Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

KCNH2

N588K-KCNH2

Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burachnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schrimpf R, Brugada P, Antzelevich CCirculation 2004,109:30-35

In this paper genetic testing was performed in the two families previously described by Gaita et al. in 2003 and in a family from the US not previously published, consisting of a 51 y.o. father with aborted SCD and his 20 y.o. son who both had a QTc < 300 msec.

In the German family they identified a missense mutation (c to g substitution at nucleotide 1764) in KCNH2 and in the Italian family a different missense mutation in the same residue (c to a substitution at nucleotide 1764). Both mutations, however, substituted the asparagine (N) at codon 588 in KCNH2 protein for a positively charged lysine (K) resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2).

No mutation was found in the American family.

The net effect of the mutation is to increase the repolarization currents active during the early phases of the AP, by eliminating current inactivation leading to loss of normal rectification of the current at plateau voltages with abbreviation of the action potential and thus abbreviation of the QT interval.

The N588K missense mutation was also shown to reduce the affinity of the channel for drugs with class III antiarrhythmic action such as Sotalol and Dofetilide. Sotalol did not prolong the QT interval in patients with short QT.

This was the first description of a genetic abnormality responsible for some cases of SQTS – later referred to as SQT1.

Standard whole-cell patch-clamp technique was used to measure currents in transfected human embryonic kidney cells (TSA201). KCNH2 channels (N588K) were co-expressed with and without the ancillary β-subunit KCNE2 (MiRP1).The N588K missense mutation was shown to abolish rectification of the HERG-current and reduce the affinity of the channel for drugs with class III antiarrhythmic action. The net effect of the mutation is to increase the repolarizing currents active during the early phases of the AP leading to abbreviation of the AP and thus to abbreviation of QT.

In silico study of action potential and QT interval shortening due to loss of inactivation of the cardiac rapid delayed rectifier potassium current. Zhang H, Hancox JC. Biochem Biophys Res Commun 2004;322(2):693-699

Here, computer simulations were used to investigate the effects of the selective loss of voltage-dependent inactivation of IKr upon ventricular action potentials and on the QT interval in the electrocardiogram.The results from this study substantiate the notion that selective loss of IKr inactivation produces a gain in IKr function that causes QT interval shortening.

Short QT Syndrome and Atrial Fibrillation Caused by Mutation in KCNH2. Hong K, Bjerregaard P, Gussak I, Brugada R. J Cardiovasc Electrophysiol 2005;16:394-396

This is a description of the genetic analysis of the first family with SQTS (Gussak I et al.2000), who turned out to have a c to a substitution at nucleotide 1764 resulting in the amino acid change (N588K in KCNH2 similar to the previously described Italian family. The family had no history of sudden cardiac death, but all members had a history of paroxysmal atrial fibrillation.

Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome. Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. (Masonic Medical Research Laboratory, Utica, NY) Cardiovascular Research 2005;67:498-509.

The authors measured the characteristics of HERG current generated by wild-type KCNH2 and the N588K mutant channel (as in SQT1) expressed in mammalian TSA201 cells. They found that the ventricular action potentials were shortened except for the Purkinje fiber action potentials, which remained unchanged. This would lead to a shortening of the refractory period in the ventricles, but not in the Purkinje fibers. They suggested that the longer action potentials in the Purkinje fibers might re-excite the repolarized endocardial cells of the ventricles and cause VT by phase 2 re-entry.

This may also explain the wider than usual separation between T and U waves (final repolarization of Purkinje fibers?) seen in SQTS patients.

The N588K-HERG K+ channel mutation in the ‘short QT syndrome’: Mechanism of gain-in-function determined at 37 oC. McPate MJ, Duncan RS, Milnes JT, Witchel HJ, Hancox JC. (School of Medical Sciences, University of Bristol, UK Biochemical and Biophysical Research Communications 2005;334:441-449

This study was undertaken in order to determine how the N588K mutation alters HERG channel current kinetics at mammalian physiological temperature. Chinese Hamster ovary cells we used.They demonstrated that N588K-HERG contributes increased repolarising current earlier in the ventricles action potential due to a ~+60 mV positive-shift in voltage dependence of IHERG inactivation that results in increased current earlier during the ventricular AP. This helps explain the mechanism of gain-in-function, accelerated repolarisation and short QT interval in SQT1 patients.

