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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
JACC Clin Electrophysiol. Author manuscript; available in PMC 2017 September 27.
Published in final edited form as:
PMCID: PMC5617358

The Pharmacogenomics of a Mutation ‘Hotspot’ for the Short QT Syndrome

Dawood Darbar, MBChB, MD and Mark McCauley, MD, PhD

Short QT syndrome (SQTS) is a recently described genetic cardiac ion channelopathy that predisposes patients to atrial arrhythmias, ventricular arrhythmias, and sudden cardiac death (SCD)(1). Clinical manifestations of SQTS include symptoms of palpitations, presyncope/syncope, and sudden or aborted cardiac death. Given that SQTS is rare, patients are often first diagnosed by ECG, which typically shows a corrected QT interval (QTc) of < 370 msec by the Gollob Criteria (2), though several reports have described highly symptomatic patients and kindreds with QTc between 220–280 msec (1, 3). The QTc cut-off defining pathophysiologic patient risk is still under investigation (4); as occurred in the long QT syndrome, it may take decades of observations to truly refine a meaningful predictive QTc threshold for SQTS (5). Other salient ECG features of SQTS include: tall, sharp T waves immediately following the QRS complex; the interval from J point to T wave peak < 120 msec; brief or absent ST segments; and evidence of early repolarization as evidenced by J-point elevation in the infero-lateral leads (6, 7). The differential diagnosis of a SQT interval includes hyperkalemia, hypercalcemia, hyperthermia, acidosis, catecholamine effects, activation of potassium channels (KAch , KATP), and digitalis effect; therefore, a comprehensive assessment of ECG features must be compared with relevant clinical and family histories to elicit whether a genetic disorder contributed to enhanced ventricular repolarization as seen on the ECG (5).

SQTS is an autosomal dominant genetic disorder associated with mutations in at least one of six genes, corresponding to SQTS1-6: KCNH2 (HERG), KCNQ1, KCNJ2, CACNA1C, CACNB2b, and CACNA2D1. SQTS1-3 involve gain-of-function mutations in genes coding for three membrane potassium channels and corresponding repolarization currents: KCNH2 (HERG) coding for the α-subunit of the rapidly activating delayed rectifier potassium channel current (IKr); KCNQ1 coding for the slow component of the cardiac delayed rectifying potassium current (IKs); and KCNJ2 coding for the inwardly rectifying Kir2.1 current (IK1). Of these, KCNH2 (SQTS1) and KCNJ2 (SQTS3) have been associated with familial inheritance (5), while SQTS2 was described only as a sporadic case (8). SQTS4-6 involve mutations in genes coding for the L-type Ca2+ channel, which result in a loss of ICa function, and which contribute to a combined Brugada-SQTS phenotype (9).

To date, much progress has been made in understanding the natural history (4, 9) and molecular pathophysiology of SQTS especially how gain-of-function KCNH2 mutations cause enhanced repolarization current and predispose to SQTS (1013). However, the most common and clinically significant forms of SQTS remain poorly defined, and molecular analyses examining potential pharmacogenetic solutions to this syndrome are much needed. In this issue of JACC: Clinical Electrophysiology, Hu et al. screened the coding regions of known SQTS genes in probands diagnosed with the syndrome, assessed the phenotype in family members, and functionally characterized the most common KCNH2 variant (T618I) by expression in a heterologous expression system. The KCNH2-T618I mutation was identified in 18 members of 7 unrelated families and was shown to correlate with a high incidence of SCD. While the penetrance was 100% there was variable expressivity. The QTc of probands and affected family members was markedly shortened, and 7 family members received an implantable cardioverter defibrillator (ICD). Although quinidine was not universally effective in prolonging the QTc, bepridil was successful at treating drug-refractory ventricular fibrillation. Furthermore, functional expression of the mutated KCNH2-T618I channel revealed a gain-of-function that increased IKr tail current density, and action potential clamp recordings showed a larger current and peak repolarizing current that occurred earlier than previous.

The authors should be congratulated on their characterization of a large number of probands and families with SQTS, and for characterizing the phenotype of the disease by functionally expressing the most frequent KCNH2 mutation associated with this rare channelopathy linked with ventricular arrhythmias and SCD. Their data collected over a 5 year period also provide novel insights into the natural history, underlying genetic basis and response to therapy for patients with SQTS1. Hu et al. identified a mutation ‘hotspot’, which is defined as a nucleotide position with a high mutation frequency and >95% probability of causing the disease (14). While this is not the first mutation hotspot associated with SQTS1, it is the most frequent with 7 probands carrying the KCNH2-T618I variant. Additional support for this variant causing the SQTS comes from data showing cosegregation of the SQTS phenotype with the genotype. Furthermore, the fact that the KCNH2-T618I was discovered in unrelated SQTS kindreds from North America, Europe and Asia suggests that the mutation does not arise from a ‘founder effect.’

