Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family

Abstract

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.

Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome

“…It is an autosomal dominant disorder with a penetrance estimated at 94% (Dhorne-Pollet et al 1994). Following a study of linkage analysis in three generations of an AGS family (Hol et al 1995), and of AGS patients with submicroscopic deletion or with balanced translocation Rand et al 1995;Pollet et al 1995;Spinner et al 1994), the chromosomal region responsible for AGS was localized at 20p12. Recently, the JAG1 gene, which encodes a ligand for the Notch receptor and plays a role in determining cell fates in early embryonic development, was mapped to the AGS critical region, and its mutations in AGS patients were reported by two groups (Li et al 1997;Oda et al 1997).…”

Steatocystoma multiplex and leuconychia in a child with Alagille syndrome

“…Alagille syndrome is an inheritable syndrome of congenital paucity of interlobular bile ducts. [1][2][3][4][5] The major features of the disorder are peculiar facies, chronic cholestasis, posterior embryotoxon, butterfly-like vertebral arch defects and peripheral pulmonary artery stenosis or hypoplasia. 2 course, 7 in selected patients with the severe form liver transplantation provides long-term survival and a better quality of life.…”

“…[1][2][3] The disorder is inheritable as an autosomal dominant trait with variable expressivity and has been localized on the short arm of chromosome 20. 4,5 Recently, Alagille syndrome has been described in association with an extensive form of naevus comedonicus. 6 We report on a patient having Alagille syndrome together with congenital leuconychia and widespread cysts and comedones consistent with the diagnosis of steatocystoma multiplex.…”

Recent advances in the understanding of genetic causes of congenital heart defects

“…Subsequently, other patients with similar deletions were identified and linkage analysis of a three-generation kindred using markers from 20p11.2-p12 was confirmatory (110). Two groups independently identified the Alagille syndrome disease gene as JAGGED1 (111,112).…”