A Novel c.91dupG JAG1 Gene Mutation Is Associated with Early Onset and Severe Alagille Syndrome

Abstract

Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome.

Clinical, Laboratory, Radiological, and Genetic Characteristics of Pediatric Patients with Alagille Syndrome

“…[ 1 5 6 7 8 9 10 ] However, others showed male patients. [ 2 3 4 11 12 13 ] Nevertheless, all of these were case reports and there were no case series that suggest the sex pattern of this disease.…”

“…This is similar to several studies in which their patients also presented with jaundice since birth. [ 1 2 4 5 6 10 11 12 13 ]…”

“…Most of the previous studies also reported ALGS patients with an associated cardiac defect and the majority reported peripheral pulmonary stenosis. [ 1 4 7 9 10 11 ] Other congenital heart diseases such as atrial septic defect, right hypoplastic heart, and ventricular septal defect were also reported. [ 1 5 7 12 ] Fiorda-Diaz et al .…”

“…Hannoush et al ., Reyes-de la Rosa et al ., and Sousa and Resende studies also reported similar finding on their patients. [ 4 11 12 ]…”

Alagille Syndrome: A Novel Mutation in JAG1 Gene

“…Although clinical features may differ significantly, the diagnosis of ALGS is mainly based on clinical findings (5, 6). Initial diagnosis is based on the presence of intrahepatic bile duct paucity and at least of 3 other clinical features: chronic cholestasis, cardiac disease (pulmonary stenosis), ocular abnormalities (posterior embryotoxon), skeletal abnormalities (butterfly-like vertebrae), and peculiar facial features (broad forehead, deep-set eyes, bulbous nose, and small pointed mandible) (7–9). Patients have a high prevalence of renal and vascular disease as well (1).…”