Clinical and Molecular Genetic Study of an Alagille Syndrome Type 1 Case.

introductionAlagille syndrome (ALGS) is a rare autosomal dominant disorder with several clinical manifestations including facial, hepatic, cardiovascular, skeletal, and renal complications. ALGS is a result of pathogenic variants in either JAG1 or NOTCH2 genes, which lead to the disruption of the Notch signaling pathway. Here, we present the case of a 17-year-old female patient, clinically and genetically diagnosed with ALGS1. MATERIAL AND

methodsThe 17-year-old patient, with an ALGS-free family history, was clinically diagnosed with ALGS due to liver dysfunction, cholestasis, kidney cysts, distinct craniofacial features, and skeletal malformations. Following genetic counseling and parental informed consent, genomic DNA was extracted from a sample of peripheral blood. Subsequently, whole-exome sequencing analysis was conducted, and clinically significant findings were additionally confirmed through Sanger DNA sequencing.

resultsThe genetic analysis revealed the presence of a likely pathogenic donor splice variant (c.2372+1G>C) in heterozygosity with the normal allele in the JAG1 gene at intronic position 1 of 493 (affecting splicing, MAF < 0.01), which was validated by Sanger sequencing. Bioinformatic analysis indicated that the detected donor splice variant may disrupt spliceosome recognition of the canonical splice site and lead to exon skipping.

conclusionBased on the clinical picture, personal/family history and genetic analyses, the patient was diagnosed with autosomal dominant ALGS type 1, caused by a de novo pathogenic mutation in the JAG1 gene. It is the first time this variant has been described in the relevant literature.