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Excerpt
Jagged1 (JAG1) has been identified as the disease gene for Alagille syndrome (AGS), a dominantly inherited multisystem disorder involving the liver, heart, and other systems. Pedigree analysis has demonstrated that expression of this disorder is highly variable, with partial phenotypes seen in family members of probands. We therefore hypothesized that individuals with partial phenotypes of AGS (i.e. isolated heart defects) will be found to haveJagged1 mutations. To test this, we studied family members of patients with classically defined AGS and patients ascertained through cardiology with isolated heart defects of the type seen in AGS (peripheral pulmonic stenosis, tetralogy of Fallot).
Thirty two AGS patients with mutations in JAG1 were identified and in seven cases the mutation was found to be inherited. In 4 of these 7, there is a family member with cardiac findings and no clinical liver disease(unspecified heart murmur in 2 parents, peripheral pulmonic stenosis in a daughter and an atrial septal defect in another father). JAG1 mutations seen in these families were variable and included 2 small deletions, a five base pair insertion and a splicing mutation.
To determine if cardiology patients without a family history of Alagille syndrome also have JAG1 mutations, we initiated screening of patients with isolated cardiac disease. While these studies are still ongoing, to date, we have found JAG1 mutations in three patients. The first is a 3 1/2 year old with pulmonic stenosis, and a maternal family history of heart defects who has a single base pair insertion in exon 2 ofJAG1. Patient 2 is a 5 1/2 year old with tetralogy of Fallot and hypoplastic pulmonary arteries. Molecular cytogenetic analysis showed a deletion of 20p12, encompassing the entire JAG1 gene. The third patient is a 24 year old male with tetralogy of Fallot and a single base mutation in exon 5 that leads to an immediate stop codon. After identification of these mutations, patient 1 was found to have abnormal liver function tests.
We have identified JAG1 mutations in multiple patients with partial phenotypes of AGS including family members of classically affected probands, and patients with “isolated” cardiac defects. We therefore propose that the diagnosis of AGS include patients without hepatic manifestations. Delineation of the spectrum of clinical features associated with JAG1 mutations is important both in order to understand the action of this gene in liver and heart development and for genetic counseling of mildly affected individuals who may be at risk for having children with a more severe clinical picture.
