Allelic Complexity in Long QT Syndrome: A Family-Case Study
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...
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doaj-cb928895f8b34c22935ca6d41f460ebc2020-11-24T20:41:19ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-07-01188163310.3390/ijms18081633ijms18081633Allelic Complexity in Long QT Syndrome: A Family-Case StudyAlberto Zullo0Giulia Frisso1Nicola Detta2Berardo Sarubbi3Emanuele Romeo4Angela Cordella5Carlos G. Vanoye6Raffaele Calabrò7Alfred L. George8Francesco Salvatore9CEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, ItalyCEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, ItalyCEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, ItalyU.O.C. Cardiologia, A.O. Monaldi, Seconda Università di Napoli, 80131 Naples, ItalyU.O.C. Cardiologia, A.O. Monaldi, Seconda Università di Napoli, 80131 Naples, ItalyCEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, ItalyDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAU.O.C. Cardiologia, A.O. Monaldi, Seconda Università di Napoli, 80131 Naples, ItalyDepartment of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USACEINGE Biotecnologie Avanzate s.c.ar.l., 80145 Naples, ItalyCongenital 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.https://www.mdpi.com/1422-0067/18/8/1633long-QT syndromecardiac arrhythmiaspotassium channelselectrophysiologyKCNQ1KCNH2HERG |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alberto Zullo Giulia Frisso Nicola Detta Berardo Sarubbi Emanuele Romeo Angela Cordella Carlos G. Vanoye Raffaele Calabrò Alfred L. George Francesco Salvatore |
spellingShingle |
Alberto Zullo Giulia Frisso Nicola Detta Berardo Sarubbi Emanuele Romeo Angela Cordella Carlos G. Vanoye Raffaele Calabrò Alfred L. George Francesco Salvatore Allelic Complexity in Long QT Syndrome: A Family-Case Study International Journal of Molecular Sciences long-QT syndrome cardiac arrhythmias potassium channels electrophysiology KCNQ1 KCNH2 HERG |
author_facet |
Alberto Zullo Giulia Frisso Nicola Detta Berardo Sarubbi Emanuele Romeo Angela Cordella Carlos G. Vanoye Raffaele Calabrò Alfred L. George Francesco Salvatore |
author_sort |
Alberto Zullo |
title |
Allelic Complexity in Long QT Syndrome: A Family-Case Study |
title_short |
Allelic Complexity in Long QT Syndrome: A Family-Case Study |
title_full |
Allelic Complexity in Long QT Syndrome: A Family-Case Study |
title_fullStr |
Allelic Complexity in Long QT Syndrome: A Family-Case Study |
title_full_unstemmed |
Allelic Complexity in Long QT Syndrome: A Family-Case Study |
title_sort |
allelic complexity in long qt syndrome: a family-case study |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2017-07-01 |
description |
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. |
topic |
long-QT syndrome cardiac arrhythmias potassium channels electrophysiology KCNQ1 KCNH2 HERG |
url |
https://www.mdpi.com/1422-0067/18/8/1633 |
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