High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients with Early-Onset Lone Atrial Fibrillation
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High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients with Early-Onset Lone Atrial Fibrillation. / Olesen, Morten S; Yuan, Lei; Liang, Bo; Holst, Anders G; Nielsen, Nikolaj; Nielsen, Jonas B; Hedley, Paula L; Christiansen, Michael; Olesen, Søren-Peter; Haunsø, Stig; Schmitt, Nicole; Jespersen, Thomas; Svendsen, Jesper H.
In: Circulation: Cardiovascular Genetics, Vol. 5, No. 4, 2012, p. 450-459.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients with Early-Onset Lone Atrial Fibrillation
AU - Olesen, Morten S
AU - Yuan, Lei
AU - Liang, Bo
AU - Holst, Anders G
AU - Nielsen, Nikolaj
AU - Nielsen, Jonas B
AU - Hedley, Paula L
AU - Christiansen, Michael
AU - Olesen, Søren-Peter
AU - Haunsø, Stig
AU - Schmitt, Nicole
AU - Jespersen, Thomas
AU - Svendsen, Jesper H
PY - 2012
Y1 - 2012
N2 - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A.METHODS AND RESULTS: The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current.CONCLUSIONS: In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.
AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A.METHODS AND RESULTS: The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current.CONCLUSIONS: In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.
KW - Faculty of Health and Medical Sciences
U2 - 10.1161/CIRCGENETICS.111.962597
DO - 10.1161/CIRCGENETICS.111.962597
M3 - Journal article
C2 - 22685113
VL - 5
SP - 450
EP - 459
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
SN - 1942-325X
IS - 4
ER -
ID: 38320364