Biallelic Loss-of-Function <i>ZFYVE19</i> Mutations Are Associated with Congenital Hepatic Fibrosis, Sclerosing Cholangiopathy, and High-GGT Cholestasis

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Background: For many children with intrahepatic cholestasis and high serum gamma-glutamyl transferase (GGT) activity, a genetic etiology of hepatobiliary disease remains undefined. We sought novel genes mutated in children with idiopathic high-GGT intrahepatic cholestasis and evaluated clinical, histopathologic, and functional correlations. Methods: In two cohorts of 29 children with undiagnosed high-GGT cholestasis and without clinical or imaging-study features of choledochal malformation, sclerosing cholangitis, cholelithiasis, or biliary-tract infection, we reviewed histopathologic findings; we identified mutations through whole-exome sequencing and targeted Sanger sequencing. Using immunofluorescence microscopy, we assessed the phenotypic effects of mutations in cultured fibroblast-like cells and human retinal pigmented epithelial cells. Findings: Nine Han Chinese cohort members harboured biallelic, predictedly complete-loss-of-function pathogenic mutations in ZFYVE19 (c.314C>G, p.S105X; c.379C>T, p.Q127X; c.514C>T, p.R172X; c.547C>T, p.R183X; c.226A>G, p.M76V). All had portal hypertension and histopathologic features of the ductal plate malformation/congenital hepatic fibrosis (DPM/CHF). Four required liver transplantation for recurrent gastrointestinal hemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme. Interpretation: ZFYVE19 modulates abscission, the terminal event in cytokinesis, at the cytoplasmic-bridge midbody. The midbody and centriole subsequently migrate to the same cell-surface site and participate in ciliogenesis. In vivo, biallellic ZFYVE19 mutations can lead to high-GGT cholestasis and CHF. In vitro, they can lead to centriolar and axonemal abnormalities. We propose that mutation in ZFYVE19 results, through undefined mechanisms, in a ciliopathy. Funding Statement: Support for this study was provided by the National Natural Science Foundation of China, grant numbers 81570468 and 81873543 (to J.S.W.). Declaration of Interests: None declared. Ethical Approval Statement: The study was approved by the ethics committees of both hospitals and was in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.