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Heart Rhythm. 2014 Jan;11(1):46-52. doi: 10.1016/j.hrthm.2013.10.025. Epub 2013 Oct 10.

Candidate gene approach to identifying rare genetic variants associated with lone atrial fibrillation.

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Department of Medicine, Vanderbilt University, Nashville, Tennessee; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark.
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee.
Department of Medicine, Vanderbilt University, Nashville, Tennessee. Electronic address:



Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown.


The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands.


We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89-303], 63 screened for all) identified in the Vanderbilt AF Registry (2002-2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ≤0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible.


Median age at AF onset was 46.0 years [interquartile range 33.0-54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3-5-fold (P <.05).


No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors.


AAC; AF; Atrial fibrillation arrhythmia; BMI; Candidate genes; ECG; ESP; Exome Sequencing Project; Family study; GWAS; Genetic epidemiology; Genetic variation; IQR; LVEDD; LVEF; LVESD; MAF; Proarrhythmia; Rare variants; SNP; amino acid coding; atrial fibrillation; body mass index; electrocardiogram; genome-wide association study; interquartile range; left ventricular ejection fraction; left ventricular end-diastolic diameter; left ventricular end-systolic diameter; minor allele frequency; single nucleotide polymorphism

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