Long QT syndrome (LQTS)
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Long QT syndrome (LQTS) is a genetic heart disease characterised by prolonged ventricular repolarisation and increased susceptibility to life-threatening arrhythmias. Pathogenic variants in the KCNQ1, KCNH2, and SCN5A genes are involved in up to 95% of diagnosed cases. The condition can present in different forms, and early identification of carriers enables preventive treatment strategies, including avoidance of certain medications and taking beta-blockers.
LQTS is a clinically and genetically heterogeneous heart disease characterised by prolonged ventricular repolarization. An extended frequency-corrected QT interval (QTc) of 460 to >500 ms can be demonstrated. At the molecular level, the extended QTc interval is the consequence of a decrease in the outward K+ currents (mainly IKs, IKr and IK1) or an increase in the inward currents (mainly INa and ICaL). Depending on the QTc, arrhythmias occur, which can lead to unconsciousness and sudden cardiac death. The 10-year mortality rate is 50% if untreated.
The prevalence of LQTS in the Caucasian population is at least 1:2000-2,500.
Pathogenic variants in one of the three genes KCNQ1, KCNH2 and SCN5A are detected in about 90-95% of molecular genetic positive LQTS cases. KCNQ1 and KCNH2 code for the cardiac potassium channels Kv7.1 and Kv11.1; while Kv7.1 mediates the IKs current (slow delayed rectifier K+ current), Kv11.1 is responsible for the IKr-current (rapid delayed rectifier K+ current). Both channels contribute to the repolarisation of the cell and so terminate the cardiac action potential. The SCN5A gene codes for the Nav1.5 channel, which mediates the influx of sodium ions (INa) across the cell membrane and is thus involved in the rapid depolarisation of the cardiac action potential. A pathologically reduced potassium current flow or a pathologically increased sodium current flow can prolong the duration of ventricular repolarisation and consequently QTc. In about 25% of clinically confirmed LQTS cases, no genetic cause can be found.
The molecular classification and nomenclature is based on the genes concerned:
- KCNQ1 (LQTS type 1; 45% of pathogenic variants, company data): variants with dominant or recessive expression (RW and JLN forms) have been reported. Patients with pathogenic variants in the KCNQ1 gene usually show a distinct phenotype early, with a high risk for cardiac events.
- KCNH2 (LQTS type 2; 39% of pathogenic variants, company data): there is a high risk of cardiac events. These are RW forms.
- SCN5A (LQTS type 3; 8% of pathogenic variants, company data): cardiac events are less frequent, but mortality is five times higher. Clinically, LQTS type 3 presents clinically as an RW form.
In rare forms of long‑QT syndrome, pathogenic variants have also been identified in additional genes such as CACNA1C, CALM1, CALM2, CALM3, KCNE1, KCNE2, KCNJ2, or TRDN. Several of these genes are associated with more complex or syndromic phenotypes. KCNJ2 for example is typically linked to Andersen–Tawil syndrome, which combines QT prolongation with hyperkalemic periodic paralysis. Pathogenic variants in the CALM genes can cause a particularly severe, early‑onset arrhythmogenic disorder that can present features of both LQTS and
Additionally, drugs of various classes can prolong QT time. Delayed drug metabolism, potentially caused by variants in the CYP2D6, CYP2C9, or CYP2C19 genes, can exacerbate this effect. In cases of drug-induced LQTS, supplementary diagnostics of cytochrome P450 genes may be useful.
A distinction is made between the frequent autosomal dominant Romano-Ward (RW) form and the very rare autosomal recessive Jervell-Lange-Nielsen (JLN) form, which combines biallelic pathogenic KCNQ1 or KCNE1 variants with fulminant prolonged QTc intervals and congenital sensorineural hearing loss. However, current evidence shows a continuous spectrum in which milder or low‑penetrance variants may remain clinically silent in heterozygous carriers and manifest as a long‑QT phenotype only in the biallelic state, typically without hearing loss.
A diagnosis of long QT syndrome should not rely on a single QTc threshold, but should combine ECG findings, clinical symptoms, family history, and genetic findings. A QTc ≥480 ms on repeated ECGs in the absence of secondary causes, a sufficiently high Schwartz score, or the presence of a pathogenic LQTS‑associated variant can each establish the diagnosis, while QTc values in the borderline range (around ≥460 ms) may support the diagnosis particularly in patients with unexplained syncope or aborted sudden cardiac death.
- The main diagnostic challenge in patients with QT prolongation is to distinguish congenital long QT syndrome from acquired or secondary causes of delayed ventricular repolarization. These include QT-prolonging medication, electrolyte disturbances such as hypokalaemia, hypomagnesaemia or hypocalcaemia, bradyarrhythmias, myocardial ischaemia, structural heart disease, endocrine disorders, and systemic illness. A careful review of medication exposure, metabolic status, clinical history, and serial ECG findings is therefore essential before establishing the diagnosis of congenital LQTS.
- A prolonged QT interval may also occur as a gene–environment interaction: individuals with an inherited susceptibility may develop marked QT prolongation only after exposure to QT-prolonging drugs, electrolyte imbalance, or other acquired triggers. For this reason, apparent “acquired” LQTS does not always exclude an underlying genetic predisposition.
- Genetic testing has a central role in the evaluation of clinically suspected congenital long QT syndrome. Current European and international expert recommendations support genetic testing as a Class I (“recommended”) indication in patients with a strong clinical diagnosis or high clinical suspicion of LQTS. Testing should focus on genes with robust disease association, particularly KCNQ1, KCNH2, and SCN5A, which account for the majority of genetically confirmed cases.
- Identification of a pathogenic or likely pathogenic variant can confirm the molecular diagnosis, define the LQTS subtype, and support genotype-informed clinical management. This is particularly relevant because disease triggers, arrhythmic risk, and therapeutic considerations differ between major LQTS subtypes: for example, exercise and swimming are typical triggers in LQT1, auditory or emotional stimuli in LQT2, and events during rest or sleep in LQT3. Genetic results can therefore help refine counselling, risk stratification, and individualized follow-up by the treating physicians.
- Genetic testing is also important for family management. Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives enables early identification of genotype-positive family members, including those with a normal or borderline QTc interval. This allows preventive counselling, avoidance of QT-prolonging drugs, appropriate clinical surveillance, and timely initiation of therapy where indicated.
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- Crotti L, Spazzolini C, Nyegaard M, Overgaard MT, Kotta MC, Dagradi F, et al. Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry. Eur Heart J. 2023;44(35):3357-3370. PMID: .
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