Genetic testing helps identify cause of neonatal cholestasis
Screening allows for prompt, targeted treatment
Genetic testing can help doctors find the cause of neonatal cholestasis more quickly, so children can receive more targeted treatment sooner, according to a study in Turkey.
Genetic conditions were identified in more than a quarter of nearly 300 children, with the most common diagnosis being progressive familial intrahepatic cholestasis (PFIC), a rare form of cholestasis caused by mutations in a number of genes. More than half of the genetically diagnosed children were born from blood-related parents.
“Expanded genetic testing in clinical practice is critical for timely and accurate diagnosis of these rare disorders,” the researchers wrote.
The study, “Neonatal Cholestasis: Exploring Genetic Causes and Clinical Outcomes,” was published in the Journal of Paediatrics and Child Health.
Neonatal cholestasis occurs when the flow of the digestive fluid bile from the liver to the intestines is slowed or stalled in newborns. As bile builds up in the liver, it causes damage to the organ and its components leak into the bloodstream. This causes cholestasis symptoms such as itching and jaundice (yellowing of the skin and whites of the eyes).
Rare disorders, diverse potential causes
Many disorders can cause neonatal cholestasis. Among them is PFIC, in which cholestasis occurs due to genetic mutations that affect bile’s transport out of the liver. There are several PFIC types, each associated with mutations in different genes.
“Challenges persist in the management of neonatal cholestasis, including delayed diagnosis, limited treatment options, and the risk of disease progression to … liver failure,” the researchers wrote. “Furthermore, the rarity and [variability] of genetic cholestatic disorders pose obstacles to large-scale clinical studies and therapeutic trials.”
To better understand the genetic and clinical features of children with genetically diagnosed neonatal cholestasis, the team of researchers in Turkey retrospectively analyzed data from 378 such children who were seen at a Turkish hospital between 1997 and 2024.
Children’s mean age when they were admitted to the hospital was 12.5 months, and their symptoms had started at a mean age of 2.2 months. The most common symptom was jaundice (60%).
Among non-genetic cholestatic conditions, biliary atresia, a disease in which the bile ducts (the tubes that transport bile) are blocked or missing, was the most common diagnosis (19.3%). Choledochal cysts, or abnormal enlargements of the bile ducts, were the cause of cholestasis in 3.4% of the children.
After removing these cases, doctors reviewed records from the remaining 292 children to find other causes of cholestasis.
Genetic tests such as targeted gene panels and whole exome sequencing — which looks at all the protein-coding genes in the body — identified genetic causes of cholestasis in 82 of those children (28%). More than half of them (56%) had parents who were related by blood.
The most common mutations were located in genes known to cause PFIC, accounting for a total of 28 children with this condition. Specifically, 12 children carried mutations in the ABCB4 gene (which cause PFIC type 3), nine had ABCB11 mutations (the cause of PFIC type 2), and seven carried mutations in the ATP8B1 gene (which cause PFIC type 1).
Other mutated genes included DCDC2, DGUOK, KIF12, and USP53, as well as those involved in making bile acids, bile’s main component (HSD3B7 and PEX1).
The levels of an enzyme called gamma-glutamyl transferase (GGT), a biomarker of liver function, were also measured in blood. Low or normal GGT levels were linked to PFIC types 1 and 2 or abnormalities in the formation of bile acids. High levels were linked to PFIC type 3, alpha-1 antitrypsin deficiency, and cystic fibrosis.
Some children were also diagnosed with genetic causes of cholestasis, including Alagille syndrome, based on clinical and laboratory features alone, without the need for genetic testing.
The percentage of children diagnosed with genetic cholestatic disorders increased from 18.2% before 2010 to 35.5% thereafter, likely because of better and more affordable access to genetic testing.
Also, “genetic disease was confirmed in the last 10 years in some of the patients whose follow-up started before 2010,” the researchers wrote.
Available data showed that 25.6% of the children experienced a lessening of cholestasis, and 36.5% were living with chronic cholestasis. A few children either progressed to liver failure and were waiting for a liver transplant (3.6%) or had already undergone the procedure (1.7%). Six children died.
The team recommended genetic testing become a routine part of diagnosing neonatal cholestasis.
“Considering the increased diagnosis of genetic diseases and genetic studies have become easier and faster in recent years, we believe that … performing genetic testing after excluding red-flag or urgent causes will help achieve faster diagnoses for a greater number of patients,” the researchers wrote.
Tests related to a specific disease should be conducted if a patient has a characteristic for that disease, “but if they do not indicate a specific disease, direct genetic examination should be requested,” they concluded.
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