Short QT Syndrome

Monogenic (Mendelian): a minority with a definite variant: gain-of-function KCNH2 (SQT1), KCNQ1, KCNJ2^[2]

Acquired: secondary short QT (hyperkalaemia, hypercalcaemia, acidosis, digoxin) is separate and reversible^[3]

Complex (likely polygenic): most cases are gene-elusive; the genetic architecture is incompletely defined^[2]

Inheritance: Autosomal dominant; male predominance (estimated 2.7 in 100,000; 0.02–0.1% prevalence). First described by Gussak et al. in 2000^[4]; first genetic subtype identified by Ramon Brugada et al. in 2004.^[3]

Genetic yield: Only ~20% with genetic testing, majority (>80%) are genetically elusive. Nine genotypes described to date.

ClinGen-validated genes (Walsh et al, EHJ 2022, SQTS reappraisal)^[2]:

• KCNH2 (SQT1), Definitive: Gain-of-function in IKr channel (hERG/Kv11.1); accelerates repolarisation; paradoxically the same gene causes LQT2 when loss-of-function. Key mutations: N588K, T618I. Most evidence.
• KCNQ1 (SQT2), Strong: Gain-of-function in IKs channel (same gene as LQT1 when loss-of-function). Very few described variants (only 1 in ClinGen curation).
• KCNJ2 (SQT3), Moderate: Gain-of-function in IK1 channel (inward rectifier); same gene as Andersen-Tawil syndrome when loss-of-function. Very limited evidence (5 variants).
• SLC4A3, Moderate: Anion exchanger; novel candidate gene with moderate evidence.

Important caveat (Walsh et al 2022)^[2]: Evidence for most SQTS genes is derived from very few variants (5 in KCNJ2, 2 in KCNH2, 1 in KCNQ1/SLC4A3). All SQTS genes lack a definitive replication across independent studies. Genetic results must be interpreted with extreme caution, low pre-test probability → high false-positive risk. Other reported genes (CACNA1C, CACNB2, SCN5A) are likely phenocopies or overlap syndromes rather than true SQTS.

Pathophysiology: Accelerated K⁺ efflux (SQT1–3) or attenuated Ca²⁺ influx → shortened ventricular action potential → abbreviated QTc → shortened refractory period → susceptibility to re-entrant AF and VF.

Very rare, estimated prevalence 2.7 per 100,000 (0.02–0.1%); first described by Gussak et al in 2000^[4][3]

Affects a wide age range, from neonates to elderly; the syndrome is present across all age groups from infancy to old age^[3]

Strongly associated with ventricular fibrillation and sudden cardiac death; paroxysmal AF is often an early manifestation

Genetic testing identifies a causal variant in only ~20% of cases, the majority (>80%) remain genetically elusive; nine genetic subtypes described to date^[3]

Common mutations: KCNH2 (SQT1, gain-of-function, definitive), KCNQ1 (SQT2, strong), KCNJ2 (SQT3, moderate)^[3]

Diagnostic Criteria:

• High probability: QTc ≤330 ms (some use ≤340 ms with clinical features)
• Intermediate/diagnostic: QTc <360 ms AND ≥1 of: (a) pathogenic mutation; (b) family history of SQTS; (c) family history of SCD <40 years; (d) survival of VT/VF without structural heart disease
• Gollob score (analogous to Schwartz score), ECG, clinical history, family history, genetics scored to classify low/intermediate/high probability

ECG features (Pérez-Riera et al, J Electrocardiol 2024; Boulmpou et al, J Pers Med 2025)^[6][3]:

• Very short QTc (often <300 ms in symptomatic cases)
• Tall, narrow, peaked T waves: short isoelectric ST segment; rapid transition from J-point to T-wave peak
• T wave appears symmetric on 12-lead ECG, but vectorcardiogram confirms T loop asymmetry, efferent branch dashes are closer together (Pérez-Riera 2024)^[6]
• "Minus-plus T wave sign", described as a specific ECG marker
• Short atrial refractory period → paroxysmal AF (often first manifestation); Holter may capture AF spontaneously converting to sinus rhythm
• Short ventricular refractory period → VF susceptibility

Clinical Features:

• Wide age range, from neonates to elderly; presentations at any age from infancy to old age
• Often asymptomatic, incidental ECG finding
• Palpitations, presyncope, syncope
• Cardiac arrest (VF), may be first presentation
• Paroxysmal AF, often early onset (<40 years), may convert spontaneously
• Sudden infant death syndrome reported in SQTS families

Baseline:

• 12-lead ECG (measure QTc accurately - multiple formulas may underestimate)
• Holter monitoring - assess for atrial/ventricular arrhythmias
• Echocardiography - exclude structural disease

Provocation testing:

• Exercise ECG - less pronounced QT shortening with exercise
• Pharmacological testing (epinephrine, ajmaline) - research setting

High-risk patients (cardiac arrest, documented VF):

• ICD: Only proven therapy for secondary prevention, first-line in survivors of cardiac arrest^[1]

Primary prevention / medical therapy:

• Hydroquinidine (preferred where available, prolongs QTc via IKr inhibition; most pharmacological evidence in SQTS^[3]): reduces arrhythmic events; first-line pharmacological option in high-risk patients unsuitable for ICD
• Quinidine (bisulfate formulation, alternative): may prolong QT interval and reduce VF inducibility; consider alongside ICD to reduce device therapies
• ESC 2022 guideline: quinidine Class IIb for primary prevention in SQTS with strong family history of SCD^[2]

Atrial fibrillation management:

• Anticoagulation as per standard AF guidelines
• Quinidine/hydroquinidine may help AF control and simultaneously address arrhythmic risk

• VF and sudden cardiac death: possible from infancy, and no QTc threshold reliably predicts it^[1]
• Atrial fibrillation: often at a young age, and may be the presenting feature
• Inappropriate ICD shocks: from T-wave oversensing (tall, peaked T waves)

Quantitative natural history: In the largest natural-history cohort (73 patients; mean QTc 314 ms), cardiac arrest was frequently the sentinel event, and the estimated probability of a first arrhythmic event by age 40 was approximately 41% in probands. Crucially, QTc duration itself did not predict events, a very short QTc alone should not be used to reassure or to drive ICD decisions. Hydroquinidine prevented arrhythmia recurrence in all treated patients during follow-up.^[5]

High-risk features for SCD:

• Prior cardiac arrest or documented VF: the strongest independent predictor of recurrence^[5]
• Syncope (probable arrhythmic)
• Family history of sudden death <40 years
• Very short QTc (e.g. <320 ms), a diagnostic feature, but on its own a weak risk discriminator (see above)

• Accurate QT measurement essential - use multiple leads and formulas
• Exclude secondary causes of QT shortening (hypercalcemia, hyperkalemia, acidosis, digoxin)^[1]
• Family screening essential given AD inheritance^[1]
• Avoid QT-shortening drugs if possible^[1]