Arrhythmogenesis in the Short-QT Syndrome Associated with Combined HERG Channel Gating Defects. A Simulation Study. oh H, Horie M, Ito M, Imoto K.(Shiga University, Otsu, Japan) Circ J 2006;70:502-508

The authors used a computer model including a N588K-KCNH2 mutant Markov model integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP.They were unable to confirm previous suggestions of transmural dispertion of depolarization (TDR), and simulation studies suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of the N588K-HERG channel (loss-of-function). At a BCL of 2000 msec EADs occurred in M cells, but not in epicardial or endocardial cells.

Biophysical Characterization of the Short QT Mutation hERG-N588K reveals a Mixed Gain-and Loss-of-function. Grunnet M, Diness TG, Hansen RS, Olesen S-P. (The Danish National Research Foundation Center for Cardiac Arrhythmia, University of Copenhagen, Denmark) Cell Physiol Biochem 2008;22:611-624 Patch-clamp experiments were conducted after heterologous expression in both Xanopus laevis oocytes and mammalian cells and at both room temperature and at 37 oC. Also the impact of the β-subunits KCNE2 was investigated.The present study describes a profound biophysical characterization of hERG-N588K revealing both loss-of-function and gain-of-function. The most prominent loss-of-function property was reduced tail currents, but also slower activation and faster deactivation kinetics. It must therefore be expected that the hERG-N588K mutant will have reduced ability to conduct current at the end of repolarization. Furthermore this mutant will also have a diminished open probability in the diastolic interval. The gain-of-function stems from severely compromised ability to inactivate.The authors therefore stress that in patients carrying hERG-N588K the loss-of-function of repolarization current and diastolic hERG current may be at least as pro-arrhythmic as the gain-of-function of plateau current. Potential pro-arrhythmia from loss-of-function: 1) Due to the fast deactivation the number of channels able to counteract depolarization events in the post-repolarization period is significantly reduced and thereby the ability of the myocytes to counteract triggered activity, and 2) reduction in the repolarising reserve can lead to triangulation and early afterdepolarization.

Comparative Effects of the Short QT N588K Mutation at 37oC on HERG K+ Channel Current during Ventricular, Purkinje Fibre and Atrial Action Potentials: An Action Potential Clamp Study. McPate MJ, Zhang H, Adeniran I, Cordeiro JM, Witchel HJ, Hancox JCJ of Physiol Pharmacol 2009;60(1):23-41

HERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome McPate MJ, Zhang H, Cordeiro JM, Dempsey CE, Witchel HJ, Hancox JC Biochem Biophys Res Commun 2009;386(1):111-117

All information on the likely consequences for IKr kinetics of N588K hERG mutation comes from studies of the hERG1a isoform. Recent evidence suggests, however, that native cardiac _I_Kr may not be comprised of hERG1a alone, but rather of hERG1a heteromerically expressed with an alternative transcript, hERG1b, an isoform with a truncated N-terminus.

The present study was conducted to determine the effects of the N588K hERG SQT1 mutation on co-expressed hERG1a/1b channels. The data showed that the inactivation-attenuation effects of the N588K mutation were markedly greater when co-expressed hERG1a and 1b were studied than when hERG1a alone was studied. The study also confirmed the differential effect the N588K hERG mutation has on current during ventricular and Purkinje APs as initially suggested by data from the study by Cordeiro JM et al. and McPate MJ et al.

This is the first study to have investigated hERG1a/1b heteromeric channels in the context of the short QT syndrome. Similar studies have never been done for LQTS.

R1135H-KCNH2

A novel KCNH2 mutation as a modifier for short QT interval. Itoh H, Sakaguchi T, Ashihara T, Ding W-G, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Ito M, Nakamura K, Ohe T, Matsuura H, Horie M. Int J Cardiol 2008

This study using voltage clamp experiments describes a novel C-terminal KCNH2 mutation, R1135H, which was found to explain both the marked QT shortening (QTc 329 msec) and the Brugada-type ECG in a 34 year-old man.

