Identifying pathogenic variants in the JAG1 or NOTCH2 genes through next-generation sequencing could help in accurately diagnosing Alagille syndrome (ALGS) in pediatric patients with cholestatic liver disease, according to a new study published in the International Journal of Molecular Sciences.

“ALGS diagnosis may be especially difficult in infants with a few classical features or with a biopsy without bile duct paucity. Detection of pathogenic variants in the causative genes is particularly useful for patients who do not meet a sufficient number of clinical diagnostic criteria,” the study’s authors said.

In the study, traditional diagnostic criteria for ALGS were met by only 6 patients in the cohort (n=18) without the aid of genetic testing. This highlights the relevance of genetic analysis in accurately diagnosing ALGS and differentiating it from other forms of cholestasis.

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Sixteen of 18 patients (88.9%) presented with a distinctive facial phenotype, aiding in the identification of ALGS. Heart defects were found in 8 patients (44.4%), with pulmonary stenosis being the most common alteration.

Read more about ALGS differential diagnosis

In addition, 5 of 14 patients (35.7%) displayed butterfly vertebrae, and renal involvement was detected in 2 cases (11.1%), with 1 patient having renal cysts and another experiencing obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only 1 (8.3%) had posterior embryotoxon.

Liver biopsies were conducted on 9 patients, revealing bile duct paucity in 6 patients (66.7%). Notably, 2 patients required liver transplantation due to cirrhosis.

Genetic analysis led to the identification of 9 novel variants in the JAG1 gene, including 8 frameshift variants and 1 missense variant. None of the patients presented with NOTCH2 variants.

The study enrolled 18 children with cholestasis who were ultimately diagnosed as having ALGS.


Semenova N, Kamenets E, Annenkova E, et al. Clinical characterization of Alagille syndrome in patients with cholestatic liver disease. Int J Mol Sci. Published online July 21, 2023. doi:10.3390/ijms241411758