Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland

Area of Science:

• Cardiovascular Genetics
• Human Genetics
• Molecular Cardiology

Background:

• Long-QT syndrome (LQTS) is a cardiac repolarization disorder linked to sudden cardiac death.
• Pathogenic variants in KCNQ1, KCNH2, and SCN5A are primary causes of LQTS.
• Limited data exist on LQTS epidemiology, variant expressivity, and penetrance.

Purpose of the Study:

• To screen for rare coding variants associated with the corrected QT (QTc) interval in Iceland.
• To investigate the frequency, penetrance, and association with severe events of identified variants.
• To enhance understanding of LQTS genetic underpinnings and clinical implications.

Main Methods:

• Screening for rare coding variants impacting the QTc interval in an Icelandic cohort.
• Analysis of variant frequencies, penetrance, and correlation with severe clinical outcomes.
• Statistical association testing for QTc interval prolongation and sudden cardiac death.

Main Results:

• Twelve variants associated with the QTc interval were identified, including in KCNQ1, KCNH2, MYBPC3, PKP2, ISOC1, and MYOM2.
• Combined carrier frequency for 8 variants in known LQTS genes was 1:190.
• KCNQ1 variants p.Tyr315Cys and p.Leu273Phe showed strong QTc prolongation and p.Leu273Phe associated with sudden cardiac death; p.Val215Met had a smaller QTc effect and no severe event association.

Conclusions:

• The carrier frequency of variants associated with LQTS is higher than previously estimated.
• Identified variants exhibit variable expressivity, influencing QTc interval and clinical severity.
• Findings support improved identification, risk stratification, and personalized clinical management for QTc prolongation.