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.

Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

“…NOTCH2 mutations were identified in about 1.5% of patients with Alagille syndrome in a previous study (15). In this study, our detection rate of mutations in JAG1 and NOTCH2 was lower than that in Western countries (8), but approximately compatible with those in East Asian countries, namely 87.3% in China (16) and 73.6% in Korea (6). There may have been a correlation between the detection rate and the ethnic background.…”

Identification of genomic deletions causing inherited retinal degenerations by coverage analysis of whole exome sequencing data

“…It is therefore reasonable to assume that the current estimated fraction of large deletions (about 7.5%—12 565 out of 166 768 mutations, http://www.hgmd.cf.ac.uk/ac/hahaha.php and ref. 1, 2) is an underestimation.…”

JAG1 loss‑of‑function mutations contributed to Alagille syndrome in two Chinese families

“…Mutation c.1261delT has not been reported in the Human Gene Mutation Database (www.hgmd.cf.ac.uk/) or the NHLBI Exome Sequencing Project (evs.gs.washington.edu/). While c.1382_1383delAC had been detected in a retrospective study (24), it had not been analyzed yet. Mutations c.1261delT and c.1382_1383delAC resulted in the conversion of the respective amino acid resides 421, a cysteine and 461, an aspartate to stop codons, leading to the loss of subsequent domains.…”

“…Protein-truncating mutations account for up to 70% of JAG1 mutations in ALGS patients. Nevertheless, no mutation hotspots have been identified yet (13,24), and the pathological mechanisms of these kinds of mutations have been controversial. This study was aimed at analyzing the biological functions of two JAG1 protein-truncating mutations detected in Chinese ALGS patients, which may allow for the possibility of future genetic counseling.…”