Case report

Long-QT syndrome in a family witha KCNH2 mutation

Cliona Murphy and Jas GillDepartment of Cardiology, St Thomas’ Hospital, London, UK

Correspondence: Dr Cliona Murphy, Cardiology Department, 6th Floor East Wing,St Thomas’ Hospital, London SE1 7EH, UK.

E-mail: clionamurphy@hotmail.com

Conflicts of interest: None.

Abstract

Long-QT syndrome (LQTS) is an inherited ion channelopathy resulting in abnormal ventricularrepolarization and abnormal prolongation of the QT interval on the electrocardiogram. Clinicalfeatures vary, from asymptomatic individuals to those with presyncope, life threatening ventriculararrhythmias and sudden cardiac death (SCD). This case report describes a family with a mutation of theKCNH2 gene expressed phenotypically as LQT2 syndrome. The variability in phenotypic expression,the importance of family and genetic screening, and the difficult dilemma of deciding which individualswith LQTS should receive an ICD are discussed.

Heart Metab. 2008;41:30–33.

Keywords: Implantable cardioverter-defibrillator, KCNH2, long-QT syndrome, torsades de pointes

Case report

Ms X was diagnosed with epilepsy as a teenagerand for years had recurrent blackouts diagnosedas seizures. In her 40s, the episodes became morefrequent and the differential diagnosis of cardiacsyncope was raised. An electrocardiogram (ECG)showed her QT interval corrected for heart rate(QTc) to be at the upper limit of normal. Holtermonitoring was normal and she opted not to havean implantable loop recorder.

One year later, her older sister, Ms Y, suffered acardiac arrest. Recurrent torsades de pointes ventri-cular tachycardia was documented and her ECGrevealed abnormal prolongation of the QTc interval.She was diagnosed with long-QT syndrome (LQTS)and an implantable cardioverter-defibrillator (ICD)was implanted for secondary prevention. She wasplaced on prophylactic b-Blocker therapy.

Given the inherited nature of LQTS, ECG screeningwas performed in the family. The ECG of Ms X nowshowed a clearly prolonged QTc interval of 560 ms(Figure 1a). She too was diagnosed with LQTS andonly 1 week later presented with recurrent syncope

30

and torsades de pointes ventricular tachycardia(Figure 1b). Like her sister, an ICD was implanted.The ECG of child A (a niece of Ms X) revealed a QTcinterval at the upper limit of normal, but with clearlyabnormal T-wave morphology (Figure 1c).

Family genetic screening for long-QT genemutations revealed that several members were foundto have a heterozygous mutation of the potassiumchannel subunit gene, KCNH2 (also known asthe human ether-a-go-go-related gene [HERG]), onchromosome 7 (Figure 2). KCNH2 mutations arephenotypically expressed as LQT2 syndrome. Themutation, c.2306T>G (p.L769R), had not beenreported previously. It was predicted to result in thenon synonymous substitution of a conserved aminoacid, indicating a high likelihood that it was a patho-genic variant.

Phenotypic expression within the family varied;with three sisters experiencing syncope and ventri-cular arrhythmia (Ms X, Ms Y, and Ms Z) while thechildren carrying the mutation were asymptomatic.Child A had reported infrequent dizzy spells charac-teristic of vasovagal episodes which improved withb-blockers.

Heart Metab. 2008; 41:30–33

Case reportKCNH2 mutation and long-QT syndrome

Figure 1. (a) 12-Lead electrocardiogram (ECG) of Ms X,showing a prolonged QTc interval of 560 ms and low-amplitude T waves. (b) Rhythm strip recorded duringsyncope in Ms X, showing onset of torsades de pointesventricular tachycardia. (c) 12 lead ECG of child A (nieceof Ms X), showing a borderline QT interval corrected forheart rate (QTc) and broad based T wave with a late peakand indistinct T-U complex termination. HR, heart rate;PVC, premature ventricular contraction.

