Clinical and genetic characteristics of patients with Alagille syndrome in China: identification of six novel JAG1 and NOTCH2 mutations.

Background: Alagille syndrome (ALGS) is a rare disease. The variable clinical manifestations make the diagnosis of ALGS difficult. This study aimed to provide a basis for the early diagnosis of ALGS patients whose clinical identification is difficult and to enrich the spectrum of genetic variants implicated in Chinese children with ALGS.

Methods: From August 2016 to August 2022, 14 children with ALGS were enrolled in this retrospective study. Clinical and related data were obtained from medical records.

Results: Among the 14 patients, 11 were males and 3 were females. The age of first manifestation of liver disease mean (Q1, Q3) was 0.4 (0.1, 37.0) months, and the age of diagnosis mean (Q1, Q3) was 5.6 (2.4, 48.5) months. Cholestasis was seen in 14 patients, cardiac defects in eight, characteristic facial features in 11, skeletal abnormalities in six, and renal abnormality in one. Among eight patients who underwent ophthalmological examination, posterior embryotoxon was seen in two. We identified 12 different JAG1 gene mutations and two different NOTCH2 gene variations. Among the mutations detected, six were novel, including c.2849_2850del (p.S950*), c.35_45delGCCCCCTAAGC (p.R12Pfs*57), c.1860delC (p.F621Sfs*122), and c.1293_1294insTAGTAGACA (p.A432*) in JAG1, and c.6040_6041 del (p.L2014Vfs*10) and c.1915+1G>T (splicing) in NOTCH2. The follow-up time mean (Q1, Q3) was 48.5 (11.5, 69.0) months; four patients had delayed growth, eight had pruritus, two had xanthomas, seven had elevated bilirubin, and 13 had elevated transaminase. All patients were stable after medical treatment.

Conclusions: ALGS presents a variety of clinical manifestations. Some patients may be misdiagnosed with biliary atresia due to bile duct proliferation in liver biopsies along with biochemical abnormalities. Genetic testing is helpful for early diagnosis. JAG1 and NOTCH2 gene mutant spectra are abundant and there are many novel mutations in Chinese children with ALGS.