Author + information
- Received April 12, 2004
- Revision received June 3, 2004
- Accepted June 7, 2004
- Published online September 15, 2004.
- Li Zhang, MD*,
- G. Michael Vincent, MD, FACC*,†,* (, )
- Marco Baralle, PhD‡,
- Francisco E. Baralle, MD, PhD‡,
- Blake D. Anson, PhD§,
- D. Woodrow Benson, MD, PhD∥,
- Bryant Whiting, BA*,
- Katherine W. Timothy, BS†,
- John Carlquist, PhD*,†,
- Craig T. January, MD, PhD, FACC§,
- Mark T. Keating, MD¶ and
- Igor Splawski, PhD¶
- ↵*Reprint requests and correspondence:
Dr. G. Michael Vincent, Department of Medicine, LDS Hospital, 324 10th Avenue, Suite 130, Salt Lake City, Utah 84103
Objectives The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2is 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 KCNH2splicing 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.
Sources of funding: LDS Hospital/Deseret Foundation grant DF400, Salt Lake City, Utah; Telethon Onlus Foundation grant E1038, Trieste, Italy; NHLBI grant R01 HL60723, Madison, Wisconsin; NIH grants R01 HL46401 and SCOR HL52338, Salt Lake City, Utah.
- Received April 12, 2004.
- Revision received June 3, 2004.
- Accepted June 7, 2004.
- American College of Cardiology Foundation