Genetic link for childhood liver disease

Published online 29 July 2022

A mutant gene could explain the rare occurrence of severe liver disease in infants.

Bianca Nogrady

Liver disease in children is extremely rare, but can lead to liver failure and the need for a transplant. While there are some congenital conditions that are known to be associated with paediatric liver disease, around one-third of cases are still unexplained.

An international research effort, including scientists from Saudi institutions such as King Saud bin Abdulaziz University for Health Sciences and King Fahad Medical City, has identified a genetic mutation that may shed new light on the causes of liver disease and potentially provide new targets for treatment.

The study involved 14 children from 10 families across seven countries, all of whom had syndromes that cause severe liver scarring, known as cirrhosis, as well as a range of other symptoms such as lung, heart and digestive system problems. 

The research team sequenced the protein-coding genes in parents and the affected children, and found a mutation in a gene called FOCAD, which appeared in all the children with the syndrome.

Unusually, this gene has not previously been linked to any form of liver disease, although mutations in FOCAD have been associated with the development of cancers, including brain glioblastoma.

To make sure, the researchers engineered zebrafish with a ‘knocked out’ FOCAD gene, and found they developed the same clinical syndrome as the affected children.

The researchers then studied what happened when they knocked out the gene in human liver cells in the lab, and found it played a key role in a quality control process that looks for and removes corrupt messenger RNA. They found that liver cells are particularly sensitive to the loss of FOCAD, which may explain why the disruption of this pathway has such devastating effects in the liver, but not so much elsewhere in the body.

“It does explain a proportion of children developing liver disease fairly early in life, which is unusual,” says Nedim Hadžić, from King’s College London, who was not involved in the study. 

“It seems to be offering a plausible explanation for why the normal regenerative processes in the liver are not working very well in affected children and therefore lead to fairly early cirrhosis.” 


Traspas, R. et al. Loss of FOCAD, operating via the SKI messengerRNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nat Genet (2022).