Later (Wilders R, Verkerk AO. Role of the R1135H KCNH2 mutation in Brugada syndrome. Int J Cardiol 2010;144:149-51) computer simulation studies confirmed the findings

T618I-KCNH2

A novel mutation in the KCNH2 gene associated with short QT syndrome. Sun Y, Quan X-Q, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan G-XJ Molecular and Cellular Cardiology 2011;50:433-441

In 4 members of a Chinese family with markedly short QT interval and a strong family history of sudden cardiac death, a C1853T mutation in the KCNH2 gene encoding for the HERG channel resulting in an amino change T618I was identified.Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 +/- 16.7 vs 23.8 +/- 5.5 pA/pF) that occurred at 20 mV more positive potential compared to the wild type. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT –78.6 +/- 6.8 vs T618I – 29.3 +/- 1.7 mV). Kinetic analysis revealed slower inactivation rates of T618I, but faster rates of recovery from inactivation.

The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome Dan Hu, Yiang Li, Lianchenh Zhang et al. JACC Clinical Physiology 2017;3:727-43

Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and Sotalol. 

Shugang Zhang, Weigang Lu, Fei Yang, Zhen Li, Shuang Wang, Mingjlan Jiang, Xiaofang Wang, Zhiqang Wei (Ocean University of China, China)

Short QT Syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenisis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of IKr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrate for the ventricular arrhythmias. Using this T618I Markov model we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also succesfully reproduced the changed dynamics of reentrant spiral waves and impared rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we not only simulated the actions of an effective drug (Quinidine) at various physiological levels, but also elucidated why the IKr inhibitor Sotalol failed in SQT1 patients through profoundly analyzing its mutation dependent actions.

npj Systems Biology and Applications (2022) 8:43;https://doi.org/10.1038/s41540-022-00254-5

E50D-KCNH2

Rapid genetic testing facilitating the diagnosis of short QT syndrome. Redpath CJ, Green MS, Birnie DH, Gollob MH. Can J Cardiol 2009;25(4):e133-e135

Novel Gain-of-Function N-terminal KCNH2 Mutation Associated with the Short QT Syndrome. Martinez HB, Hu D, Gollob M, Antzelevitch C. AHA Scientific Sessions 2011, Abstract # 12845

22-year-old man “experienced unheralded syncope for the first time while driving, resulting in a motor vehicle accident”. The patient had no documented arrhythmias, but a QT interval of 366 msec at 66 bpm. Treadmill testing did not result in ventricular arrhythmia, but did reveal a lack of adaptation of the QT interval to increasing heart rate during exercise and a failure to adapt to decreasing heart rate during recovery.Direct DNA sequencing of the KCNQ1 and KCNH2 genes identified a novel mutation of highly conserved residue, Glu50Asp, in KCNH2, which was also present in the patient’s mother, who had a normal QT interval. The E50D-KCNH2 mutation was not found in 1300 healthy controls and alignment of the amino acid sequence of HERG showed that residue E50 is highly conserved among species. Functional expression of E50D-KCNH2 in TSA201 cells at 370C showed a 6-fold gain in function of Ikr tail current density, slower deactivation and, a positive shift in the voltage dependence of inactivation (WT: -76.8 vs. E50D: -65.3 mV. This is the first report of a pathogenic mutation in the N-terminal of KCNH2 associated with SQT1. The E50D missense mutation causes a gain of function of Ikr tail current density, slower deactivation and a positive shift in the voltage-dependence of inactivation

p.Pro872fs-KCNH2

HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency. Paulussen AD, Raes A, Jongbloed RJ, Gilissen RA, Wilde AA, Snyders DJ, Smeets HJ, Aerssens J. (University of Maastricht, Maastricht, The Netherlands__) Cardiovasc Res 2005;67(3):467-475

In a Dutch family of Caucasian origin diagnosed with long QT syndrome genetic screening revealed a heterozygous frameshift mutation p.Pro872fs located in the C-terminus of the KCNH2 gene. The authors found that the KCNH2 mutation that clinically leads to long QT syndrome causes at a cellular level both a “gain” and a “loss” of HERG-channel function due to a kinetic increase in repolarising power and a decrease in trafficking efficiency of heteromultimeric channels.The finding provides a novel proof of concept for heteromultimeric channels.

S631A-KCNH2

Action potential clamp characterization of the S631H hERG mutation associated with short QT syndrome.

