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.^[7]
• 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 at approximately 2.7 per 100,000 (~0.0027%), though estimates vary with the QTc threshold and clinical criteria used; 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:

• Current ESC ventricular-arrhythmia guideline approach (2022): a stand-alone clinical diagnosis is generally made with an extremely short QTc, around ≤320 ms, without requiring additional supporting features, provided the measurement has been carefully verified and secondary causes of QT shortening (for example hyperkalaemia, hypercalcaemia, acidosis, hyperthermia, digoxin effect) have been excluded. A broader, less short QTc (roughly 320-360 ms) requires additional clinical, familial or genetic context (e.g. a pathogenic variant, family history of SQTS, family history of SCD <40 years, or survival of VT/VF without structural heart disease) before the diagnosis is supported^[1]
• Gollob probability score (an older, pre-ESC scoring system, analogous to the Schwartz score for LQTS): weights ECG findings, clinical history, family history and genetics to classify low/intermediate/high probability; useful as contextual evidence but is a separate, older framework from the current ESC diagnostic classes above and the two should not be conflated as a single unified rule

NHS Genomic Medicine Service testing-eligibility criteria (R-codes) are a separate funding/eligibility framework for who qualifies for NHS-funded genetic testing, they are not themselves diagnostic criteria for SQTS.

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

1. General measures:

• Genetic counselling and family cascade testing, see the Genetic Testing page

2. 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: anticoagulation as per standard AF guidelines; quinidine/hydroquinidine may help AF control and simultaneously address arrhythmic risk

3. Device therapy:

• ICD: the therapy with the strongest evidence for secondary prevention, first-line in survivors of cardiac arrest^[1]

• 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]