Whole exome sequencing reveals a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia
Lam, W.-Y.; So, M.-T.; Hsu, J. S.; Chung, P. H.-Y.; Ngo, D. N.; Nguyen, P. A. H.; Mitchison, H. M.; Jenkins, D.; O'Callaghan, C.; Sham, P.-C.; Garcia-Barcelo, M.-M.; Lui, V. C.-H.; Tang, C. S.-M.; Tam, P. K.-H.
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Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution remains poorly defined. We conducted exome sequencing on 89 nonsyndromic BA trios. In 31.5% of the patients, rare and deleterious de novo, homozygous recessive and/or compound heterozygous variants were detected in liver-expressed ciliary genes of diverse ciliary functions. Enrichment of deleterious mutations in liver-expressed ciliary geneset was significant compared to 148 control trios (OR 2.58, 95% CI 1.15-6.07). KIF3B, PCNT and TTC17 are essential for ciliogenesis. Reduced ciliary proteins expression were detected in the BA livers with KIF3B and TTC17 mutations. CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Our findings support a larger genetic contribution to nonsyndromic BA risk than expected. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis.
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