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ELECTROPHYSIOLOGY

An intronic mutation causes long QT syndrome

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^¶

^* LDS Hospital, Salt Lake City, Utah, USA
University of Utah School of Medicine, Salt Lake City, Utah, USA
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
University of Wisconsin, Madison, Wisconsin, USA
^|| Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
^¶ Children's Hospital, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts, USA

Manuscript received April 12, 2004; revised manuscript received June 3, 2004, accepted June 7, 2004.

^* Reprint requests and correspondence: Dr. G. Michael Vincent, Department of Medicine, LDS Hospital, 324 10th Avenue, Suite 130, Salt Lake City, Utah 84103 (Email: ldgvince{at}ihc.com).

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.

Abbreviations and Acronyms   Ex QTc-max = maximum QTc value during the exercise test, either exercise or recovery   LQTS = long QT syndrome   LQT2 = second described variant of LQTS, due to mutations of the KCNH2 (HERG) gene   RT-PCR = reverse transcription-polymerase chain reaction   Ser QTc-max = maximum QTc value among serial electrocardiograms during follow-up

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