The known high-risk p.R190Q KCNQ1-variant needs a second hit for QTc prolongation

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Electrophysiology

Background:

• Long QT syndrome (LQTS) is a disorder of cardiac repolarization.
• The KCNQ1 p.R190Q mutation is a frequent high-risk variant associated with LQTS.
• Understanding variant penetrance is crucial for risk stratification in inherited arrhythmia syndromes.

Observation:

• The heterozygous KCNQ1 p.R190Q missense mutation often presents with a low-penetrant clinical and electrocardiographical phenotype.
• This variant's low penetrance suggests that additional genetic or environmental factors are required for significant QTc prolongation.

Findings:

• Co-inheritance of the KCNQ1 p.R190Q variant with the SCN5A p.E1053K variant increases the risk of QTc prolongation.
• Concomitant LQTS-associated variants or acquired QTc-prolonging conditions (e.g., certain medications) can unmask the arrhythmogenic potential of the KCNQ1 p.R190Q variant.
• The combination of the KCNQ1 p.R190Q variant with other risk factors triggers significant QTc prolongation.

Implications:

• The KCNQ1 p.R190Q variant alone may not warrant aggressive management but necessitates careful monitoring when other risk factors are present.
• Genetic testing and risk assessment for LQTS should consider combined variant analysis and potential environmental triggers.
• This finding aids in refining genetic counseling and personalized risk management strategies for patients with potential LQTS-related mutations.