier IK1 current gene that participates in the control of the late repolarization phase and resting membrane potential. LQTS7 is a rare variant (< 1%) that can sometimes include extracardiac manifestations (periodic paralysis and dysmorphic features).

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Based on current guidelines, all of the following patients may be given a presumptive diagnosis of long QT syndrome except:

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A. An asymptomatic 22-year-old female, on no medications, with a QTc of 485 ms in repeated ECGs

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B. An asymptomatic 10-year-old female with a normal ECG and a positive mutation in the KCNH2 gene discovered on cascade screening

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