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.
Highlights
Alagille syndrome (ALGS; OMIM 118450) is an autosomal dominant disorder that results from defects in the Notch signaling pathway, typically via mutations in the gene encoding a ligand for Notch receptors, JAGGED1 (JAG1)
Sequence analysis was successful for all cases, and an multiplex-ligation-dependent probe amplification (MLPA) dosage result was obtained for 22 cases in which no mutation or only a missense variant was identified by sequencing and sufficient DNA was available
Two of the missense variants were not seen in 1000 Genomes and singlenucleotide polymorphism (SNP) databases (Table 3); c.1511A>G (p.N504S) was identified in case 67 and inherited from his healthy mother, and c.3178C>T (p.R1060W) was identified in case 29 and inherited from his mildly affected mother
Summary
Alagille syndrome (ALGS; OMIM 118450) is an autosomal dominant disorder that results from defects in the Notch signaling pathway, typically via mutations in the gene encoding a ligand for Notch receptors, JAGGED1 (JAG1). ALGS is associated with a wide variety of clinical features and manifestations, including abnormalities of the liver, heart, skeleton, eyes, kidneys, and facial features [1]. It is one of the most common causes of pediatric chronic liver disease and occurs with a minimal estimated frequency of 1 in 70,000–100,000 newborn infants [2]. The classical criteria for ALGS diagnosis include bile duct paucity on liver biopsy in association with three of the following: cholestasis, congenital heart disease, vertebral abnormalities, characteristic facial features, and posterior embryotoxon [3]. To further characterize JAG1 mutations and their origins in Chinese patients with ALGS, we performed a genetic study on a cohort of sporadic patients with at least two of the six major clinical features (chronic cholestasis, cardiac murmur, skeletal abnormalities, ocular abnormalities, a characteristic face, and renal abnormalities)
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