The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases
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The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. / Winkel, Bo Gregers; Larsen, Maiken Kudahl; Berge, Knut Erik; Leren, Trond Paul; Nissen, Peter Henrik; Olesen, Morten Salling; Hollegaard, Mads Vilhelm; Jespersen, Thomas; Yuan, Lei; Nielsen, Nikolaj; Haunsø, Stig; Svendsen, Jesper Hastrup; Wang, Yinman; Kristensen, Ingrid Bayer; Jensen, Henrik Kjaerulf; Tfelt-Hansen, Jacob; Banner, Jytte.
I: Journal of Cardiovascular Electrophysiology, Bind 23, Nr. 10, 10.2012, s. 1092-8.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases
AU - Winkel, Bo Gregers
AU - Larsen, Maiken Kudahl
AU - Berge, Knut Erik
AU - Leren, Trond Paul
AU - Nissen, Peter Henrik
AU - Olesen, Morten Salling
AU - Hollegaard, Mads Vilhelm
AU - Jespersen, Thomas
AU - Yuan, Lei
AU - Nielsen, Nikolaj
AU - Haunsø, Stig
AU - Svendsen, Jesper Hastrup
AU - Wang, Yinman
AU - Kristensen, Ingrid Bayer
AU - Jensen, Henrik Kjaerulf
AU - Tfelt-Hansen, Jacob
AU - Banner, Jytte
N1 - © 2012 Wiley Periodicals, Inc.
PY - 2012/10
Y1 - 2012/10
N2 - INTRODUCTION: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting.METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations.RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype.CONCLUSION: In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.
AB - INTRODUCTION: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting.METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations.RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype.CONCLUSION: In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.
KW - Adolescent
KW - Adult
KW - Age Factors
KW - Analysis of Variance
KW - Autopsy
KW - Child
KW - Child, Preschool
KW - Cohort Studies
KW - DNA Mutational Analysis
KW - Death, Sudden, Cardiac
KW - Denmark
KW - Electrophysiologic Techniques, Cardiac
KW - Ether-A-Go-Go Potassium Channels
KW - Female
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - HEK293 Cells
KW - Humans
KW - Infant
KW - KCNQ1 Potassium Channel
KW - Long QT Syndrome
KW - Male
KW - Membrane Potentials
KW - Mutation
KW - NAV1.5 Voltage-Gated Sodium Channel
KW - Patch-Clamp Techniques
KW - Pedigree
KW - Phenotype
KW - Romano-Ward Syndrome
KW - Transfection
KW - Young Adult
U2 - 10.1111/j.1540-8167.2012.02371.x
DO - 10.1111/j.1540-8167.2012.02371.x
M3 - Journal article
C2 - 22882672
VL - 23
SP - 1092
EP - 1098
JO - Journal of Cardiovascular Electrophysiology
JF - Journal of Cardiovascular Electrophysiology
SN - 1045-3873
IS - 10
ER -
ID: 46807044