title: A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block.
abstract: BACKGROUND
  LMNA/C mutations have been linked to the premature aging syndrome Hutchinson's progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype-phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.
  
  
  RESULTS
  DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members. In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype-phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.
  
  
  CONCLUSIONS
  Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.
authors.affiliation: ITB-CNR, Segrate, MI Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Villa
authors.affiliation: IRCCS Multimedica, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Maciąg
authors.affiliation: ITB-CNR, Segrate, MI Italy.
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Spinelli
authors.affiliation: ITB-CNR, Segrate, MI Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrario
authors.affiliation: IRCCS Neuromed - Parco Tecnologico, Pozzilli, IS Italy.
authors.forename: Albino
authors.initials: A
authors.lastname: Carrizzo
authors.affiliation: Università degli Studi di Roma "Foro Italico", Rome, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Parisi
authors.affiliation: Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Torella
authors.affiliation: Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Montenero
authors.affiliation: Istituto Clinico Humanitas, Rozzano, MI Italy ; Università degli Studi di Milano, Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.affiliation: IRCCS Neuromed - Parco Tecnologico, Pozzilli, IS Italy ; Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano Salerno, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.affiliation: Seconda Università degli Studi di Napoli, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
authors.affiliation: IRCCS Multimedica, Milan, Italy.
authors.forename: Annibale S
authors.initials: AS
authors.lastname: Montenero
authors.affiliation: IRCCS Multimedica, Milan, Italy ; Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano Salerno, Italy.
authors.forename: Annibale A
authors.initials: AA
authors.lastname: Puca
keywords: Arrhythmia; Atrioventricular block; Dilated cardiomyopathy; Exome sequencing; Lamin A/C