Whole exome sequencing analysis in biliary atresia: a follow-up study

Abstract

Biliary Atresia (BA) is a severe and complex neonatal disorder characterized by aggressive fi brosclerosis and infl ammatory obliteration of the extrahepatic biliary tract. The Southeast Asian population has the highest prevalence (1/5000 live births). The Kasai portoenterostomy is often performed to improve bile drainage, but the majority of the BA patients ultimately require liver transplant, making the disease the most common cause of pediatric liver transplant. Most BA cases are sporadic, and the etiology of BA remains unclear. In cholangiocytes, vascular endothelial growth factor A (VEGF-A) regulates cell proliferation during development, and mutations in VEGF were suggested to be associated with BA. Previously, we identifi ed ADD3 as a susceptibility factor for BA through genome-wide association analysis and showed that reduced ADD3 expression levels correlated with the risk ADD3 allele. In this follow-up study, we performed whole exome sequencing on 92 BA trios from the Southeast Asian population to identify potential variants, genes and biological pathways associated with BA. Our preliminary analysis found a de novo frameshift insertion in the FLT1 gene, which encodes VEGF receptor 1 to regulate VEGFA signaling. FLT1 is highly intolerant to loss-offunction mutation (pLI=1.0), and the insertion is extremely rare, not found in the ExAC or gnomAD databases. Further analysis results will be presented for additional insights on the pathogenesis of BA, which will guide our functional studies using in-house human organoid system.