Alagille syndrome with heterozygous JAG1 c.224 T > C variant: a case report and literature review

Background To study Alagille Syndrome (ALGS), a complex genetic disorder characterized by chronic cholestasis, congenital abnormalities, dyslipidemia, and distinctive facial features that manifest from infancy. Case presentation A 4-month-old girl with chronic cholestasis was referred to our Gastrohepatology clinic for further investigation to determine the underlying cause and confirm the diagnosis. Genetic analysis was performed using whole-exome sequencing (WES), and a literature review of similar genetic variants was also conducted. This study highlights a patient with a heterozygous JAG1 c.224 T > C (p.Phe75Ser) variant who presents with cholestatis and hypercholesterolemia, which is occasionally refractory and resistant to conventional treatments, followed by the development of extensive xanthomas. Despite being categorized as a variant of uncertain significance (VUS), in silico analyses and 3D modeling suggest that this variant is likely damaging to protein function, as indicated by increased hydrophilicity in the mutant (MT) compared to the wild type (WT), supporting its likely pathogenicity. Conclusion ALGS is a complex multisystem disorder requiring early diagnosis and management. As the variant is a VUS, parental testing or functional studies are needed for reclassification.