A new genetic may shed light on the causes of the rare childhood disease biliary atresia. The leading cause of liver transplantation in children, biliary atresia (BA) is a rare, life-threatening condition in which the ducts that carry bile from the liver to the gallbladder become blocked.

Children's Hospital's Randy Matthews, MD, PhD, led this new collaborative genetic study of BA, a condition occurring exclusively in neonatal livers. A relatively rare disease, BA affects approximately one out of every 15,000 infants, and is more common in Asians and African Americans.

With this study, Dr. Matthews and other CHOP researchers, including Marcella Devoto, PhD, and Nancy B. Spinner, PhD, hoped to better understand BA's etiology, which, while still poorly understood, is "believed to involve exposure of a genetically susceptible individual to certain environmental factors."

The study was published recently in Gastroenterology.

"Despite recent inroads into the understanding the mechanisms leading to fibroinflammatory damage to the biliary tree, uncovering the cause of BA continues to be a major challenge," Dr. Matthews noted. After searching for copy number variations (CNVs) — losses or gains in DNA sequence - in patients with BA compared to healthy individuals, Dr. Spinner and her team identified a candidate gene, GPC1. Moving to an animal model, Dr. Matthews and his team then studied the effects of using morpholino antisense oligonucleotides to reduce expression of gpc1 in zebrafish.

The researchers showed that disruption of gpc1 led to biliary defects in zebrafish. This finding, combined with the fact that the investigators also found "GPC1 abnormalities in all BA patient liver samples examined," support "a potential role for GPC1 as a susceptibility gene for BA," Dr. Matthews said.

While "the ability to test infants for genetic susceptibility to BA is clearly far off," future studies that shed light on biliary atresia's pathogenesis could help "identify treatments that are more effective than the existing therapy," Dr. Matthews said. That said, once tests for BA genetic susceptibility are developed, they will likely include testing for GPC1 defects, he added.