Study identifies gene variants associated with biliary atresia splenic malformation syndrome in children

Researchers have identified gene variants present in infants with biliary atresia splenic malformation syndrome that may increase susceptibility to this severe and potentially deadly childhood liver disease. Biliary atresia is a serious liver disease that occurs during the first few months of life in which bile ducts that drain from the liver, delivering bile acids to the intestine, become inflamed and scarred, leading to a back-up of bile into the liver. This back-up can result in liver damage and, if not treated with surgery or liver transplantation, can lead to liver failure and death. Although a rare disease, biliary atresia remains the most common form of severe liver disease in children and the leading cause for pediatric liver transplantation. Some infants with biliary atresia have additional complications caused by improper positioning of some internal organs, such as the spleen, within the body; this condition is referred to as biliary atresia splenic malformation (BASM) syndrome. The causes of biliary atresia and the rarer BASM syndrome are not fully understood.

With support from the NIDDK, the National Center for Advancing Translational Sciences, and other sources, researchers set forth to identify genetic factors that might play a role in the development of BASM syndrome by studying infants enrolled in the NIDDK’s Childhood Liver Disease Research Network (ChiLDReN) and their parents. They sequenced portions of the genomes of the families and looked for genetic variants that likely disrupt biological functions previously implicated in biliary development and in organ positioning. In particular, they examined variants that might be associated with blockage of bile flow or dysfunction in the cilia (hair-like projections) that line the bile ducts and play a role in cell signaling. The investigators found variants of one gene in particular, called PKD1L1, in about 12 percent of the children studied with BASM. The protein produced by this gene is important for both ciliary signaling and proper positioning of internal organs during embryonic development, underscoring its possible role in BASM syndrome. Also, the researchers tested a tissue sample from one of the children with PKD1L1 variants and found reduced activity of this gene within the bile ducts, meaning the functionality of the gene may be affected.

This study identifies PKD1L1 as a new candidate gene in the development of BASM syndrome—and possibly some cases of biliary atresia without BASM syndrome, given the important role of this gene product in biliary function—in young children. Future studies in both humans and cell or animal models could explore the functions of this gene and the possible mechanisms by which these genetic variants might contribute to these rare diseases.