Butler A. Zhang Y, Stuart AG, Dempsey CE, Hancox JC. Physiol Rep. 2018 Sep;6(17)

KCNQ1

In Silico investigation of a KCNQ1 mutation associated with short QT syndrome. Adeniran I, Whittaker DG, El Harchi A.Hancox JC, Zhang H. Sci Rep 2017;7:8469

V307L-KCNQ1

Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome. Bellocq C, van Ginneken ACG, Bezzina CR, Alders M, Escande D, Mannens MMAM, Baro I, Wilde AAM. Circulation 2004;109:2394-2397This paper describes a 70-year old male with aborted VF episode and a short QT interval of 290 msec in several ECGs during a 3-year follow-up period. Analysis of candidate genes identified a g919c substitution in KCNQ1 (V307L (valine to leucine) mutation) encoding the K+ channel KvLQT1, which, in association with the ß-subunit KCNE1 (mink, IsK), forms the slow component of the cardiac rectifier K+ current (IKs). Patch-clamp data and computational studies showed that the mutation caused the channel to activate faster and at more negative potentials favoring the association of a short QT interval with mutation in KCNQ1.

This was the second description of a genetic defect leading to SQTS – later called SQT2

Repolarization and vulnerability to re-entry in the Human heart with short QT syndrome arising from KCNQ1 mutation – A simulation study. Zhang H, Kharche S, Holden AV, Hancox JC. Progress in Biophysics and Molecular Biology 2008;96:112-131

In this study a computer modeling approach was adopted in order to determine whether and how the V307L-KCNQ1 mutation might generate an electrical substrate for arrhythmias in SQT2 patients. The V307L-KCNQ1 mutation is: (i) causally linked to QT interval shortening; (ii) leads to an increased transmural heterogeneity of APD, ERP and membrane potential (δV), that increases tissue’s vulnerability to the genesis of re-entry by a premature excitation; (iii) and shortens tissue’s ERP that facilitates the maintenance of re-entry.

The findings from this study both substantiate a causal link between the V307L-KCNQ1 mutation and QT interval shortening and provide a comprehensive explanation for increased susceptibility to re-entry and perpetuation of reentrant arrhythmia in SQT2.

Action Potential Clamp and Mefloquine Sensitivity of Recombinant ‘IKS’ channels incorporating the V307L-KCNQ1 Mutation. Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancox JC. J Physiol Pharmacol 2010;61(2):123-131

Perforated-patch voltage-clamp recordings (Chinese Hamster Ovary cells) at 370C of whole-cell current carried by co-expressed KCNQ1 and KCNE1 showed a marked (-36 mV) shift in half-maximal activation for V307L compared to WT KCNQ1; a significant slowing of current deactivation was also observed. Under AP clamp peak repolarising current was significantly augmented for V307L-KCNQ1 compared to WT for both ventricular and atrial AP commands, consistent with an ability of the V307L mutation to increase repolarising Iks in both regions. The quinoline agent mefloquine showed effective inhibition of recombinant ‘Iks’ channels incorporating this SQT2 KCNQ1 mutation.

V141M-KCNQ1

De novo KCNQ1 mutation responsible for atrial fibrillation and Short QT Syndrome in utero. Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P, Sachse F, Sanguinetti MC, Brugada R. (Masonic Medical Research Laboratory, Utica, NYCardiovasc Res 2005;68:433-440

The first description of a newborn with atrial fibrillation in the setting of SQTS diagnosed in utero and linked to a De Novo KCNQ1 mutation.

The HR was 60 bpm and an EP study showed normal HV interval suggesting AV nodal block. DC cardioversion was unsuccessful.

Genetic testing showed a missense mutation, G to A substitution at nucleotide 421 (g421a). This mutation results in substitution of valine by methionine at position 141 (V141M) adjacent to a previously described S140G mutation for familial AF. Oocytes from Xenopus laevis were injected with WT or V141M-KCNQ1 cRNA with or without KCNE1 cRNA and 2-3 days later exposed to two electrode voltage clamp recordings. The V141M mutation did not noticeably alter the gating of KCNQ1 channels expressed alone in oocytes.

The WT-KCNQ1/KCNE1 channels exhibited a voltage-dependent threshold of activation near -50 mV and activated very slowly. In sharp contrast, the V141M-KCNQ1/KCNE1 channel current developed instantly at all voltages tested, consistent with the interpretation that these channels were constitutively open. Computer modeling showed decrease in peak voltage and shortening of APD consistent with shortening of the QT interval.

The effect of the 141M gain of function mutation was also modeled in a model of rabbit sinoatrial node cells. The results indicate that the enhanced outward Iks causes cessation of spontaneous activity and a stabilization of the resting membrane potential at a level positive to the normal maximum diastolic potential of these cells.

