Over the past several years, clinicians have made use of a free genetic test to help properly diagnose infants presenting with signs of liver disease. The test looks for 77 genes that are known to be related to cholestasis — a condition that impairs the flow of bile from the liver to the small intestine — and identifies variants of those genes that are likely to contribute to liver disease. 

But in some 70%–75% of cases, the tests also reveal at least one genetic variant of unknown significance (VUS), says Brett Hoskins, a postdoctoral clinical fellow in Pediatric Gastroenterology, Hepatology and Nutrition at Johns Hopkins Children’s Center. 

“We don’t know the causal relationship of having this VUS to the development of liver disease, or to worse liver disease if there is another liver process occurring,” he says. “That really challenges the management of care in these kids.”

To gain a better understanding of these genetic variants and how they might relate to one another or cause disease, Hoskins and Wikrom Karnsakul, director of the pediatric liver center at Johns Hopkins Children’s Center, started a multicenter prospective study. The aims are to determine which patients with certain VUSes progress to develop chronic liver disease, chronic cholestasis, both or neither, in one to five years of testing, as well as to investigate the natural history of patients with VUSes in multiple genes. Along the way, the researchers hope to determine which variants are associated with progression of chronic cholestasis, acute or intermittent liver failure, end-stage liver disease or resolution of liver disease.

There’s a spectrum of different disease processes and different treatments that could be used if we know that a particular variant is going to contribute to development of liver disease,” Hoskins says. “This has the potential to change management and maybe reduce some more invasive procedures such as liver biopsies or expensive imaging studies.”

Initially, the team will look at variants in 20 genes of interest. These include genes that have been known to cause Alagille syndrome (a condition involving a reduced number of bile ducts), bile acid synthesis defects, progressive familial intrahepatic cholestasis and cystic fibrosis.

Children’s Center researchers will incorporate several types of information into their analysis, such as patient gender and ethnicity, and medical history including age of liver disease onset, presumed diagnoses, medication use, relevant surgeries and procedures. They’ll also review laboratory test results of liver-relevant markers, radiology reports such as ultrasound or MRI scans, and further genetic testing. 

To prepare for the study, which so far involves over 10 centers, investigators reviewed results of 8,621 genetic panel tests previously collected at Johns Hopkins from patients at the Children’s Center and other contributing hospitals. Among these, 6,193 (72%) had at least one VUS. Some 18,283 total VUSes were identified, 6,384 of which were in the group of 20 genes to be studied first. These results were presented at the Liver Meeting of the American Association for the Study of Liver Diseases, held in Washington, D.C., last fall.