Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation

Kenshi Hayashi, Tetsuo Konno, Hayato Tada, Satoyuki Tani, Li Liu, Noboru Fujino, Atsushi Nohara, Akihiko Hodatsu, Toyonobu Tsuda, Yoshihiro Tanaka, Masa-aki Kawashiri, Hidekazu Ino (+2 others)
2015 Circulation: Arrhythmia and Electrophysiology  
mia, with a prevalence of 1% to 2% in the general population. 1 In most cases, AF occurs along with hypertension, mitral stenosis, ischemic heart disease, cardiomyopathy, and hyperthyroidism. 1 In addition to these underlying diseases, age, obesity, smoking, and alcohol are clinical risk factors for AF. 1 However, 11% of AF patients present with AF in the absence of predisposing factors; these are categorized as having lone AF. 2 Previous studies have shown that at least 5% of all patients with
more » ... f all patients with AF and 15% of those with lone AF had a positive family history. 3 Another study has shown that the risk for lone AF was 3.5× higher in those with a family history of lone AF in parents or in siblings, compared with the risk in individuals without such family history. 4 Recent studies have shown that people with certain genotypes have an increased risk for future AF. 5,6 These reports indicate that the development of AF is influenced by genetic background. Editorial see p 1005 Genetic linkage analysis and candidate gene analysis for familial AF in 1997 indicated that a gene responsible for familial AF is located in the region of 10q22 to 10q24, and in 2003, a gain-of-function mutation in KCNQ1 was implicated in a large Chinese kindred with autosomal dominant AF. 7 To date, many variants in genes encoding ion-channel subunits, cardiac gap junctions, and signaling molecules have been identified in monogenic AF families. 8,9 These genetic variants predispose individuals to AF by reducing the atrial refractory period as a substrate for re-entrant arrhythmias, by lengthening the atrial action potential duration, which results in ectopic activity, or by causing impaired Background-Few rare variants in atrial fibrillation (AF)-associated genes have been functionally characterized to identify a causal relationship between these variants and development of AF. We here sought to determine the clinical effect of rare variants in AF-associated genes in patients with lone AF and characterized these variants electrophysiologically and bioinformatically. Methods and Results-We screened all coding regions in 12 AF-associated genes in 90 patients with lone AF, with an onset of 47±11 years (66 men; mean age, 56±13 years) by high-resolution melting curve analysis and DNA sequencing. The potassium and sodium currents were analyzed using whole-cell patch clamping. In addition to using 4 individual in silico prediction tools, we extended those predictions to an integrated tool (Combined Annotation Dependent Depletion). We identified 7 rare variants in KCNA5, KCNQ1, KCNH2, SCN5A, and SCN1B genes in 8 patients: 2 of 8 probands had a family history of AF. Electrophysiological studies revealed that 2 variants showed a loss-of-function, and 4 variants showed a gain-of-function. Five of 6 variants with electrophysiological abnormalities were predicted as pathogenic by Combined Annotation Dependent Depletion scores. Conclusions-In our cohort of patients with lone AF, 7 rare variants in cardiac ion channels were identified in 8 probands. A combination of electrophysiological studies and in silico predictions showed that these variants could contribute to the development of lone AF, although further in vivo study is necessary to confirm these results. More than half of AFassociated rare variants showed gain-of-function behavior, which may be targeted using genotype-specific pharmacological therapy.
doi:10.1161/circep.114.002519 pmid:26129877 fatcat:x2lw6jw55jfytonlt5ogx62doe