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A missense mutation (G604S) in the S5/pore region of HERG causes long QT syndrome in a Chinese family with a high incidence of sudden unexpected death

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Abstract

Long QT syndrome (LQTS) is characterized by abnormalities in cardiac repolarization that lead to prolongation of the electrocardiographic (ECG) QT interval. Mutations in the human ether-a-go-go-related gene (HERG, KCNH2) cause the chromosome 7-linked LQT2 form of congenital LQTS, which is characterized by a prolonged QT interval and a bifid T-wave with an increased susceptibility to life-threatening cardiac arrhythmias, especially in children. We describe the genotypic and phenotypic pedigree of a large Chinese family (n = 36) in which 11 members were diagnosed with LQTS on the basis of typical ECG patterns for LQT2. Symptomatic syncopal episodes appeared in seven members of this family at a young age; an additional four members had died suddenly at ages of 18, 19, 24 and 70 years, respectively. Screening for SCN5A and HERG candidate genes identified a heterozygous missense mutation 1810G→A in exon 7 of HERG that leads to the substitution of the amino acid glycine by serine (G604S); this mutation was located in the S5/pore region of the HERG protein and was associated with a malignant phenotype. Ten of the family members carrying the mutation showed a prolongation of the corrected QT interval (QTc), and seven of these had experienced multiple syncopal episodes. The retrospective examination of documented ECG records revealed that one family member who had died suddenly also had a prolonged QT interval. This study is the first to demonstrate a close correlation between clinical phenotype and genotype with a 100% penetrance based on the pedigree of a Chinese family with LQT2.

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Abbreviations

ANKB:

ANKYRIN-B

CACNAIC:

calcium channel, voltage-dependent, l type, alpha-1c subunit

ECG:

electrocardiogram

HERG :

human ether-a-go-go-related gene

KCN:

potassium channel subfamily Q

KCNE:

potassium channel ISK-related subfamily J

KCNH:

potassium channel subfamily H

KCNJ:

potassium channel subfamily J

LQTS:

long QT syndrome

QTc:

corrected QT interval

SCN5A:

sodium channel type V alpha

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Acknowledgments

The authors are grateful to the family members who participated in this study, and to Nina Ghais for a careful reading of the manuscript. This study was supported by grant 30371571 from National Nature Sciences Foundation of China, and grants 2003DF000037 from Ministry of Science and Technology of the People’s Republic of China. We also thank the Wellcome Trust for generous project grant support (grant No: 077156/Z/05/Z).

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Author notes

  1. Yanmin Zhang

    Present address: Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, United Kingdom

Authors and Affiliations

  1. Department of Pediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China

    Yanmin Zhang

  2. Department of Cardiology, Children’s Hospital of Xi’an, Xi’an, Shaanxi, People’s Republic of China

    Nan Zhou, Jun Peng & Zenghui Xie

  3. First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China

    Wenhui Jiang & Hongmei Wan

  4. Medical College of Xi’an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, Shaanxi, People’s Republic of China

    Chen Huang

  5. Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, United Kingdom

    Andrew A. Grace

  6. Department of Cardiology, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical College of Xi’an Jiaotong University, 177 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China

    Aiqun Ma

  7. Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, United Kingdom

    Christopher L.-H. Huang

Authors
  1. Yanmin Zhang
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  2. Nan Zhou
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Corresponding authors

Correspondence to Yanmin Zhang or Aiqun Ma.

Additional information

Yanmin Zhang and Nan Zhou contributed equally to this investigation.

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Zhang, Y., Zhou, N., Jiang, W. et al. A missense mutation (G604S) in the S5/pore region of HERG causes long QT syndrome in a Chinese family with a high incidence of sudden unexpected death. Eur J Pediatr 166, 927–933 (2007). https://doi.org/10.1007/s00431-006-0346-2

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  • DOI: https://doi.org/10.1007/s00431-006-0346-2

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