Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy.
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.
['Brun|Francesca|F|', 'Barnes|Carl V|CV|', 'Sinagra|Gianfranco|G|', 'Slavov|Dobromir|D|', 'Barbati|Giulia|G|', 'Zhu|Xiao|X|', 'Graw|Sharon L|SL|', 'Spezzacatene|Anita|A|', 'Pinamonti|Bruno|B|', 'Merlo|Marco|M|', 'Salcedo|Ernesto E|EE|', 'Sauer|William H|WH|', 'Taylor|Matthew R G|MR|', 'Mestroni|Luisa|L|', '|||']
D000293:Adolescent D000328:Adult D017668:Age of Onset D000368:Aged D019571:Arrhythmogenic Right Ventricular Dysplasia D002648:Child D064211:Connectin D003896:Desmosomes D004562:Electrocardiography D005260:Female D006352:Heart Ventricles D006801:Humans D008297:Male D008875:Middle Aged D010375:Pedigree D055815:Young Adult
Cardiomyopathy Genetics Arrhythmias Clinical Genetics