Localization of Alagille Syndrome to 2 0 P Ll.2 -p L2 by Linkage Analysis of a Three-generation Family

A bstract Alagille syndrome (AGS) or arteriohepatic dysplasia is a rare but well-defined clinical entity that is usually inherited as an autosomal dominant trait. A lim­ ited number of patients carry a deletion in chromosome 20p, with 20p 11.23— pi 2.2 as the area of minimal overlap. Recently, a family has been identified in which a balanced translocation with a breakpoint in 20p l 2 co-segregates with the AGS phenotype. Here, we report a three-genera­ tion family with AGS and in which the affected members have a normal karyotype. Linkage analysis was perfozTned with markers from the 20p candidate region. A lod score of Z=2.96 was obtained with D20S27 at no recombina­ tion. Combining D20S27 and D20S61 to a single highly informative locus resulted in a maximum lod score of Z-+ 3.56 at 0=0.0. Haplotype analysis positioned AGS between D20S59 and D20S65, markers that define an in­ terval of about 40 cM. Allelic loss was not observed for the tested markers and no abnormalities in the PAX1 can­ didate gene were detected. These findings demonstrate that the locus on chromosome 20p could be responsible for AGS in cytogenetically normal patients and argues for a general role of this locus in the aetiology of AGS.