A team of researchers reported that isolated aneurysmal disease remains an underestimated finding in patients with JAG1 pathogenic variants, and published their findings in Human Mutation.

JAG1 pathogenic variants are known to cause Alagille syndrome (ALGS), a multiorgan disorder that heavily affects the heart and liver. Although cardiac pathology is commonly characterized in ALGS, thoracic aortic aneurysms tend to only be sporadically reported in postmortem autopsies.

The authors of the study used an example of a family to highlight this point. A fetus presenting with hypoplastic heart syndrome and left renal agenesis was found to have a missense variant in JAG1 upon whole exome sequencing.

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The mother was found to have the same JAG1 variant. She underwent surgery for aortic coarctation at the age of 10 years. The mother’s siblings who were twins were discovered to both have thoracic aortic aneurysms, with a diameter of 40 mm in the sister and 58 mm in the brother. The brother was then advised to undergo immediate Bentall surgery with mechanical aortic valve replacement.

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“Histological examination of aorta obtained during surgery showed fragmentation of elastic fibers with marked decrease in elastin content,” the authors wrote. “Collagen was drastically increased and disorganized compared to a healthy control sample.”

In addition, the father of the proband was also found to harbor the JAG1 pathogenic variant but did not show any signs of aneurysmal disease. However, the uncle suffered from a ruptured arteria communicans anterior aneurysm, and the aunt presented with a bicuspid aortic valve but normal aortic measurements.

“We anticipate [thoracic aortic aneurysms] might be an underestimated finding in ALGS and we therefore advise to early and thoroughly examine the vascular system in such patients, with focus on intracranial and thoracic aorta imaging, since vascular events are estimated to account for over 30% of ALGS mortality,” the authors said.


Bento JR, Krebsová A, Van Gucht I, et al. Isolated aneurysmal disease as an underestimated finding in individuals with JAG1 pathogenic variantsHum Mutat. Published online July 12, 2022. doi:10.1002/humu.24433