title: Exome sequencing of a family with lone, autosomal dominant atrial flutter identifies a rare variation in ABCB4 significantly enriched in cases.
abstract: 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; P = 0.013).
  
  
  CONCLUSIONS
  rs58238559 in ABCB4 is a rare missense variant with a significant effect on the development of AFL/AF.
authors.affiliation: IRCCS MultiMedica, Milano, Italy. amaciag@libero.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Maciąg
authors.affiliation: ITB-CNR, Segrate, MI, Italy. checco.villa@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Villa
authors.affiliation: ITB-CNR, Segrate, MI, Italy. annina.fer@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrario
authors.affiliation: ITB-CNR, Segrate, MI, Italy. spinelli.chiara@libero.it.
authors.forename: Chiara Carmela
authors.initials: CC
authors.lastname: Spinelli
authors.affiliation: IRCCS Neuromed, Parco Tecnologico, Pozzilli, IS, Italy. albino.carrizzo@gmail.com.
authors.forename: Albino
authors.initials: A
authors.lastname: Carrizzo
authors.affiliation: Università di Pavia, Pavia, Italy. alberto.malovini@unipv.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Malovini
authors.affiliation: Seconda Università degli Studi di Napoli, Napoli, Italy. annalaura.torella@unina2.it.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Torella
authors.affiliation: Università degli Studi di Roma Tor Vergata, Roma, Italy. chiara.montenero@yahoo.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Montenero
authors.affiliation: Università degli Studi di Roma "Foro Italico", Rome, Italy. attilio.parisi@uniroma4.it.
authors.forename: Attilio
authors.initials: A
authors.lastname: Parisi
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, MI, Italy. gcondorelli@yahoo.com.|Università degli Studi di Milano, Milan, Italy. gcondorelli@yahoo.com.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.affiliation: IRCCS Neuromed, Parco Tecnologico, Pozzilli, IS, Italy. cvecchione@unisa.it.|Università degli Studi di Salerno, Salerno, Italy. cvecchione@unisa.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.affiliation: Seconda Università degli Studi di Napoli, Napoli, Italy. vincenzo.nigro@unina2.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
authors.affiliation: IRCCS MultiMedica, Milano, Italy. montenero@hotmail.com.
authors.forename: Annibale Sandro
authors.initials: AS
authors.lastname: Montenero
authors.affiliation: IRCCS MultiMedica, Milano, Italy. apuca@unisa.it.|Università degli Studi di Salerno, Salerno, Italy. apuca@unisa.it.
authors.forename: Annibale Alessandro
authors.initials: AA
authors.lastname: Puca
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000235:genetics*; D001282:Atrial Flutter / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3