Allelic complexity in long QT syndrome: A family-case study

Alberto Zullo, Giulia Frisso, Nicola Detta, Berardo Sarubbi, Emanuele Romeo, Angela Cordella, Carlos G. Vanoye, Raffaele Calabrò, Alfred L. George, Francesco Salvatore

Research output: Contribution to journalArticle

Abstract

Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers.

Original languageEnglish
Article number1633
JournalInternational Journal of Molecular Sciences
Volume18
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

Keywords

  • Cardiac arrhythmias
  • Electrophysiology
  • HERG
  • KCNH2
  • KCNQ1
  • Long-QT syndrome
  • Potassium channels

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Zullo, A., Frisso, G., Detta, N., Sarubbi, B., Romeo, E., Cordella, A., Vanoye, C. G., Calabrò, R., George, A. L., & Salvatore, F. (2017). Allelic complexity in long QT syndrome: A family-case study. International Journal of Molecular Sciences, 18(8), [1633]. https://doi.org/10.3390/ijms18081633