Human Molecular Genetics, 2001, Vol. 10, No. 2 163-169
© 2001 Oxford University Press
Familial Tetralogy of Fallot caused by mutation in the jagged1 gene
1Division of Cardiology, 2Institute of Genetic Medicine, 3Department of Surgery and 6Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4Division of Pediatric Endocrinology, The University of Maryland Medical Center, Baltimore, MD, USA and 5Section of Thoracic and Cardiovascular Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Tetralogy of Fallot (ToF) is the most common form of complex congenital heart disease, occurring in 
1 in 3000 live births. Evaluation of candidate loci in a large kindred segregating autosomal dominant ToF with reduced penetrance culminated in identification of a missense mutation (G274D) in JAG1, the gene encoding jagged1, a Notch ligand expressed in the developing right heart. Nine of eleven mutation carriers manifested cardiac disease, including classic ToF, ventricular septal defect with aortic dextroposition and isolated peripheral pulmonic stenosis (PPS). All forms of ToF were represented, including variants with pulmonic stenosis, pulmonic atresia and absent pulmonary valve. No individual within this family met diagnostic criteria for any previously described clinical syndrome, including Alagille syndrome (AGS), caused by haploinsufficiency for jagged1. All mutation carriers had characteristic but variable facial features, including long, narrow and upslanting palpebral fissures, prominent nasal bridge, square dental arch and broad, prominent chin. This appearance was distinct from that of unaffected family members and typical AGS patients. The glycine corresponding to position 274 is highly conserved in other epidermal growth factor-like domains of jagged1 and in those of other proteins. Its substitution in other 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 disease.
+ To whom correspondence should be addressed at: Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Ross 858, 720 Rutland Avenue, Baltimore, MD 21287, USA. Tel: +1 410 614 0701; Fax: +1 410 614 2256; Email: hdietz@welch.jhu.edu
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