De novo JAG1 gene deletion causes atypical severe Alagille syndrome in a Chinese child

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder caused by defects in the Notch signaling pathway. 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. However, the diagnosis is very difficult in an atypical case. Molecular confirmation of ALGS diagnosis is valuable. Here we report an atypical severe ALGS case with de novo JAG1 gene deletion. A 2-month-old Chinese boy presented with cholestasis and was initially referred to our hospital. Biliary atresia (BA), progressive familial intrahepatic cholestasis, ALGS, and other conditions with cholestasis were suspected. BA was ruled out by Omnipaque imaging through peritoneoscopy. The etiology of the child’s cholestasis was unclear after liver biopsy, Sanger sequencing of the JAG1 gene, and next-generation sequencing of a panel of 41 genes known to cause genetic cholestasis disorders in children. The child’s ALGS was eventually diagnosed through multiplexligation-dependent probe amplification dosage analysis. Heterozygosis JAG1 gene deletion was found in the child’s JAG1 gene. The child died because of liver failure when he was 9 months old, although he underwent adequate treatment. We concluded that even though the child had no other typical ALGS manifestation, an infant with cholestasis should always prompt pediatricians to exclude ALGS with different genetic testing methods. And the heterozygosis De Novo JAG1 gene deletion can lead to severe liver disease and cause liver failure and death at an early age.