Savio-Galimberti, Eleonora2; Weeke, Peter3; Muhammad, Raafia2; Blair, Marcia2; Ansari, Sami2; Short, Laura2; Atack, Thomas C2; Kor, Kaylen2; Vanoye, Carlos G2; Olesen, Morten Salling1; LuCamp2; Yang, Tao2; George, Alfred L2; Roden, Dan M2; Darbar, Dawood2
1 Hjertemedicinsk Klinik, Hjertecentret Rigshospitalet, Rigshospitalet, The Capital Region of Denmark2 unknown3 Cardiology, Herlev and Gentofte Hospital, The Capital Region of Denmark
AIMS: To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology. METHODS AND RESULTS: We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype. CONCLUSION: Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility.
Cardiovascular Research, 2014, Vol 104, Issue 2, p. 355-63