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 -