title: JAG1 Mutation Spectrum and Origin in Chinese Children with Clinical Features of Alagille Syndrome.
abstract: Alagille syndrome is an autosomal dominant disorder that results from defects in the Notch signaling pathway, which is most frequently due to JAG1 mutations. This study investigated the rate, spectrum, and origin of JAG1 mutations in 91 Chinese children presenting with at least two clinical features of Alagille syndrome (cholestasis, heart murmur, skeletal abnormalities, ocular abnormalities, characteristic facial features, and renal abnormalities). Direct sequencing and/or multiplex-ligation-dependent probe amplification were performed in these patients, and segregation analysis was performed using samples available from the parents. JAG1 disease-causing mutations were detected in 70/91 (76.9%) patients, including 29/70 (41.4%) small deletions, 6/70 (8.6%) small insertions, 16/70 (22.9%) nonsense mutations, 8/70 (11.4%) splice-site mutations, 6/70 (9.4%) missense mutations, and 5/70 (7.1%) gross deletions. Of the mutations detected, 45/62 (72.6%) were novel, and almost all were unique, with the exception of c.439C>T, c.439+1G>A, c.703C>T, c.1382_1383delAC, c.2698C>T, and c.2990C>A, which were detected in two cases each; three cases exhibited entire gene deletions. A majority (69.2%) of the point and frameshift mutations could be detected by the sequencing of eleven exons (exons 3, 5, 6, 11, 14, 16, 18, 21, and 23-25). The mutation detection rate was 50.0% (10/20) in atypical cases that only presented with two or three clinical features of Alagille syndrome. Segregation analysis revealed that 81.1% (30/37) of these mutations were de novo. In conclusion, JAG1 mutations are present in the majority of Chinese pediatric patients with clinical features of Alagille syndrome, and the mutations concentrate on different exons from other reports. Genetic study is important for the diagnosis of atypical Alagille syndrome in Chinese patients.
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Liting
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Dong
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Guo
authors.affiliation: The Molecular Genetic Diagnosis Center, Shanghai Key Lab of Birth Defect, Translational Medicine Research Center of Children Development and Disease, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
authors.forename: Kuerbanjiang
authors.initials: K
authors.lastname: Abuduxikuer
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China; Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Wang
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D002681:China; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins