A 38-year-old woman is evaluated for palpitations and syncope. A 12-lead ECG reveals a prolonged QT interval (QTc = 520 ms; normal <450 ms in women). She has no structural heart disease on echocardiography. Which investigation is most appropriate to establish the diagnosis and risk stratify this patient?

## Investigation of Choice in Congenital Long QT Syndrome **Key Point:** In a patient with prolonged QTc on resting ECG, syncope, and no structural heart disease, genetic testing for ion channel mutations (KCNQ1, KCNH2, SCN5A) is the investigation of choice to confirm congenital long QT syndrome (LQTS) and enable risk stratification and family screening. ### Why Genetic Testing? 1. **Diagnostic confirmation**: Identifies pathogenic mutations in genes encoding cardiac potassium and sodium channels - **KCNQ1** → LQT1 (most common, ~40% of cases; β-blocker responsive) - **KCNH2** → LQT2 (~35% of cases; auditory triggers) - **SCN5A** → LQT3 (~10% of cases; bradycardia-triggered; responds to sodium channel blockers) 2. **Risk stratification**: Genotype-phenotype correlation predicts arrhythmia risk, syncope severity, and sudden cardiac death risk 3. **Family screening**: Enables identification of asymptomatic carriers and cascade genetic testing 4. **Therapeutic guidance**: Genotype determines optimal antiarrhythmic therapy (β-blockers for LQT1; ICD for high-risk LQT3) ### Role of Other Investigations | Investigation | Role | Limitation | |---|---|---| | **Holter monitor** | Detects spontaneous arrhythmias (torsades de pointes); assesses QT variability | Non-specific; does NOT diagnose LQTS or identify genetic cause | | **Stress test** | Provokes QT prolongation in LQT1 (exercise-triggered); diagnostic aid | Carries arrhythmia risk in LQTS; NOT first-line; does NOT replace genetic testing | | **Electrolyte panel** | Rules out acquired LQTS (hypocalcemia, hypomagnesemia, hypokalemia) | Acquired causes are secondary; does NOT diagnose congenital LQTS | **High-Yield:** Prolonged QTc + syncope + no structural disease = **suspect congenital LQTS → genetic testing is diagnostic**. **Mnemonic:** **LQTS Genotypes & Triggers** - **LQT1 (KCNQ1)**: Exercise/emotion → β-blockers - **LQT2 (KCNH2)**: Auditory startle → β-blockers + ICD - **LQT3 (SCN5A)**: Sleep/bradycardia → sodium channel blockers + ICD **Clinical Pearl:** Torsades de pointes (polymorphic VT with QT prolongation) is the hallmark arrhythmia in LQTS and carries sudden death risk. Genetic testing enables preventive therapy (β-blockers, ICD) before life-threatening events occur. [cite:Harrison 21e Ch 226]