Ms Z Ms X Ms YProband

= KCNH2 mutation and clinically affected

= KCNH2 mutation

Child A

Figure 2. Pedigree of a family with a heterozygous mutationof the potassium channel subunit gene, KCNH2, onchromosome 7. Ms X, Ms Y, and Ms Z are clinicallyaffected; four children are mutation carriers. The pedigreeillustrates a female predominance of inheritance andvariable penetrance.

Heart Metab. 2008; 41:30–33

Discussion

Long-QT syndromeLong-QT syndrome is a rare inherited genetic disordercaused by mutations in cardiac potassium or sodiumion channel genes [1–3]. Reductions in the effectiverepolarising currents of these defective ion channelslead to prolonged ventricular repolarisation and asusceptability to ventricular arrhythmias and suddencardiac death. The ECG QTc interval, representingactivation and recovery duration of the ventricularmyocardium, is abnormally prolonged.

Genetics

Most LQTS mutations have a heterogeneous auto-somal dominant pattern of inheritance, with anestimated prevalence of around 1 : 10 000 of thepopulation. Hundreds of mutations in eight genes(LQTS 1–8), have been identified to date [4]. LQTS1–3 account for 95% of known mutations, with eachsyndrome exhibiting different genetic and clinicalcharacteristics (Table I). Clinical presentation oflong-QT syndrome can vary significantly due to thedifferent genotypes and variable penetrance. Affectedfamilies tend to have their own novel or ‘‘private’’mutations. Transmission is not strictly Mendelian withan excess of female carriers among the offspring ofmutation carriers.

The LQT2 gene, KCNH2, is located on the long (q)arm of chromosome 7 and encodes the pore-formingsubunit of the potassium channel. The mutationresults in diminution of the repolarising rectifyingpotassium current (IKR) with abnormal ventricularrepolarisation [5]. Over 200 mutations in the KCNH2gene have been identified.

Clinical features and diagnosis

LQTS carriers may be identified because of symptoms,incidentally, or during family screening. Most muta-tion carriers remain asympomatic throughout life,hence clinical disease is less common than themutation rate. LQTS is identified by abnormal pro-longation of the QT interval on the ECG. Normalupper limits of the QTc interval are <460 ms forwomen and <450 ms for men. However, highly vari-able disease expression means that such screeningtests such as have a sensitivity less than 100%. Indeed,mutation carriers may have normal ECGs or dynamicQTc intervals as illustrated in the case of Ms X, whoseQTc interval was initially normal. Causes of acquiredprolongation of the QT interval should be excludedbefore a diagnosis of LQTS is made.

There is a spectrum of clinical manifestations inLQTS from presyncope to syncope from ventriculararrhythmias and sudden cardiac death. The classic

31

Case reportCliona Murphy and Jas Gill

Tab

leI.

Com

mon

form

sof

long-

QT

synd

rom

e:ge

net

ican

dcl

inic

alch

arac

teri

stic

s.

Long

QT

syndro

me

LQT1

LQT2

LQT3

Dis

ease

-ass

oci

ated

gene

KC

NQ

1K

CN

H2

(HER

G)

SCN

5A

In-v

itro

effe

ctD

ecre

ased

I Ks

Slow

del

ayed

rect

ifier

pota

ssiu

mcu

rren

tD

ecre

ased

I Kr

Rap

iddel

ayed

rect

ifier

pota

ssiu

mcu

rren

tPro

longe

dpla

teau

I Na

Dep

ola

rizi

ng

inw

ard

sodiu

mcu

rren

tR

esti

ng

ECG

Bro

adT

wav

eLo

w-a

mpli

tude

Tw

ave,

bifi

d/n

otc

hed

Tw

ave

Long

isoel

ectr

icST

segm

ent,

bra

dyc

ardia

Arr

hyt

hm

iapre

cipit

ants

Phys

ical

or

emoti

onal

stre

ss,

swim

min

gA

coust

icst

imuli

/sta

rtle

,phys

ical

or

emoti

onal

stre

ss,

rest

Res

t,sl

eep

ECG

atonse

tof

arrh

ythm

iaN

opau

sePau

seco

mm

on

Not

know

nC

linic

alre

sponse

tob

-blo

cker

sY

esY

es(l

ess

than

LQT1)

Insu

ffici

ent

dat

a?