The unsuccessful attempt of cardioversion and slow HR suggest both sinus ndal and AV nodal disease.

Upper limits of QT/QTc intervals in the Short QT Syndrome. Review of the World-Wide Short QT Syndrome Population and 3 new USA families. Bjerregaard P, Collier JL, Gussak I. Heart Rhythm 2008;5(5S):AB43-4

This review contains a US case similar to the one described by Hong K et al.. Only the proband had the KCNQ1 mutation.

I274V-KCNQ1

Gain of Function KCNQ1 Mutation Associated With Sudden Infant Death Syndrome. Rhodes TE, Crotti L, Arnestad M, Insolia R, Pedrazzini M, Ferrandi C, Rognum T, Schwartz PJ, George AL. Heart Rhythm 2006;3(5):S2

During the examination of 201 Norwegian SIDS cases for genetic variants in the major LQTS genes, a gain-of-function mutation (I274V) was found in theKCNQ1 gene. This mutation is predicted to enhance cardiac repolarization resulting in a shortened QT interval and an increased risk of atrial and ventricular tachyarrhythmias - features typical of the Short QT Syndrome.

The finding was later described in more detail in:

Prevalence of Long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome Arnestad M et al. Circulation 2007;115:361-367

In a patient with Sudden Infant Death Syndrome Arnestadt et al. found an an I274V-KCNQ1 mutation.

And in:

Cardiac Potassium Channel Dysfunction in Sudden Infant Death Syndrome Rhodes TE et al. J Moll Cell Cardiol 2008;44(3):571-581

Electrophysiological data from patch clamp recordings (Chinese hamster ovary cells) showed that I274V-KCNQ1 in the presence of KCNE1 causes gain of function in Iks characterized by increased current density, faster activation, slower deactivation, and accumulation of instantaneous current during repeated stimulation.

To test the hypothesis that I274V may promote a short QT syndrome phenotype, computerized modeling of ventricular action potentials were performed comparing WT-Iks to heterozygous I274V-Iks. At all cycle length the AP was shorter for I274V-Iks supporting the prediction that I274V-KCNQ1 will cause a short QT phenotype, a plausible explanation for sudden death in an infant carrying this mutation.

R259H-KCNQ1

KCNJ2

D172N-KCNJ2

A Novel Form of Short QT Syndrome (SQT3) Is Caused by a Mutation in the KCNJ2 Gene. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, Raffaele di Bartella M, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J. (IRCCS Fondazione Maugeri, Pavia, Italy__) Circ Res. 2005;96:800-807

An asymptomatic 5-year-old girl presented with an ECG during routine clinical evaluation with QTc of 315 ms and noticeably narrow, peaked and asymmetrical T waves. Her father had a QTc of 320 ms and a history of presyncopal events and palpitations since the age of 15. He underwent electrophysiologic investigation showing VERP of 160 msec and induction of VF by 3 extrastimuli. He refused an ICD.

Genetic analysis led to the identification in both affected individuals of a single base pair substitution (G514A) in KCNJ2, resulting in an amino acid change from aspartic acid to asparagine at position 172 in the Kir2.1 potasseum channel (IK1).

The authors hypothesized that the tall and asymmetrical T-waves with an exceedingly rapid terminal phase not seen in SQT1 or SQT2 patients may be related to a sudden acceleration of the final phase of action potential repolarization in the D172N mutation.

None of the patients had any documented spontaneous tachy-arrhythmias.

Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated larger outward IK1 than the wild-type at potentials between 75mV and –45 mV, with the peak current being shifted in the former with respect to the later (WT, -75mV; D172N and –65 mV). Coexpression of WT and mutant channels to mimic heterozygous condition of the proband yilded an outward current that was intermediate between WT and D172N.

This was the first case of what was later called SQT3.

Short QT Syndrome or Anderson Syndrome. Yin and Yang of Kir2.1 Channel Dysfunction. Schulze-Bahr E. Circ Res. 2005;96:703-704)

Editorial comment to the above article.

