Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population

Paul A. Brink, Lia Crotti, Valerie Corfield, Althea Goosen, Glenda Durrheim, Paula Hedley, Marshall Heradien, Gerhard Geldenhuys, Emilio Vanoli, Sara Bacchini, Carla Spazzolini, Andrew L. Lundquist, Dan M. Roden, Alfred L. George, Peter J. Schwartz

Research output: Contribution to journalArticle

Abstract

Background - In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results - The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions - KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Original languageEnglish
Pages (from-to)2602-2610
Number of pages9
JournalCirculation
Volume112
Issue number17
DOIs
Publication statusPublished - Oct 25 2005

Fingerprint

Long QT Syndrome
Mutation
Population
Founder Effect
Heart Rate
South Africa
Natural History
Phenotype

Keywords

  • Arrhythmia
  • Death, sudden
  • Genetics
  • Long-QT syndrome
  • Nervous system, autonomic

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. / Brink, Paul A.; Crotti, Lia; Corfield, Valerie; Goosen, Althea; Durrheim, Glenda; Hedley, Paula; Heradien, Marshall; Geldenhuys, Gerhard; Vanoli, Emilio; Bacchini, Sara; Spazzolini, Carla; Lundquist, Andrew L.; Roden, Dan M.; George, Alfred L.; Schwartz, Peter J.

In: Circulation, Vol. 112, No. 17, 25.10.2005, p. 2602-2610.

Research output: Contribution to journalArticle

Brink, PA, Crotti, L, Corfield, V, Goosen, A, Durrheim, G, Hedley, P, Heradien, M, Geldenhuys, G, Vanoli, E, Bacchini, S, Spazzolini, C, Lundquist, AL, Roden, DM, George, AL & Schwartz, PJ 2005, 'Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population', Circulation, vol. 112, no. 17, pp. 2602-2610. https://doi.org/10.1161/CIRCULATIONAHA.105.572453
Brink, Paul A. ; Crotti, Lia ; Corfield, Valerie ; Goosen, Althea ; Durrheim, Glenda ; Hedley, Paula ; Heradien, Marshall ; Geldenhuys, Gerhard ; Vanoli, Emilio ; Bacchini, Sara ; Spazzolini, Carla ; Lundquist, Andrew L. ; Roden, Dan M. ; George, Alfred L. ; Schwartz, Peter J. / Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. In: Circulation. 2005 ; Vol. 112, No. 17. pp. 2602-2610.
@article{2754910aa7174a739919b9a1bb71ad9d,
title = "Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population",
abstract = "Background - In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results - The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12{\%} of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95{\%} CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions - KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.",
keywords = "Arrhythmia, Death, sudden, Genetics, Long-QT syndrome, Nervous system, autonomic",
author = "Brink, {Paul A.} and Lia Crotti and Valerie Corfield and Althea Goosen and Glenda Durrheim and Paula Hedley and Marshall Heradien and Gerhard Geldenhuys and Emilio Vanoli and Sara Bacchini and Carla Spazzolini and Lundquist, {Andrew L.} and Roden, {Dan M.} and George, {Alfred L.} and Schwartz, {Peter J.}",
year = "2005",
month = "10",
day = "25",
doi = "10.1161/CIRCULATIONAHA.105.572453",
language = "English",
volume = "112",
pages = "2602--2610",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "17",

}

TY - JOUR

T1 - Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population

AU - Brink, Paul A.

AU - Crotti, Lia

AU - Corfield, Valerie

AU - Goosen, Althea

AU - Durrheim, Glenda

AU - Hedley, Paula

AU - Heradien, Marshall

AU - Geldenhuys, Gerhard

AU - Vanoli, Emilio

AU - Bacchini, Sara

AU - Spazzolini, Carla

AU - Lundquist, Andrew L.

AU - Roden, Dan M.

AU - George, Alfred L.

AU - Schwartz, Peter J.

PY - 2005/10/25

Y1 - 2005/10/25

N2 - Background - In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results - The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions - KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

AB - Background - In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results - The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions - KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

KW - Arrhythmia

KW - Death, sudden

KW - Genetics

KW - Long-QT syndrome

KW - Nervous system, autonomic

UR - http://www.scopus.com/inward/record.url?scp=27444442331&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27444442331&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.105.572453

DO - 10.1161/CIRCULATIONAHA.105.572453

M3 - Article

C2 - 16246960

AN - SCOPUS:27444442331

VL - 112

SP - 2602

EP - 2610

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -