TY - JOUR T1 - Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy JF - Journal of Medical Genetics JO - J Med Genet SP - 669 LP - 676 DO - 10.1136/jmedgenet-2014-102591 VL - 51 IS - 10 AU - Francesca Brun AU - Carl V Barnes AU - Gianfranco Sinagra AU - Dobromir Slavov AU - Giulia Barbati AU - Xiao Zhu AU - Sharon L Graw AU - Anita Spezzacatene AU - Bruno Pinamonti AU - Marco Merlo AU - Ernesto E Salcedo AU - William H Sauer AU - Matthew R G Taylor AU - Luisa Mestroni Y1 - 2014/10/01 UR - http://jmg.bmj.com/content/51/10/669.abstract N2 - 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. ER -