Action potential clamp and chloroquine sensitivity of mutant Kir2.1 channels responsible for variant 3 short QT syndrome. Harchi AE, McPate MJ, Zhang YH, Zhang H, Hancoc JC. J Moll Cell Cardiol 2009;47(5):743-747

Proarrhythmia in KCNJ2-linked short-QT syndrome: insights from modelling**.** Adeniran I, Harchi AE, Hancox JC, Zhang H. Cardiovascular Research 2012;94:66-76

K364T-KCNJ2

Novel Mechanism of KCNJ2-Related Short QT Syndrome Ruan Y, Cerrone M, Novelli V, Liu N, Blaufox AD, Sicca F, Moro F, Pessia M, Napolitano C, Priori SG.. AHA Scientific Sessions 2011, Abstract 13462

A not previously described KCNJ2 gene mutation was identified in two 8-years old homozygous twins with short QT intervals (QTc 316ms and 310 ms).Whole-cell patch-clamp studies demonstrated that the K364 T mutation presents a larger outward IK1 than WT at potentials between –75 mV and – 55 mV, therefore the biophysical properties overlap with those of the D172N mutation.

E299V-KCNJ2

(First presented as Abstract 13462 at AHA Scientific Sessions 2011: Ruan Y, Cerrone M, Novelli V, Liu N, Blaufox AD, Sicca F, Moro F, Pessia M, Napolitano C, Priori SG. Novel Mechanism of KCNJ2-Related Short QT Syndrome.)

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia. Deo M, Ruan Y, Pandit SV, Shah K, Berenfeld O, Blaufox A, Cerrone M, Noujaim SF, Denegri M, Jalife J, Priori SG. PNAS 2013;110(11):4291-4296

A new mutation (E299V) in KCNJ2 was found in an 11-y-old boy with recurrent atrial fibrillation and mild LV dysfunction. The patients ECG showed extremely abbreviated QT interval of 200 ms at 60 bpm with merging of the QRS and peaked T waves. Holter recording showed paroxysmal AF with an average HR of 98 bpm and confirmed the presence of a short QT interval that failed to adapt to HR.

Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward IK1 at potentials above –55 mV due to lack of inward rectification.

M301K-KCNJ2

A novel gain of function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents. Hattori T, Makiyama T, Akao M, Ehara E, Ohno S, Iguchi M, Nishio Y, Sasaki K, Itoh H, Yokode M, Kita T, Horie M, Kimura T. Cardiovasc Res 2012;93(4):666-673

An 8-year-old girl with a markedly short QT interval (QT/QTc = 172/194 ms) who suffered from paroxysmal AF was studied. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than –30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification.

In addition to paroxysmal AF the girl had been suffering from multiple disorders, such as severe mental retardation, abnormal proliferation of oesophageal blood vessels, epilepsy, and Kawasaki disease. Her family did not undergo genetic evaluation but ECGs from her father, elder brother and a younger sister showed a normal QT in all of them.

Decreased inward rectification of Kir2.1 channels is a novel mechanism underlying the short QT syndrome Casini S, Postma AV.. Cardiovasc Res 2012;93:535-536

Editorial comments to previous article.

Genetic mutations in patients with Brugada Syndrome and a short QT interval

CACNA1C & CACNB2

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short OT Intervals, and Sudden Cardiac Death. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu L-F, Jaissaguerre M, Schrimpf R, Borggrefe M, Wolpert C. Circulation 2007;115:442-449

By screening of 82 consecutive probands with clinically robust diagnosis of Brugade Syndrome for ion channel gene mutations, they found 3 probands displaying ST-segment elevation in V1 through V3 and QTc </= 360msec among 7 who had mutations in genes encoding the cardiac L-type calcium channel. Rate adaptation of QT interval was reduced just like in patients with SQTS and Quinidine normalized the QT intervals and prevented stimulation-induced VT.Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the α1 and β2b –subunits of the L-type calcium channel.Patch-clamp experiments showed that the two mutations in CACNA1C and the one mutation in CACNB2__b all cause a major loss of function in calcium channel activity.

This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada Syndrome phenotype is combined with shorter-than-normal QT intervals.

Presence of Short QT Identifies Brugada Syndrome Patients With Higher Yield of CACNA1c Mutations: Implications for Genotyping Strategies**.** Novelli V, Memmi M, Cerrone M, Bkoise R, Zucca F, Song C, Napolitano C, Priori SG. AHA Scientific Sessions 2011, Orlando Florida

By screening for CACNA1c mutations in 26 BrS patients with QTc < 360 msec, 4 were found to have the mutations (15%) compared to only 2 (1.1%) in 168 BrS patients with QTc > 360 msec. Because of the high cost of genetic screening it is therefore suggested that screening of BrS patients for CACNA1c should be limited to patients with QTc < 360 msec, where the incidence of this mutation is comparable to the incidence of SCN5A mutations in BrS patients in general.

