An intronic mutation causes long QT syndrome. J Am Coll Cardiol 2004 Sep 15;44(6):1283-91
Date
09/15/2004Pubmed ID
15364333DOI
10.1016/j.jacc.2004.06.045Scopus ID
2-s2.0-4444273245 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
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.
Author List
Zhang L, Vincent GM, Baralle M, Baralle FE, Anson BD, Benson DW, Whiting B, Timothy KW, Carlquist J, January CT, Keating MT, Splawski IMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
DNA Mutational Analysis
ERG1 Potassium Channel
Electrocardiography
Ether-A-Go-Go Potassium Channels
Family Health
Follow-Up Studies
Genetic Carrier Screening
Genetic Linkage
Genetic Predisposition to Disease
Genotype
Humans
Introns
Long QT Syndrome
Male
Middle Aged
Mutation
Pedigree
Phenotype
Potassium Channels
Potassium Channels, Voltage-Gated
RNA, Complementary
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Statistics as Topic