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Open AccessArticle

Allelic Complexity in Long QT Syndrome: A Family-Case Study

CEINGE Biotecnologie Avanzate, 80145 Naples, Italy
Dipartimento di Scienze e Tecnologie, Università del Sannio, 82100 Benevento, Italy
Dipartimento di Medicina Molecolare e Biotecnologie, Università di Napoli Federico II, 80131 Naples, Italy
U.O.C. Cardiologia, A.O. Monaldi, Seconda Università di Napoli, 80131 Naples, Italy
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
IRCCS-Fondazione SDN, 80143 Naples, Italy
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2017, 18(8), 1633;
Received: 18 May 2017 / Revised: 13 July 2017 / Accepted: 21 July 2017 / Published: 27 July 2017
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: long-QT syndrome; cardiac arrhythmias; potassium channels; electrophysiology; KCNQ1; KCNH2; HERG long-QT syndrome; cardiac arrhythmias; potassium channels; electrophysiology; KCNQ1; KCNH2; HERG
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Zullo, A.; Frisso, G.; Detta, N.; Sarubbi, B.; Romeo, E.; Cordella, A.; Vanoye, C.G.; Calabrò, R.; George, A.L., Jr.; Salvatore, F. Allelic Complexity in Long QT Syndrome: A Family-Case Study. Int. J. Mol. Sci. 2017, 18, 1633.

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