Key result
Novel KCNH2 intronic splice variant cosegregates strongly with long QT syndrome.
Why the study?
Long QT syndrome is often caused by mutations in coding regions or splice sites, but no mutation is found in 30% to 50% of families, indicating a need to investigate intronic variants and improved phenotyping criteria.
Does the T1945+6C KCNH2 intronic variant cause long QT syndrome, and do expanded ECG criteria improve clinical diagnosis in carriers with reduced penetrance?
Observational (n=52)
Does the T1945+6C KCNH2 intronic variant cause long QT syndrome, and do expanded ECG criteria improve clinical diagnosis in carriers with reduced penetrance?
An intronic mutation (T1945+6C) in KCNH2 causes long QT syndrome by disrupting normal splicing, and expanded ECG screening helps accurately identify carriers who might otherwise be missed due to reduced penetrance.
Supports expanded ECG phenotyping to detect LQTS carriers missed by baseline QTc; extends evidence for pathogenic intronic KCNH2 variants but needs broader validation.
OBJECTIVES: The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2 is a disease-causing mutation, and if expanded phenotyping criteria produce improved identification of long QT syndrome (LQTS) patients. BACKGROUND: Long QT syndrome is usually caused by mutations in conserved coding regions or invariant splice sites, yet no mutation is found in 30% to 50% of families. In one such family, we identified an intronic variant in KCNH2. Long QT syndrome diagnosis is hindered by reduced penetrance, as the long QT phenotype is absent on baseline electrocardiogram (ECG) in about 30%. METHODS: Fifty-two family members were phenotyped by baseline QTc, QTc maximum on serial ECGs (Ser QTc-max), and on exercise ECGs (Ex QTc-max) and by T-wave patterns. Linkage analysis tested association of the intronic change with phenotype. The consequences of T1945+6C on splicing was studied using a minigene system and on function by heterologous expression. RESULTS: Expanded phenotype/pedigree criteria identified 23 affected and 29 unaffected. Affected versus unaffected had baseline QTc 484 +/- 48 ms versus 422 +/- 20 ms, Ser QTc-max 508 +/- 48 ms versus 448 +/- 10 ms, Ex QTc-max 513 +/- 54 ms versus 444 +/- 11 ms, and LQT2 T waves in 87% versus 0%. Linkage analysis demonstrated a logarithm of odds score of 10.22. Splicing assay showed T1945+6C caused downstream intron retention. Complementary deoxyribonucleic acid with retained intron 7 failed to produce functional channels. CONCLUSIONS: T1945+6C is a disease-causing mutation. It alters KCNH2 splicing and cosegregates with the LQT2 phenotype. Expanded ECG criteria plus pedigree analysis provided accurate clinical diagnosis of all carriers including those with reduced penetrance. Intronic mutations may be responsible for LQTS in some families with otherwise negative mutation screening.
No takes yet. Share an insight, caveat, or question.
Zhang et al. (2004) conducted an observational in Long QT syndrome (n=52). Intronic variant (T1945+6C) in KCNH2 vs. Unaffected family members (non-carriers) was evaluated on Linkage of the intronic change with the long QT phenotype (LOD score 10.22). The KCNH2 intronic variant T1945+6C altered splicing, failed to produce functional channels, and cosegregated with the long QT syndrome phenotype with a logarithm of odds score of 10.22.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: