RT Journal Article
SR Electronic
T1 Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 669
OP 676
DO 10.1136/jmedgenet-2014-102591
VO 51
IS 10
A1 Francesca Brun
A1 Carl V Barnes
A1 Gianfranco Sinagra
A1 Dobromir Slavov
A1 Giulia Barbati
A1 Xiao Zhu
A1 Sharon L Graw
A1 Anita Spezzacatene
A1 Bruno Pinamonti
A1 Marco Merlo
A1 Ernesto E Salcedo
A1 William H Sauer
A1 Matthew R G Taylor
A1 Luisa Mestroni
YR 2014
UL http://jmg.bmj.com/content/51/10/669.abstract
AB 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.