Human Mutations that Cause Tetralogy of Fallot

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Tetralogy of Fallot (TOF) accounts for approximately 8-10% of congenital heart disease. Although malformations of the cardiac outflow tract and the origins of the great arteries represent some of the severest forms of congenital heart disease, little is known about the normal molecular signals or pathways that direct development of the cardiac outflow tract, nor how and why these processes sometimes fail. Major advances in surgical correction of these anomalies over the past 30 years have led to markedly improved clinical outcome, reproductive fitness and long-term survival in some but not all patients with TOF (see Projects 1 and 2 for discussion). Whether this range in clinical outcomes reflects different causes of TOF is unknown. Molecular genetic analyses have defined a genetic etiology in approximately 25% of TOF cases (single gene defects and/or cytogenetic abnormalities). We hypothesize that unidentified monogenic mutation accounts for most TOF cases. A central theme of this project is to define the spectrum of gene mutations that cause TOF. The incidence of TOF recurrence in families implies that the TOF genetics may be complex: some cases may be dominant, but exhibit variable expressivity and incomplete penetrance, as occurs in NKX2.5 or TBX5 mutations. Other TOF cases may reflect recessive mutations. De novo germline mutations and/or somatic mutation of the developing myocardium may further contribute to nonfamilial cases of TOF. Our proposal suggests several novel approaches to define TOF disease genes and to integrate this information into data derived from other SCCOR projects so as to improve clinical outcomes in TOF. Specifically we propose to: 1. Analyze known TOF disease genes (JAG1, TBX1, TBX5, NKX2.5, FOX2 and others) for mutations to establish genotype/phenotype relationships and to identify individuals with TOF of unknown cause. 2. Clinically evaluate family members of individuals with TOF of unknown cause to stratify probands and kindreds for further genetic studies. 3. Identify potential novel TOF genes through SAGE analyses of human RV tissues. 4. Screen candidate genes for germline mutations in probands with familial TOF of unknown cause and for somatic mutations in probands with nonfamilial TOF of unknown cause. 5. Identify the genetic basis for TOF and other congenital heart malformations in pedigrees appropriate for positional cloning techniques.