It is important to emphasize that, without knowledge of the HR in the 2 patients with positive mutation among BrS patients with QTc > 360 msec, it is still possible that they may belong to the overlapping phenotype patients who show very little change in QT with changes in HR, as shown in the paper by Antzelevitch et al.

S755T-CACNA2D1

Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Templin C, Ghadri JR, Rougier JS, Baumer A, Kaplan V, Albesa M, Sticht H, Rauch A, Puleo C, Hu D, Barajas-Martinez H, Antzelevitch C, Lüscher TF, Abriel H, Duru FEur Heart J. 2011;32(9):1077-1088

A 17-year old Caucasian female presented following sudden loss of consciousness while sitting during a church service. Initial ECG showed VF. After defibrillation the patient arrived at a hospital where the ECG showed SR with a QT interval of 317 msec (QTc 329 msec) and intermittent incomplete RBBB. Flecainide provocation test with IV Flecainide 2 mg/kg while the ECG showed incomplete RBBB did not produce Brugada-like changes, but slight depression of the J-point with doming of the ST-segment. Programmed ventricular stimulation in the right atrium induced self-terminating atrial tachycardia and atrial fibrillation and the atrial effective refractory period was 180 ms. Stimulation from the RV apex with S1/S2 of 600/260 ms induced VF. No numbers given for the ventricular effective refractory period, but it is mentioned that it was short. DNA screening showed a new variant at a heterozygous state in the CACNA2D1 gene (nucleotide c.2264G>C; amino acid p.Ser755Thr) encoding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. In vitro analysis of the S755T variant in the CACNA2D1 gene showed a strongly reduced current compared with the WT.

The CACNA2D1 gene has recently been linked to Brugada Syndrome and early repolarization syndrome and since it is known that there is a low penetrance for clinical manifestations of the Brugada Syndrome in young females, and a false negative response to Flecainide is common, it is somewhat unsettled whether this patient has SQTS only or a short QT interval combined with some other abnormality.

R689H-SCN5A

Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation Hong K, Hu J, Yu J, Brugada R.. European Journal of Human Genetics 2012;20:1189-1192

Asymptomatic 40-year-old male with family history of sudden death of unknown origin was found to have a Brugada-like ECG with a QT interval of 320 ms at 71 bpm. Sequence analysis of the coding region of the SCN5A gene identified an R689H mutation, and patch clamp analysis confirmed it to be a loss-of-function mutation.

Molecular Insights into Short QT Syndrome Srikanth Perike, Mark D. McCauley. J Innov Card Rhythm Manag 2018;9(3):3065-3070

Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants Oscar Campuzano, Anna Fernandez-Falgueras, Ximena Lemus, Georgia Sarquella-Brugada, Sergi Cesar, Monica Coll, Jesus Mates, Elena Arbelo, Paloma Jordà, Alexandra Perez-Serra, Bernat del Olmo, Carles Ferrer-Costa, Anna Iglesias, Victoria Fiol, Marta Puigmulé, Laura Lopez, Josep Brugada and Ramon Brugada J. Clin. Med. 2019;8:1035-1052

An Update on the Structure of hERG Andrew Butier,Matthew V. Hellwell, Yihong Zhang, Jules C. Hancox and Christopher E. Dempsey Front. Pharmacol. 2020;10:1-13

CACNA1C-Related Disorders Carlo Napolitano, Katherine W Timothy, Raffaella Bloise, Silvia G Priori, Margaret P Adam, Holly H Ardinger, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Ghayda Mirzaa, Anne Amemiya Gene Reviews 2021:1-3

A novel variant in KCNQ1 associated with short QT syndrome Kristin Schneider, Ashley Parrott, David Spar, Timothy Knilans, Richard Czosek, Erin Miller, Jeffrey Anderson. Heart Rhythm Case Reports 2021;7:650-654

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population Estefania Martinez-Barrios, Sergio Cesar, Jose Cruzalegui, Clara Hernandez, Elema Azbelo, Victoria Fiol, Josep Brugada, Ramon Brugada, Oscar Campuzano and Georgia Sanguella-Brugada.

Abstract: Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children