Alagille syndrome case series: five new variants and two large deletions

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by intrahepatic bile duct insufficiency, cardiac, skeletal, ocular, and characteristic facial features, most commonly caused by pathogenic variants in the JAG1gene and, less frequently, in the NOTCH2 gene. This study aimed to expand the existing literature by reporting novel JAG variants identified in our cohort. This retrospective cross-sectional study included 17 patients diagnosed withALGS between 2010-2025 at the Pediatric Gastroenterology, Hepatology, and Nutrition Clinic of İnönü University Faculty of Medicine. Genetic analysis was performed in 12 patients using JAG1 gene sequencing (n = 6), a targeted cholestasis gene panel (n = 4), or whole-exome sequencing (n = 2). Symptom onset ages ranged from 1 to 150 days. Cholestasis was the most common initial presentation, observed in 13 patients (76.5%). Peripheral pulmonary stenosis was the most frequent cardiac anomaly, identified in 12 patients (70.6%). A molecular diagnosis was established in 12 patients, while five were diagnosed clinically due to the unavailability of genetic testing at presentation. All genetically tested patients harbored pathogenic variants in the JAG1 gene. Ten variants were point mutations and two were large deletions. Five point mutations were classified as novel, as they had not been previously reported in the literature or genomic databases. Additionally, two large deletions involving previously undescribed genomic regions were identified and reported for the first time.

Alagille syndrome should be considered in patients with unexplained cholestasis, especially in populations with high rates of consanguineous marriage, and the diagnosis should be confirmed with genetic testing whenever possible. This study introduces 5 novel variants and two major deletions containing previously unidentified genomic regions to the literature for the first time.

• Alagille syndrome (ALGS) is a multisystem disorder most commonly caused by pathogenic JAG1 variants. • Syndromic cholestasis requires early multidisciplinary evaluation and genetic confirmation.

• Five point mutations were classified as novel, as they had not been previously reported in the literature or genomic databases. • Two large deletions involving previously undescribed genomic regions were identified and reported for the first time.