Novel de novo JAG1 frameshift mutation in Alagille syndrome with early liver transplant requirement

Mak, C. (2024). Novel de novo JAG1 frameshift mutation in Alagille syndrome with early liver transplant requirement (Version 1) [DataSet]. GestaltMatcher Database.

We present the case of a male infant born at 35 weeks gestation as twin 2 (birth weight 1.91kg) who developed persistent conjugated hyperbilirubinemia and prolonged neonatal jaundice. The patient underwent Kasai portoenterostomy for suspected biliary atresia, but liver biopsy revealed intrahepatic cholestasis with ductopenia rather than large duct obstruction. Additional clinical features included butterfly vertebra at T5, hepatomegaly, icteric sclera, and pruritic skin. Family history was notable for twin 1 who died from complex congenital heart disease (univentricular heart with aortic valve stenosis and likely pulmonary atresia). Parents were non-consanguineous and of Han Chinese decent with no family history of liver or metabolic disease. Research exome sequencing revealed a novel de novo frameshift pathogenic variant NM_000214 (JAG1):c.2874_2875delTG;p.(Ala959GlufsTer7), never previously reported in ExAC (at the time) or literature. This variant was consistent with Alagille syndrome diagnosis. Due to progressive cholestasis and absence of suitable living donors, the patient was listed for liver transplantation and subsequently underwent deceased donor liver transplant in China at approximately 12 months of age. The post-transplant course was complicated by infections requiring multiple interventions including PTBD drainage and antimicrobial therapy. This case demonstrates the severe end of the Alagille syndrome spectrum, with early requirement for liver transplantation despite Kasai portoenterostomy. The novel JAG1 frameshift variant expands the known pathogenic variant spectrum for this condition.