A mutation in the 5’ untranslated region (UTR) of the JAG1 gene may be associated with Alagille syndrome (ALGS) and explain cases without demonstrable JAG1/NOTCH2 variants, according to a new case study published in Clinical Genetics.

The authors of the study recommend that JAG1 genetic testing should, therefore, include the 5’UTR of JAG1 in patients with suspected ALGS.

The case presented here is that of a female patient who was previously detected to have a novel pathogenic variant in the 5’UTR region of the JAG1 gene. In the present study, the researchers functionally characterized the pathogenic variant. 

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The patient had a normal family history but developed cholestasis 4 weeks after birth. She also had liver ductopenia, butterfly vertebrae in the thorax, mild lung stenosis, and congenital heart defects, which led to a diagnosis of ALGS. 

Read more about the diagnosis of Alagille syndrome

The patient’s parents were genetically analyzed and showed no abnormalities. This led the researchers to conclude that the variant occurred de novo in the patient. It was also not present in population databases but was reported by one other group in a patient with Alagille syndrome. 

The researchers then conducted in vitro experiments and showed that the variant led to a reduction in the expression of a downstream gene. This suggests that the variant may also decrease the expression of JAG1 in vivo. This, in turn, may mean that the activation of NOTCH2, the receptor of JAG1, is reduced, causing ALGS. 

“This might favor a strong phenotypic expression as observed in our . . . patient,” the researchers wrote. 

ALGS is caused by defects in the NOTCH2/JAG1 signaling pathway, which leads to errors in downstream gene expression. This, in turn, results in symptoms of the disease.


Buhl N, Pfister ED, Bohne J, et al. Functional characterization of a JAG1 5’UTR variant in a patient with clinically observed Alagille syndrome. Clin Genet. Published online June 27, 2022. doi:10.1111/cge.14179