Less

effe

ct

ECG

,el

ectr

oca

rdio

gram

;LQ

T,

long

QT.

32

arrhythmia is Torsade de pointes ventricular tachy-cardia. The mean age for first manifestation of thedisease is 12 years, but there is a wide range, from thefirst year of life to as late as the fifth and sixth decades.Sudden death and syncope are uncommon in patientsolder than 40 years. Arrhythmias may be elicited bystress and emotion or may occur at rest or during sleep[6]. In LQT2 syndrome, sudden loud noises or startlesuch as an alarm clock, may trigger arrhythmic events.To assist diagnosis, clinical criteria such as theSchwartz scoring system have been developed todetermine the probability of having LQTS, encom-passing symptoms, family history, and the QTc inter-val amongst other features [7]. Additional ECG abnor-malities such as abnormal T wave morphology arecommon. Wide-based T waves are most frequentlyseen in LQT1 whereas notched T waves are mostcommonly seen in LQT2. The diagnosis of LQTSmay only be apparent after provocation tests suchas treadmill testing which may yield an abnormal QTcresponse to exercise [8].

Risk stratification

The QTc interval is the strongest predictor of risk forcardiac events, with an interval exceeding 500 mscarrying a greater than 50% risk of an event beforethe age of 40 years. Other high-risk features includeprevious cardiac arrest, symptoms despite adherenceto adequate b-blockade, symptoms before puberty,recurrent syncope believed to be caused by arrhyth-mias, male sex in LQT3 carriers irrespective of QTinterval, or onset of syncope with noise or rest [9]. Afamily history of sudden cardiac death or the pro-band’s severity of symptoms do not appear to predictseverity in other genetically affected family members.The location of the altered amino acids(s) within theion channel may also affect prognosis, LQT2 carrierswith mutations in the pore region are at increased riskfor cardiac events compared with non-pore mutations[10].

Genetic and family screening

As an inheritable channelopathy, family screening inLQTS is clearly important. Identification of the typicaldiagnostic ECG and clinical features described aboveremains the main screening tool. Although LQTS is aclinical diagnosis, genetic testing for the more com-mon types of LQTS has now become available, andcan identify a mutation in 50–75% of probands inwhom the diagnosis appears to be clinically certain.Genetic confirmaiton of LQTS is important both forrisk stratification of the proband and for identifyingmutation carriers within the family. Once identified,silent carriers of LQTS may be prophylactically treatedwith b-blockers and receive genetic counselling. A

Heart Metab. 2008; 41:30–33

Case reportKCNH2 mutation and long-QT syndrome

negative guidance test does not, however, excludethe diagnosis, as non-coding variants or unidentifieddisease-associated genes will result in non-detection.False positive results are also possible since detectionof a previously undescribed mutation does not esta-blish a LQTS diagnosis and DNA variants of littlesignificance are well recognised.

Treatment

Therapy for LQTS is directed toward reduction of theincidence of syncope and sudden death. The lack ofrandomized trials of treatment in LQTS reflects boththe rarity of the disease and the heterogeneity of itsclinical presentations. The data to guide managementcomes from large registries and referral centers with abias toward patients with severe disease. Currenttherapeutic options involve the use of b-blockersand ICDs. Because of adrenergic triggering, affectedindividuals are also recommended to restrict theirparticipation in athletic activities.

