title: A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death.
abstract: BACKGROUND
  Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death.
  
  
  RESULTS
  We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication.
  
  
  CONCLUSIONS
  We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.
authors.affiliation: Heart Failure Research Center, Department of Experimental Cardiology, Amsterdam, The Netherlands.
authors.forename: Roos F
authors.initials: RF
authors.lastname: Marsman
authors.forename: Abdennasser
authors.initials: A
authors.lastname: Bardai
authors.forename: Alex V
authors.initials: AV
authors.lastname: Postma
authors.forename: Jan C J
authors.initials: JC
authors.lastname: Res
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Lekanne Deprez
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Jordaens
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001281:Atrial Fibrillation / Q000235:genetics*; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005260:Female; D015321:Gene Rearrangement; D008040:Genetic Linkage; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009426:Netherlands; D010375:Pedigree; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D034904:Lamin Type A