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

Weeke P, Parvez B, Blair M, Short L, Ingram C, Kucera G, Stubblefield T, Roden DM, Darbar D
Heart Rhythm. 2014 11 (1): 46-52

PMID: 24120998 · PMCID: PMC3947369 · DOI:10.1016/j.hrthm.2013.10.025

BACKGROUND - 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.

OBJECTIVE - 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.

METHODS - 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.

RESULTS - 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).

CONCLUSION - 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.

© 2013 Heart Rhythm Society Published by Heart Rhythm Society All rights reserved.

MeSH Terms (16)

Adult Aged Atrial Fibrillation Female Follow-Up Studies Gene Frequency Genetic Association Studies Genetic Predisposition to Disease Genetic Testing Genetic Variation Humans Male Middle Aged Polymorphism, Single Nucleotide Registries Retrospective Studies

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