Whole exome sequencing reveals a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia
Wai-Yee Lam, Man-Ting So, Jacob Shujui Hsu, Patrick Ho-Yu Chung, Diem Ngoc Ngo, Pham Anh Hoa Nguyen, Hannah M Mitchison, Dagan Jenkins, Christopher O'Callaghan, Pak-Chung Sham, Maria-Mercè Garcia-Barceló, Vincent Chi-Hang Lui, Clara Sze-Man Tang, Paul Kwong-Hang Tam
Received Date: 15th April 20
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.
Read in full at medRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.