Alagille syndrome associated with a paracentric inversion 20p12.2p13 disrupting the JAG1 gene

Mutations in the human gene Jagged1 (JAG1) localized in 20p12 have been rec ently identified as causal for the anomalies found in patients with Alagill e syndrome (AGS). This gene encodes a ligand for the Notch1 transmembrane r eceptor, which plays a key role in cell-to-cell signaling during differenti ation and is conserved from C. elegans to hum an. We report a paracentric i nversion (PAI) of chromosome 20p12.2p13 in an individual with AGS who also had a-l-antitrypsin deficiency. To our knowledge, this is the first publish ed case of PAI involving the short arm of chromosome 20. Using FISH, fiberF ISH, and molecular studies with a similar to 40 kb cosmid clone encompassin g the entire 36 kb JAG1 gene, we demonstrate that the gene was disrupted by the inversion breakpoint between exons 5 and 6. An unusual association bet ween two most common causes of chronic liver disease in childhood, AGS and alpha -1-antitrypsin deficiency, as well as their influence on the proband' s abnormal phenotype are discussed. (C) 2001 Wiley-Liss, Inc.