Unveiling a rare genetic enigma: A father-son duo with alagille syndrome and a novel pathogenic JAG1 variant – Case report and literature review

Abstract

Alagille syndrome (ALGS) is a rare multisystem disorder primarily caused by alterations in the JAG1 gene and, less frequently, in NOTCH2. The syndrome exhibits variable phenotypic expression, making diagnosis challenging. We report a novel heterozygous frameshift deletion variant, c.1019del (p.Cys340Serfs*72), in exon 8 of JAG1, identified in a father-son duo. This variant, located within the evolutionarily conserved EGF-like repeat domain, is predicted to be pathogenic based on its absence in population databases, in silico predictions, and clinical correlation. The father exhibited chronic cholestasis, ductal paucity, and atypical ocular findings, while the son displayed dysmorphic facies, skeletal anomalies, and hearing loss. This case highlights distinct phenotypic variations within the same family despite sharing the same JAG1 variant. Notably, features such as keratoconus, KF ring, tessellated fundus, hyperemic disc, CTEV, and inner ear anomalies have not been previously documented. It underscores the critical role of deep phenotyping, thorough family history re-evaluation, and early genetic diagnosis in ensuring timely intervention.