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

Like 0 Comment

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). KIF3BPCNT 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 KIF3BPCNT 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 It has not been peer reviewed but is currently under consideration at Nature Communications.

Go to the profile of Nature Communications

Nature Communications

Nature Research, Springer Nature