MOLECULAR ANALYSIS OF 24 ALAGILLE SYNDROME FAMILIES IDENTIFIES A SINGLE SUBMICROSCOPIC DELETION AND FURTHER LOCALIZES THE ALAGILLE REGION WITHIN 20P12

Alagille syndrome (AGS) is a clinically defined disorder characterized by cholestatic liver disease with bile duct paucity, peculiar facies, structural heart defects, vertebral anomalies, and ocular abnormaliti es. Multiple patients with various cytogenetic abnormalities involving 20p12 have been identified, allowing the assignment of AGS to this re gion. The presence of interstitial deletions of varying size led to th e hypothesis that AGS is a contiguous gene deletion syndrome. This mol ecular analysis of cytogenetically normal AGS patients was performed i n order to test this hypothesis and to refine the localization of the known AGS region. Investigation of inheritance of simple tandem repeat polymorphism alleles in 67 members of 24 cytogenetically normal Alagi lle families led to the identification of a single submicroscopic dele tion. The deletion included loci DZ0S61, D20S41, D20S186, and D20S188 and presumably intervening uninformative loci D20S189 and D20S27. The six deleted loci are contained in a single YAC of 1.9 Mb. The addition al finding of multiple unrelated probands who are heterozygous at each locus demonstrates that microdeletions at known loci within the AGS r egion are rare in cytogenetically normal patients with this disorder. This suggests that the majority of cases of AGS may be the result of a single gene defect rather than a contiguous gene deletion syndrome.