Exome sequencing of a family with lone, autosomal dominant atrial flutter identifies a rare variation in ABCB4 significantly enriched in cases

Anna Macig, Francesco Villa, Chiara Carmela Spinelli, Anna Ferrario, Albino Carrizzo, Alberto Malovini, Annalaura Torella, Chiara Montenero, Attilio Parisi, Gianluigi Condorelli, Carmine Vecchione, Vincenzo Nigro, Annibale Sandro Montenero, Annibale Alessandro Puca

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Background: Lone atrial flutter (AFL) and atrial fibrillation (AF) are common and sometimes consequential cardiac conduction disorders with a strong heritability, as underlined by recent genome-wide association studies that identified genetic modifiers. Follow-up family-based genetic analysis also identified Mendelian transmission of disease alleles. Three affected members were exome-sequenced for the identification of potential causative mutations, which were subsequently validated by direct sequencing in the other 3 affected members. Taqman assay was then used to confirm the role of any mutation in an independent population of sporadic lone AFL/AF cases. Results: The family cluster analysis provided evidence of genetic inheritance of AFL in the family via autosomal dominant transmission. The exome-sequencing of 3 family members identified 7 potential mutations: of these, rs58238559, a rare missense genetic variant in the ATP-binding cassette sub-family B, member 4 (ABCB4) gene was carried by all affected members. Further analysis of 82 subjects with sporadic lone AF, 63 subjects with sporadic lone AFL, and 673 controls revealed that the allele frequency for this variation was significantly higher in cases than in the controls (0.05 vs. 0.01; OR = 3.73; 95% CI = 1.16-11.49; = 0.013). Conclusions: rs58238559 in is a rare missense variant with a significant effect on the development of AFL/AF.

Original languageEnglish
Article number15
JournalBMC genetics [electronic resource]
Issue number1
Publication statusPublished - Feb 11 2015



  • ATP-binding cassette B4 (ABCB4)
  • Atrial fibrillation
  • Atrial flutter
  • Exome-sequencing
  • Pedigree
  • SNPs

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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