Abstract
Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.
Highlights
Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis
We recruited a total of 42 children who had been diagnosed with BA based on intraoperative findings and liver biopsy
We found that some genes from our study, including BCOR, INVS and OCRL, were included in this gene set
Summary
Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. Biliary atresia is a progressive inflammation and fibrosis of the biliary tree that results in the development of cholestatic liver disease. It is estimated that after hepatic portoenterostomy operation, 70–80% of patients with BA still require liver transplantation by adulthood due to the progressive development of liver scarring, failure and cirrhosis[5,6]. The disease occurs more frequently in Southeast Asia and the Ocean Pacific[22] It is approximately 1 in 5000 live births in Taiwan compared to 1 in 14,000–20,000 in North America or Western Europe[6,23,24]. We aimed to investigate the genetic pattern of BA by conducting a family-based WES for children with BA in hope of exploring new and characterized causative variants, which would shed light on the aetiology of the deadly disease
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