Familial Tetralogy of Fallot caused by mutation in the jagged1 gene

Tetralogy of Fallot (ToF) is the most common form of complex congenital hea rt disease, occurring in similar to1 in 3000 live births. Evaluation of can didate loci in a large kindred segregating autosomal dominant ToF with redu ced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the develop ing right heart. Nine of eleven mutation carriers manifested cardiac diseas e, including classic ToF, ventricular septal defect with aortic dextroposit ion and isolated peripheral pulmonic stenosis (PPS), All forms of ToF were represented, including variants with pulmonic stenosis, pulmonic atresia an d absent pulmonary valve, No individual within this family met diagnostic c riteria for any previously described clinical syndrome, including Alagille syndrome (AGS), caused by haploinsufficiency for jagged1, All mutation carr iers had characteristic but variable facial features, including long, narro w and upslanting palpebral fissures, prominent nasal bridge, square dental arch and broad, prominent chin. This appearance was distinct from that of u naffected family members and typical AGS patients. The glycine correspondin g to position 274 is highly Conserved in other epidermal growth factor-like domains of jagged1 and in those of other proteins, Its substitution in oth er proteins has been associated with mild or atypical variants of disease. These data support either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggest that JAG1 mutations may contribute significantly to common variants of right heart obstructive dise ase.