What genetic testing is recommended for an infant with a prolonged QTc interval (>500 ms)?

Genetic Testing for Infants with QTc >500 ms

Genetic testing for infants with a QTc interval >500 ms should include comprehensive analysis of the three main LQTS genes: KCNQ1, KCNH2, and SCN5A, as these account for approximately 90% of genetically confirmed LQTS cases. 1

Rationale for Genetic Testing

A QTc interval exceeding 500 ms in an infant represents a significant risk factor for:

• Life-threatening arrhythmias
• Sudden cardiac death
• Long-term morbidity if left untreated

The European Society of Cardiology (ESC) guidelines specifically note that a QTc >500 ms is associated with a high risk for arrhythmic events and sudden cardiac death 1. For infants, this risk is particularly concerning as sudden death can be the first manifestation of LQTS in 12% of patients, with 4% occurring in the first year of life 1.

Specific Genetic Testing Recommendations

Primary Gene Panel

• KCNQ1 (LQT1): Encodes potassium channel that conducts IKs current
• KCNH2 (LQT2): Encodes potassium channel that conducts IKr current
• SCN5A (LQT3): Encodes cardiac sodium channel

These three genes account for approximately 75% of all LQTS cases and 90% of genetically confirmed cases 1. Testing should prioritize these genes as they represent the most common genetic causes of LQTS.

Extended Testing

If initial testing is negative but clinical suspicion remains high, consider testing for less common LQTS genes:

• Minor potassium channel genes (KCNE1, KCNE2)
• Calcium channel genes (CACNA1C, CACNB2b)
• Anchoring protein genes (ANK2)

Interpretation of Genetic Test Results

The interpretation of genetic test results requires careful consideration:

• Mutation type matters: Nonmissense mutations (insertions, deletions, nonsense mutations) have >99% predictive value for LQTS regardless of location 2
• Location is critical for missense mutations: Mutations in the transmembrane, linker, and pore regions of KCNQ1 and KCNH2 have high probability of being pathogenic 2
• Novel variants: Approximately 60% of detected mutations in LQTS testing are novel 3, requiring careful interpretation

Important Clinical Considerations

Before Genetic Testing

• Rule out secondary causes of QT prolongation:
  • Electrolyte abnormalities (hypocalcemia, hypokalemia, hypomagnesemia)
  • Medications (macrolide antibiotics, prokinetics)
  • Maternal autoimmune diseases (anti-Ro/SSA antibodies) 1, 4

Family Testing

• Test parents even if they have normal QT intervals, as LQTS has variable penetrance 1
• Approximately 30% of LQTS cases are due to de novo mutations with unaffected parents 1

Timing Considerations

• Do not rely solely on ECGs obtained in the first 48 hours of life, as they may lead to both false positives and false negatives 5
• Genetic testing should be initiated before discharge from the hospital for infants with QTc >500 ms 5

Management Implications of Genetic Testing

The results of genetic testing have significant therapeutic implications:

• LQT1: Highly responsive to beta-blockers; swimming should be avoided 1
• LQT2: Moderate response to beta-blockers; avoid sudden loud noises 1
• LQT3: Less responsive to beta-blockers; sodium channel blockers may be considered for QTc >500 ms 1

Pitfalls to Avoid

• Do not wait for symptoms: Treatment should be initiated in all infants diagnosed with LQTS, even if asymptomatic, due to high risk of sudden death 1
• Do not rely solely on ECG: A normal QT interval does not exclude LQTS due to variable penetrance 1
• Do not dismiss borderline results: Even with inconclusive genetic findings, clinical management should proceed based on the QTc >500 ms 6

Genetic testing results should guide not only immediate management but also long-term follow-up strategies, as LQTS is a lifelong condition with variable expression throughout different life stages.