An intronic mutation causes long QT syndrome.

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Variants and Disease

Background:

• Long QT syndrome (LQTS) is often caused by mutations in coding regions or splice sites, but 30-50% of families lack identified mutations.
• Reduced penetrance, with absent baseline phenotype in ~30%, complicates LQTS diagnosis.
• An intronic KCNH2 variant (T1945+6C) was identified in a family with unexplained LQTS.

Purpose of the Study:

• To determine if the intronic KCNH2 variant T1945+6C is a disease-causing mutation.
• To assess if expanded phenotyping criteria improve the identification of LQTS patients.
• To investigate the impact of the intronic variant on KCNH2 splicing and channel function.

Main Methods:

• Phenotyping of 52 family members using baseline, serial, and exercise ECGs (QTc intervals) and T-wave patterns.
• Linkage analysis to associate the intronic variant with the LQTS phenotype.
• Minigene splicing assays and heterologous expression to study the functional consequences of T1945+6C.

Main Results:

• Expanded criteria identified 23 affected and 29 unaffected individuals, with significant differences in QTc intervals and T-wave morphology.
• Linkage analysis yielded a logarithm of odds score of 10.22, strongly associating T1945+6C with the phenotype.
• Splicing assays confirmed T1945+6C causes intron retention, leading to non-functional KCNH2 channels.

Conclusions:

• The intronic variant T1945+6C is a pathogenic mutation causing LQTS by disrupting KCNH2 splicing.
• Expanded ECG and pedigree analysis accurately diagnosed all LQTS carriers, including those with reduced penetrance.
• Intronic mutations should be considered in LQTS families with negative mutation screening results.