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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: J Peter van Tintelen; Mark M Entius; Zahurul A Bhuiyan; Roselie Jongbloed; Ans C P Wiesfeld; Arthur A M Wilde; Jasper van der Smagt; Ludolf G Boven; Marcel M A M Mannens; Irene M van Langen; Robert M W Hofstra; Luuk C Otterspoor; Pieter A F M Doevendans; Luz-Maria Rodriguez; Isabelle C van Gelder; Richard N W Hauer Journal: Circulation Date: 2006-03-27 Impact factor: 29.690
Authors: A Dénise den Haan; Boon Yew Tan; Michelle N Zikusoka; Laura Ibañez Lladó; Rahul Jain; Amy Daly; Crystal Tichnell; Cynthia James; Nuria Amat-Alarcon; Theodore Abraham; Stuart D Russell; David A Bluemke; Hugh Calkins; Darshan Dalal; Daniel P Judge Journal: Circ Cardiovasc Genet Date: 2009-06-03
Authors: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Oscar Campuzano; Olallo Sanchez-Molero; Irene Mademont-Soler; Helena Riuró; Catarina Allegue; Monica Coll; Alexandra Pérez-Serra; Jesus Mates; Ferran Picó; Anna Iglesias; Ramon Brugada Journal: Int J Mol Sci Date: 2015-10-27 Impact factor: 5.923
Authors: Marta Gigli; Rene L Begay; Gaetano Morea; Sharon L Graw; Gianfranco Sinagra; Matthew R G Taylor; Henk Granzier; Luisa Mestroni Journal: Front Cardiovasc Med Date: 2016-07-21
Authors: Rudolf A de Boer; Joseph Pierre Aboumsallem; Valentina Bracun; Douglas Leedy; Richard Cheng; Sahishnu Patel; David Rayan; Svetlana Zaharova; Jennifer Rymer; Jennifer M Kwan; Joshua Levenson; Claudio Ronco; Paaladinesh Thavendiranathan; Sherry-Ann Brown Journal: Cardiooncology Date: 2021-06-21