This is the largest SQTS study of its kind to date, and the investigation into potential pharmacogenetic approach for this rare syndrome has the potential to help families stricken with this disorder. Pharmacologic therapy for the SQTS can be challenging. One study showed that SQTS probands carrying the KCNH2-N588K mutation (another mutation ‘hotspot’) are resistant to QT-prolonging drugs such as sotalol, dofetilide, flecainide and ibutilide probably because the mutation modulates the affinity for the inactivated state of the IKr channel (15). However, quinidine has been shown to be effective at suppressing ventricular arrhythmias in patients with SQTS including KCNH2-N588K carriers (16, 17). In the Hu et al. study, quinidine prolonged the QTc in all 5 KCNH2-T618I patients. However, ventricular arrhythmias were suppressed in only 3 of them during the follow-up period. Furthermore, sotalol, dofetilide and bisoprolol failed to prolong the QTc in KCNH2-T618I probands. In contrast, bepridil (a class IV antiarrhythmic drug with both potassium and sodium blocking properties) terminated drug-refractory ventricular arrhythmias, albeit in only 1 KCNH2-T618I carrier. While this study supports bepridil as a potential therapy for SQTS patients, additional studies will need to be performed confirming its clinical efficacy.

Although the study has many strengths, there are a few limitations that should be addressed in future investigations. In the heterologous expression systems, it would be useful to determine the impact of modifier polymorphisms (such as K897T and R1047L) upon the expression of the KCNH2-T618I variant, as this might provide important insights into the phenotypic heterogeneity associated with this mutation. It is unusual that although atrial fibrillation is commonly reported in cases of SQTS (~50% of SQTS patients with KCNH2-T618I), no atrial fibrillation was reported with the KCNH2-T618I mutation. Further characterization of this mutation in murine or human atrial cells may shed light on the mechanism underlying this observation.

Characterization of the SQTS has come a long way since its discovery by Gussak et al. in 2000 (3). Given the complete penetrance and strong association of the KCNH2-T618I mutation with arrhythmic death, the investigation by Hu et al. adds to the understanding of the natural history of SQTS and advances the cause for a precision approach to its treatment.


This work was in part supported by NIH R01 HL092217, R01 HL124935 and K08 HL130587


1. Maluli HA, Meshkov AB. A short story of the short QT syndrome. Cleve Clin J Med. 2013;80:41–47. [PubMed]
2. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57:802–812. [PubMed]
3. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94:99–102. [PubMed]
4. Villafane J, Atallah J, Gollob MH, et al. Long-term follow-up of a pediatric cohort with short QT syndrome. J Am Coll Cardiol. 2013;61:1183–1191. [PubMed]
5. Patel C, Yan GX, Antzelevitch C. Short QT syndrome: from bench to bedside. Circ Arrhythm Electrophysiol. 2010;3:401–408. [PMC free article] [PubMed]
6. Couderc JP, Lopes CM. Short and long QT syndromes: does QT length really matter? J Electrocardiol. 2010;43:396–399. [PMC free article] [PubMed]
7. Cross B, Homoud M, Link M, et al. The short QT syndrome. J Interv Card Electrophysiol. 2011;31:25–31. [PubMed]
8. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–2397. [PubMed]
9. Mazzanti A, Kanthan A, Monteforte N, et al. Novel insight into the natural history of short QT syndrome. J Am Coll Cardiol. 2014;63:1300–1308. [PMC free article] [PubMed]
10. Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome. Cardiovasc Res. 2005;67:498–509. [PubMed]
11. Hassel D, Scholz EP, Trano N, et al. Deficient zebrafish ether-a-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants. Circulation. 2008;117:866–875. [PubMed]
12. Schimpf R, Antzelevitch C, Haghi D, et al. Electromechanical coupling in patients with the short QT syndrome: further insights into the mechanoelectrical hypothesis of the U wave. Heart Rhythm. 2008;5:241–245. [PMC free article] [PubMed]
13. Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol. 2005;16:54–58. [PMC free article] [PubMed]
14. Rogozin IB, Pavlov YI. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat Res. 2003;544:65–85. [PubMed]
15. McPate MJ, Duncan RS, Hancox JC, Witchel HJ. Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs. Br J Pharmacol. 2008;155:957–966. [PMC free article] [PubMed]
16. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43:1494–1499. [PubMed]
17. Frea S, Giustetto C, Capriolo M, et al. New echocardiographic insights in short QT syndrome: More than a channelopathy? Heart Rhythm. 2015;12:2096–2105. [PubMed]