title: Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy.
abstract: BACKGROUND
  Genotype-phenotype correlations are poorly characterised in arrhythmogenic right ventricular cardiomyopathy (ARVC). We investigated whether carriers of rare variants in desmosomal genes (DC) and titin gene (TTN) display different phenotypes and clinical outcomes compared with non-carriers (NT-ND).
  
  
  RESULTS
  Thirty-nine ARVC families (173 subjects, 67 affected) with extensive follow-up (mean 9 years), prospectively enrolled in the International Familial Cardiomyopathy Registry since 1991, were screened for rare variants in TTN and desmosomal genes (DSP, PKP2, DSG2, DSC2). Multiple clinical and outcome variables were compared between three genetic groups (TTN, DC, NT-ND) to define genotype-phenotype associations. Of the 39 ARVC families, 13% (5/39) carried TTN rare variants (11 affected subjects), 13% (5/39) DC (8 affected), while 74% (29/39) were NT-ND (48 affected). When compared with NT-ND, DC had a higher prevalence of inverted T waves in V2-3 (75% vs 31%, p=0.004), while TTN had more supraventricular arrhythmias (46% vs 13%, p=0.013) and conduction disease (64% vs 6% p<0.001). When compared with the NT-ND group, the DC group experienced a worse prognosis (67% vs 11%, p=0.03) and exhibited a lower survival free from death or heart transplant (59% vs 95% at 30 years, and 31% vs 89% at 50 years, HR 9.66, p=0.006), while the TTN group showed an intermediate survival curve (HR 4.26, p=0.037).
  
  
  CONCLUSIONS
  TTN carriers display distinct phenotypic characteristics including a greater risk for supraventricular arrhythmias and conduction disease. Conversely, DC are characterised by negative T waves in anterior leads, severe prognosis, high mortality and morbidity.
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Brun
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Carl V
authors.initials: CV
authors.lastname: Barnes
authors.affiliation: Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.affiliation: Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barbati
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Graw
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Spezzacatene
authors.affiliation: Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pinamonti
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Ernesto E
authors.initials: EE
authors.lastname: Salcedo
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Sauer
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D002648:Child; D064211:Connectin / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D055815:Young Adult
chemical_list: D064211:Connectin
keywords: Arrhythmias; Cardiomyopathy; Clinical Genetics; Genetics