Clinical features and gene mutation analysis of patients with Alagille syndrome

Objective: To analyze the clinical manifestations and gene mutations of patients with Alagille Syndrome (ALGS) to improve diagnosis and provide a boarder spectrum of gene mutagenesis. Methods: A retrospective study was performed in 18 ALGS patients admitted to Xi'an Children's Hospital from January 2016 to January 2020. Clinical characteristics, biochemical parameters, gene mutations and prognosis were collected and analyzed. Next-generation sequencing of liver disease-related gene panels or the whole exome was carried out for the probands. Mutations of candidate genes were verified by Sanger sequencing in their family members. Based on the comparison with a well-known database of disease, the harmfulness and structures of proteins with novel mutations were predicted, and the pathogenicity was evaluated. Results: There were 9 males and 9 females with ALGS in this study, and the age of initial diagnosis was 2.5 (1.9, 6.8) months. All patients initially presented with cholestasis, with other symptoms including 15 cases of special facial features, 11 cases of butterfly vertebrae, 10 cases of congenital heart disease, 5 cases of posterior corneal embryonic ring (among 16 cases with ophthalmological examination), and 1 case of polycystic kidney disease. A total of 14 JAG1 gene mutations and 6 NOTCH2 gene mutations were identified. Among these newly identified mutations, 6 were associated with JAG1 gene, including c.1213delA (p.T405Lfs*7), c.1270dupG(p.A424Gfs*5), c.1741dupG(p.A581Gfs*8), c.3045delC (p.I1016Ffs*20), c.2000-2A>C and c.625C>A(p.H209N); 4 were associated with NOTCH2 gene, including c.6961dupG(p.A2321Gfs*79), c.518G>T(p.G173V), c.6157C>T(p.R2053C) and c.710G>A(p.R237Q). Sixteen patients were followed up for (37.9±31.5) months. Among these cases, 2 died of liver failure (1 case underwent Kasai operation due to misdiagnosis with biliary atresia), 1 improved after liver transplantation, and 13 were in stable condition after medical treatment. Conclusions: The phenotypes of ALGS are diverse, genetic detection can help diagnosis. The JAG1 and NOTCH2 genes showed a wide array of mutations, with many novel mutations identified in this study.