A NEW SYNDROME OF INTRAHEPATIC BILE DUCT PAUCITY IN A NOVA SCOTIAN KINDRED NOT LINKED TO JAG1 LOCUS

M Cameron^1,2, W Greer¹, S Dyack², A Otley²

Department of Medicine, University of Calgary, Calgary, Alberta

BACKGROUND: Alagille Syndrome, an autosomal dominant condition characterized by intrahepatic bile duct paucity as well as other anomalies, is associated with mutations in the JAG1 gene on chromosome 20p. We have identified a consanguineous kindred with five individuals affected with an Alagille-like phenotype, but with apparent autosomal recessive inheritance.
AIM: We hypothesized that the Alagille-like condition present in this family was was a novel syndrome unrelated to a JAG1 mutation. We conducted a linkage analysis study to determine whether this condition was linked to the JAG1 gene.
METHODS: Facial photographs, medical histories and blood were collected and DNA was extracted from thirty members of the affected kindred. Four polymorphic DNA markers, D20S189, D20S894, D20S160, and D20S162, all closely flanking the JAG1 gene, were used to genotype family members using a PCR-based microsatellite analysis to follow the segregation of alleles through the family.
RESULTS: All five affected individuals had neonatal cholestasis with intrahepatic bile duct paucity, with three having pulmonary stenosis. None of the affected had posterior embryotoxin, or vertebral anomalies. Segregation of alleles showed that two affected siblings had different haplotypes and did not share any alleles at the JA1 locus. Further, in the second sibship, two unaffected and one affected sibling inherited the same parental haplotypes.
CONCLUSIONS: Due to the inheritance pattern, the disease presentation and the segregation pattern of the JAG1 gene in this family, we conclude that the condition present in this family is not autosomal dominant Alagille syndrome and is not caused by a JAG1 mutation. Future studies will include an analysis of additional polymorphic markers linked to other genes associated with the intracellular pathways involving JAG1.