Prophylactic treatment with b-blockers has beenshown to be effective in significantly reducing therisk of cardiac events and decreasing the death rate inLQTS [11]. b-Blockers have minimal effect on theQTc interval, but exert a protective effect by reducingthe adrenergic stress that classically precipitatesarrhythmias in LQTS. Long acting agents are recom-mended as first line treatment in all affected individ-uals, with efficacy assessed by the blunting of theexercise heart rate. They are effective in preventingcardiac events in approximately 70% of patients andthus do not provide absolute protection against fatalcardiac arrhythmias. Effectiveness in LQT3 syndromeis less clear than for LQT1 and LQT2.

Implantation of an ICD is indicated for LQTScarriers at high risk of sudden death. The pacemakerfunction is also used in those with pause-dependentor bradycardia-induced ventricular tachycardia. Animportant clinical dilemma has been deciding withcertainty who should or should not have a defibrilla-tor. The American College of Cardiology/AmericanHeart Association/European Society of Cardiologyhave issued guidelines, which include the use ofICDs, for the management of LQTS [12]. Prophylacticb-blockade has a Class I indication for all individualswith abnormal prolongation of the QT interval,regardless of symptoms. ICDs have a Class I indicationin secondary prevention for those surviving cardiacarrest, Class IIa for those with symptoms or syncopewhile taking b-blockers, and Class IIb for primaryprevention in those with possible high-risk character-istics. Thus, ICD indications for secondary preventionin LQTS are clear but their use in primary prevention

Heart Metab. 2008; 41:30–33

is more controversial and debated. One approachwould be to implant an ICD for primary preven-tion in all patients with LQTS, given the risk ofsudden cardiac death. In contrast, ICDs are typicallyimplanted in young patients with LQTS, who will havethe device for decades, with the significant risks ofcomponent failure or infection. Clinical judgment andrisk assessment must prevail while outcomes of ICDuse in primary prevention are pending.

Conclusion

Although a rare congenital disorder, LQTS can havedevastating consequences, ranging from syncope tosudden cardiac death. b-Blockers and ICDs are themainstay of treatment. A more detailed knowledgeof the risks conferred by different genetic mutations,and long-term follow-up studies of patients receivingICDs for primary prevention, will help further toinform decision making in the management of thissyndrome.

REFERENCES

1. Roden DM. Clinical practice. Long-QT Syndrome. N Engl JMed. 2008;358:169–176.

2. Kass RS, Moss AJ. Long QT syndrome: novel insights into themechanisms of cardiac arrhythmias. J Clin Invest. 2003;112:810–815.

3. Bennett PB, Yazawa K, Makita N, George AL. Molecularmechanism for an inherited cardiac arrhythmia. Nature.1995;376:683–685.

4. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutationsin long-QT syndrome genes: KVLQT1, HERG, SCN5A,KCNE1, and KCNE2. Circulation. 2000;102:1178–1185.

5. January CT, Gong Q, Zhou Z. Long QT syndrome: cellularbasis and arrhythmia mechanism in LQT2. J Cardiovasc Elec-trophysiol. 2000;11:1413–1418.

6. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype–phenotype correlation in the long-QT syndrome: gene-specifictriggers for life-threatening arrhythmias. Circulation. 2001;103:89–95.

7. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnosticcriteria for the long QT syndrome: an update. Circulation.1993;88:782–784.

8. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK,Porter CB. Epinephrine-induced QT interval prolongation: agene-specific paradoxical response in congenital long QTsyndrome. Mayo Clin Proc. 2002;77:413–421.

9. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification inthe long-QT syndrome. N Engl J Med. 2003;348:1866–1874.

10. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk ofarrhythmic events in long-QT syndrome with mutations inthe pore region of the human ether-a-go-go-related genepotassium channel. Circulation. 2002;105:794–799.

11. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limita-tions of beta-blocker therapy in congenital long-QT syndrome.Circulation. 2000;101:616–623.

12. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006guidelines for management of patients with ventriculararrhythmias and the prevention of sudden cardiac death.Circulation. 2006;114:e385–e484.

33