Screening for Genetic Mechanisms for Biliary Atresia

Children'S Hosp Pittsburgh/Upmc Hlth Sys, Pittsburgh PA

Investigators

Abstract

Extrahepatic biliary atresia (BA) is a devastating condition that affects 1 in 8000 to 1 in 18000 live births with obliteration or discontinuity of the hepatic or common bile ducts at any point from the porta hepatitis to the duodenum. Approximately 10-20% of these infants improve after hepatic portoenterostomy but the remainder must undergo liver transplantation to survive. BA is the diagnosis in approximately 50% of children who undergo liver transplantation. Very little is known about the pathogenesis of BA. We have proposed that BA is a phenotype commonly shared by a diverse number of underlying pathological mechanisms that impact during fetal and perinatal development, including potential infectious, immune/inflammatory and morphogenic mechanisms. One clue comes from the observation that approximately 10-30% of patients with BA have other congenital anomalies. The majority, but not all, of these are anomalies of visceral organ laterality. In this proposed study, we will examine the hypothesis that a subgroup of infants with B A that also have congenital anomalies will have underlying genetic defects. We will use the recently established Biliary Atresia Research Consortium (BARC) to identify groups of patients for retrospective and prospective analyses to test this hypothesis. Two strategies will be used to screen for genetic mechanisms responsible for BA and congenital anomalies. First, we will use PCR amplification/DNA sequence analysis to examine the possibility that there are mutations in 19 candidate genes implicated in laterality determination. Second, we will use spectral karyotype analysis for translocations and high resolution chromosome analysis for microdeletions to identify chromosomal anomalies which will provide a general localization for subsequent candidate gene identification. These studies will provide new information about and a basis for many additional studies of the pathogenesis, natural history, early diagnosis and treatment of BA, a rare and severe liver disease of infants