A novel JAG1 variant causing familial Alagille syndrome

Alagille syndrome (ALGS) is a rare autosomal dominant multisystem disorder typically caused by pathogenic variants in JAG1 and NOTCH2, accompanied with a wide range of clinical variability. Currently, new pathogenic variants in JAG1 and NOTCH2 have been continuously reported. Exome sequencing and Sanger sequencing were used to explore potential pathogenic variants associated with ALGS. Western blot analysis was performed on lymphoblastoid cells derived from patients to assess the variant’s impact on protein expression. In this study, we identified a novel heterozygous frameshift variant, NM_000214.3:c.1623_1624del, in JAG1 by exome sequencing and Sanger sequencing in an ALGS family. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant was predicted as a pathogenic variant (PVS1, PM2, and PP1), which could result in a premature termination codon (PTC). The impact of this variant on host protein expression was validated and we found a marked decrease in the expression of the JAG1 protein in patients carrying the variant, indicating the underlying pathogenic mechanism of this PTC variant. These findings further deepened our understanding of JAG1 variants in ALGS, and provide new insights for the diagnosis of this disease.