Journal
JOURNAL OF MEDICAL GENETICS
Volume 51, Issue 10, Pages 669-676Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2014-102591
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Funding
- NIH [UL1 RR025780, UL1 TR001082 N01-HV-48194, R01 HL69071, R01 116906, K23 JL067915, R01HL109209]
- CRTrieste Foundation
- GENERALI Foundation
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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.
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