An advanced genetic panel was able to aid in the diagnosis of genetic disorders such as Alagille syndrome (ALGS) that are causing neonatal/infantile intrahepatic cholestasis (NIIC), as published in the Journal of Pediatric Gastroenterology and Nutrition.

In previously untested patients, ALGS was the most common genetic diagnosis accounting for 10 out of the 124 cases (8.1%) of NIIC. Mutations in the JAG1 gene were discovered in 9 out of the 10 patients with ALGS while the 10th had a mutation in the NOTCH2 gene.

During the study, 191 patients who had previously been tested with an 18-gene panel in a prior study but did not receive a definitive genetic diagnosis were reanalyzed with a new 61-gene panel.

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A definitive molecular genetic diagnosis was achieved in 10 (5.2%) of these patients after reanalysis, however, ALGS was not one of the identified diseases. Of the patients who received a diagnosis previously using the 18-gene panel, ALGS was the most commonly diagnosed disorder accounting for 45 out of 101 diagnoses.

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The more expansive gene panel was also tested on a new group of 124 patients who had not been tested before. Ultimately, 26.6% of patients from this prospective cohort received a genetic diagnosis for their NIIC.

ALGS (8.1%), Dubin-Johnson syndrome (DJS; 7.3%), and neonatal intrahepatic cholestasis caused by citrin deficiency (5.6%) were the 3 most common disorders uncovered from the advanced panel. These 3 diseases accounted for 78.8% of the genetic diagnoses of NIIC made at the study sites in Japan.

“Further studies using [whole-genome sequencing] and RNA sequence analysis are needed to confirm a definitive molecular diagnosis or to find new candidate genes of NIIC, especially for patients in whom we could only identify one pathogenic variant on a single allele,” the authors suggested.

For the study, the retrospective reanalysis group was reduced from 456 patients, recruited between May 2013 and September 2017, down to 191 after exclusions of patients who already received a diagnosis, had an age of onset greater than 12 months of age, diagnosis of extrahepatic cholestasis, serum direct bilirubin levels less than 1.0 mg/dl, or insufficient clinical data. The previously untested prospective cohort was reduced from 223 patients recruited between October 2017 and October 2019 down to 124 after similar exclusion criteria were applied.


Ito S, Togawa T, Imagawa K, et al. Real-life progression of the use of a genetic panel in to diagnose neonatal cholestasis. J Pediatr Gastroenterol Nutr. 2022;3(2):e196. doi:10.1097/PG9.0000000000000196