BILIARY atresia (BA) is a hepatic condition in which bile ducts within and surrounding the liver are abnormally narrow, impeded, or missing, and is the most common cause of liver transplantation in children. Due to the disruption of bile flow and its accumulation in the liver, nutrient absorption is affected, and cirrhosis normally occurs within the first months of the child’s life. BA’s genetic underpinnings were previously unknown; however, a nationwide collaboration of scientists from the USA has now identified the first genetic defect linked to the condition.
‘‘Having the first plausible gene for BA is arguably one of the biggest findings in the field for decades,’’ explains senior author Saul J. Karpen, Emory School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA.
The results of 15 years of planning, paediatric liver specialists gathered a suitable number of patients for genetic analyses and were able to deduce that an estimated 10% of BA cases are associated with another congenital condition called heterotaxy, i.e., left-right mispositioning of organs. The researchers dubbed their finding biliary atresia with splenic malformation (BASM).
Using whole genome sequencing, 2,016 genes associated with organ development, cilia, and cellular organelles involved in embryonic patterning were genotyped in 67 children with BASM. Five of these patients were revealed to have deleterious, homozygous mutations in PKD1L1, with three others having heterozygous mutations. Additionally, PKD1L1 mutations have been linked to other pathologies such as congenital heart disease and heterotaxy.
More work is required to determine whether PKD1L1 mutations are drivers of BA, especially considering the large percentage of BASM-negative patients. However, such association studies are a promising sign for future efforts to elucidate this mysterious disease.