New mutation likely cause of PFIC type 1 in siblings with liver failure
Parents advised to undergo genetic testing for future pregnancies: Case
A novel mutation in the ATP8B1 gene was the likely cause of progressive familial intrahepatic cholestasis (PFIC) type 1 in two siblings in India who died of liver failure in childhood, a study showed.
The two brothers’ parents, who are distant cousins, were both found to be carriers of this newly identified genetic variant.
With the disease-causing mutation now known, the parents were advised to undergo genetic testing in the event of any future pregnancies to learn the mutation status of the unborn baby, according to the study.
The researchers noted that “this pathogenic [disease-causing] variant, p.Gly1224SerfsTer13, has not been reported before and adds to the ever-expanding list of pathogenic mutations known to cause PFIC 1.”
The study, “Novel ATP8B1 gene mutation in a family with progressive familial intrahepatic cholestasis,” was published in BMJ Case Reports.
Parents, both PFIC type 1 carriers, had no known history of liver disease
PFIC refers to a group of rare genetic disorders marked by cholestasis, or stalled flow of the digestive fluid bile within the liver, where it is produced. This causes bile to build up to toxic levels in the liver and leak into the bloodstream, resulting in symptoms such as jaundice, a yellowing of the skin and the whites of the eyes, and itching.
Over time, PFIC can set the stage for life-threatening complications like liver failure.
PFIC type 1, which typically manifests early in infancy, is specifically caused by mutations in the ATP8B1 gene, which provides instructions to make a protein called FIC 1. This protein is thought to be involved in maintaining a proper balance of bile acids, the main components of bile, and protecting liver cells from high bile acid levels.
All individuals inherit two copies of the ATP8B1 gene, one from each biological parent. PFIC type 1 only occurs if both copies of the gene carry a disease-causing mutation. The type of ATP8B1 mutation and the function of the resulting FIC 1 protein “govern the severity of disease manifestation,” the researchers wrote.
Here, the team described the case of a married couple who sought preconception counseling after their two children, both boys, had died due to suspected genetic conditions. The couple, who had no signs of disease, were distant cousins who had no known family history of liver or metabolic diseases.
The boys had experienced different clinical issues in early childhood, but both ultimately died from liver failure.
Couple hope to use early genetic analysis to have healthy child
The first child started to experience jaundice at 6 months and was managed conservatively for three years, during which time he developed further signs of cholestasis, including itching and elevated blood levels of liver damage markers. He also showed signs of anemia, or low counts of red blood cells.
The boy was scheduled to undergo a liver biopsy, but he died before the procedure due to complications of liver failure.
The second child showed dark, tarry stools and vomited blood at about 4 months, suggesting bleeding in the gastrointestinal tract, which can be a complication of severe liver disease.
Blood work showed signs of anemia and high levels of certain liver markers of liver damage, but “unlike his elder sibling, there was no history of accompanying jaundice,” the researchers wrote.
The child also had low levels of platelets, which are cell fragments involved in blood clotting, and are another possible complication of liver disease. The boy’s condition progressed rapidly to liver failure and he died shortly after.
We plan to conceive again in another six months. We hope that early genetic analysis in the unborn child can help us decide whether we can go ahead with the pregnancy or not.
Genetic testing in the parents showed both the father and mother carried a previously unknown mutation, called p.Gly1224SerfsTer13, in one of the ATPBB1 gene copies, the researchers noted.
This mutation dramatically changes the protein sequence and results in the production of a shorter, nonworking protein. As such, p.Gly1224SerfsTer13 is thought to be disease-causing when present in both gene copies.
“Therefore, the clinical presentation in both siblings was attributed to PFIC [type] 1, consistent with the clinicolaboratory findings reported previously,” the researchers wrote, noting that “the diagnostic evaluation for both siblings was not comprehensive, which may have provided additional support for our conclusion.”
The couple received counseling to inform them of the risk of PFIC with future pregnancies and the possibilities for genetic testing during pregnancy. When each parent carries one mutated copy of the gene, there’s a 1 in 4 chance of PFIC with each pregnancy.
“We got a clear picture of the spectrum of disease conditions suffered by our previous children only after the genetic report was explained to us,” the couple wrote in a patient perspective included in the study.
The parents noted that “the risk of recurrence in the subsequent pregnancies was clearly explained as well.”
The couple say they’re hopeful that the results of the preconception counseling will help them to have a healthy child.
“We plan to conceive again in another six months. We hope that early genetic analysis in the unborn child can help us decide whether we can go ahead with the pregnancy or not,” the parents wrote.
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