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Original article
Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy
  1. Francesca Brun1,2,
  2. Carl V Barnes1,
  3. Gianfranco Sinagra2,
  4. Dobromir Slavov1,
  5. Giulia Barbati2,
  6. Xiao Zhu1,
  7. Sharon L Graw1,
  8. Anita Spezzacatene1,2,
  9. Bruno Pinamonti2,
  10. Marco Merlo1,2,
  11. Ernesto E Salcedo1,
  12. William H Sauer1,
  13. Matthew R G Taylor1,
  14. Luisa Mestroni1
  15. on behalf of the Familial Cardiomyopathy Registry
  1. 1Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver AMC, Aurora, Colorado, USA
  2. 2Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy
  1. Correspondence to Professor Luisa Mestroni, University of Colorado Cardiovascular Institute, 12700 E. 19th Ave #F442, Aurora, CO 80045-2507, USA; luisa.mestroni{at}


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).

Methods and 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.

  • Genetics
  • Arrhythmias
  • Cardiomyopathy
  • Clinical Genetics

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