Background— The life expectancy of patients undergoing a Fontan procedure is unknown. Methods and Results— Follow-up of all 1006 survivors of the 1089 patients who underwent a Fontan procedure in Australia and New Zealand was obtained from a binational population-based registry including all pediatric and adult cardiac centers. There were 203 atriopulmonary connections (AP; 1975–1995), 271 lateral tunnels (1988–2006), and 532 extracardiac conduits (1997–2010). The proportion with hypoplastic left heart syndrome increased from 1/173 (1%) before 1990 to 80/500 (16%) after 2000. Survival at 10 years was 89% (84%–93%) for AP and 97% (95% confidence interval [CI], 94%–99%) for lateral tunnels and extracardiac conduits. The longest survival estimate was 76% (95% CI, 67%–82%) at 25 years for AP. AP independently predicted worse survival compared with extracardiac conduits (hazard ratio, 6.2; P <0.001; 95% CI, 2.4–16.0). Freedom from failure (death, transplantation, takedown, conversion to extracardiac conduits, New York Heart Association III/IV, or protein-losing enteropathy/plastic bronchitis) 20 years after Fontan was 70% (95% CI, 63%–76%). Hypoplastic left heart syndrome was the primary predictor of Fontan failure (hazard ratio, 3.8; P <0.001; 95% CI, 2.0–7.1). Ten-year freedom from failure was 79% (95% CI, 61%–89%) for hypoplastic left heart syndrome versus 92% (95% CI, 87%–95%) for other morphologies. Conclusions— The long-term survival of the Australia and New Zealand Fontan population is excellent. Patients with an AP Fontan experience survival of 76% at 25 years. Technical modifications have further improved survival. Patients with hypoplastic left heart syndrome are at higher risk of failure. Large, comprehensive registries such as this will further improve our understanding of late outcomes after the Fontan procedure.

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.