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 recently identified as causal for the anomalies found in patients with Alagille syndrome (AGS). This gene encodes a ligand for the Notch1 transmembrane receptor, which plays a key role in cell-to-cell signaling during differentiation and is conserved from C. elegans to human. We report a paracentric inversion (PAI) of chromosome 20p12.2p13 in an individual with AGS who also had alpha-1-antitrypsin deficiency. To our knowledge, this is the first published case of PAI involving the short arm of chromosome 20. Using FISH, fiberFISH, and molecular studies with a approximately 40 kb cosmid clone encompassing 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 between 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.

Phenotypic findings due to trisomy 7p15.3-pter including the TWIST locus.

We report on a three-month-old boy with a 46,XY,der(Y)t(Y;7)(p11.32;p15.3) karyotype and growth deficiency, postnatal microcephaly with large fontanels, wide sagittal and metopic sutures, hypertelorism, choanal stenosis, micrognathia, bilateral cryptorchidism, hypospadias, abnormal fingers and toes, and severe developmental delay. FISH studies showed partial trisomy 7p resulting from a de novo unbalanced translocation. The application of molecular probes from the TWIST gene region (7p15.3-p21.1) and probes from the pseudoautosomal region (PAR) demonstrated that the 7p15.3-pter fragment was translocated onto Yp with the breakpoint within approximately 20 kb from the Yp telomere. We discuss the possible role of the TWIST gene in abnormal skull development and suggest that trisomy 7p cases with delayed closure of fontanels can be a result of TWIST gene dosage effect.

Kabuki syndrome-like features associated with a small ring chromosome X and XIST gene expression.

Although clinical features in Kabuki syndrome (KS; Niikawa-Kuroki syndrome) have been well defined, the underlying genetic mechanism still remains unclear. We report a 9-year-old girl with typical KS-like facial appearance, skeletal and dermatoglyphic abnormalities, severe mental retardation, and growth deficiency. In 60 of 100 GTG-banded metaphases from peripheral blood lymphocytes, a ring chromosome smaller than a G group chromosome was found, which, according to reverse painting, consisted of Xq11.1q13. The proband's karyotype was described as mos45,X/46,X,+r(X). Several loci were analyzed with fluorescence in situ hybridization (FISH) and microsatellite markers revealing that one r(X) breakpoint mapped proximal to DXS422 (Xp11.21) and the second mapped distal to XIST gene, between loci DXS128E and DXS441 (Xq13.2). Uniparental disomy for X and r(X) was excluded and the paternal origin of r(X) was identified. XIST expression was demonstrated by nested reverse transcription polymerase chain reaction (RT-PCR) using primers spanning exons 5, 6i, and 6 in RNA prepared from lymphocytes. The observation of XIST expression is in contrast to two other cases in which the XIST gene was either not present on r(X) or not expressed. To our knowledge, this is the first case of Kabuki-like syndrome manifestations with r(X) and XIST expression.