Algorithm for genetic tests helps spot cause of newborn cholestasis

Mutations found via screenings identified infants with a genetic disorder

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration of a DNA segment and its double helix.

In infants with suspected cholestasis, targeted single-gene testing for those with symptoms that indicate a particular, associated disease and broader gene panel testing for inconclusive cases may help to diagnose potential genetic causes, a study reports.

“With the increasing importance of the genetic portion in diagnosing neonatal cholestasis, well-established diagnostic algorithms with gene panels may elucidate the clinical significance of disease mutations, identify novel [clinical profiles], decrease the need for invasive procedures, and explore the mechanisms of neonatal cholestasis,” the researchers wrote.

The study, “Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia,” was published in the Journal of Gastroenterology and Hepatology.

Newborn intrahepatic cholestasis can be caused by several genetic disorders

Cholestasis refers to a reduction in the flow of bile, a digestive substance made in the liver that normally flows to the intestines through a series of tubes called bile ducts. When this occurs in bile ducts inside the liver, the disorder is called intrahepatic cholestasis; while impaired bile flow outside the liver, it is classified as extrahepatic cholestasis.

Slow or blocked bile flow causes bile to build up and leak into the bloodstream, leading to common cholestasis symptoms such as yellowing of the skin and the whites of the eyes (jaundice).

A number of different conditions can cause intrahepatic cholestasis in newborns, including genetic disorders such as progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).

Genetic testing has become more accessible in recent years, which may aid in diagnosing these conditions early. However, there is no standard setup for how to use genetic testing for babies suspected of having intrahepatic cholestasis.

Scientists in South Korea shared the results of a diagnostic algorithm, used at their Seoul center for more than a decade, to identify genetic causes in infants with laboratory findings suggestive of intrahepatic cholestasis. The algorithm basically consists of two steps of genetic testing: single-gene testing and a cholestasis gene panel.

Single-gene testing was done when infants showed signs of a specific genetic disorders associated with intrahepatic cholestasis.

For example, infants with cholestasis and facial features characteristic of Alagille were tested for mutations in the JAG1 gene, the disease’s most common cause. Those showing NICCD’s hallmark laboratory abnormalities were tested for mutations in the SLC25A13 gene, the cause of NICCD.

“Genetic neonatal cholestasis was initially pre-filtered by performing single-gene testing if there were clinically suspected diseases,” the researchers wrote.

If infants lacked obvious signs of a specific disorder, or if single-gene testing was inconclusive, they then underwent gene panel testing, simultaneously screening for mutations in 34 genes that have been linked to newborn intrahepatic cholestasis.

16 noted mutations, all likely disease-causing, were previously unidentified

Between 2010 and 2021, a total of 148 babies (97 boys and 51 girls) with intrahepatic cholestasis at Seoul National University Hospital underwent this series of genetic testing.

Genetic disorders were diagnosed in 49 infants (33.1%): 34 through single-gene testing, 14 with gene panel testing, and one via a more comprehensive approach that screens all of a person’s genes, when gene panel testing came back negative.

Diagnoses with single-gene testing were achieved faster than with gene panel testing (six to eight weeks vs. eight to 12 weeks).

The most common genetic causes of intrahepatic cholestasis were Alagille syndrome and NICCD, each diagnosed in 14 patients (28.6%). Of note, 16 of the mutations identified by the screening procedures had not been reported before, although they were all determined to be definitively or likely disease-causing.

The cause of cholestasis, whether genetic or not, remained unknown for 72 infants (48.6%).

“This is the first study to analyze the clinical applications of single-gene testing and [screen panel testing] in patients with neonatal intrahepatic cholestasis and to develop a diagnostic algorithm for the disease in Asia,” the researchers wrote.

In it, “we present an effective diagnostic algorithm for neonatal intrahepatic cholestasis,” showing that single-gene testing and gene panel testing “are important and complementary tools for the diagnosis of genetic neonatal cholestasis,” they added.

“Our study can also serve as a benchmark in developing a well-established diagnostic algorithm for each region,” the team concluded.