TY - JOUR T1 - Biallelic loss-of-function <em>ZFYVE19</em> mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis JF - Journal of Medical Genetics JO - J Med Genet SP - 514 LP - 525 DO - 10.1136/jmedgenet-2019-106706 VL - 58 IS - 8 AU - Weisha Luan AU - Chen-Zhi Hao AU - Jia-Qi Li AU - Qing Wei AU - Jing-Yu Gong AU - Yi-Ling Qiu AU - Yi Lu AU - Cong-Huan Shen AU - Qiang Xia AU - Xin-Bao Xie AU - Mei-Hong Zhang AU - Kuerbanjiang Abuduxikuer AU - Zhong-Die Li AU - Li Wang AU - Qing-He Xing AU - A S Knisely AU - Jian-She Wang Y1 - 2021/08/01 UR - http://jmg.bmj.com/content/58/8/514.abstract N2 - Background For many children with intrahepatic cholestasis and high-serum gamma-glutamyl transferase (GGT) activity, a genetic aetiology of hepatobiliary disease remains undefined. We sought to identify novel genes mutated in children with idiopathic high-GGT intrahepatic cholestasis, with clinical, histopathological and functional correlations.Methods We assembled a cohort of 25 children with undiagnosed high-GGT cholestasis and without clinical features of biliary-tract infection or radiological features of choledochal malformation, sclerosing cholangitis or cholelithiasis. Mutations were identified through whole-exome sequencing and targeted Sanger sequencing. We reviewed histopathological findings and assessed phenotypical effects of ZFYVE19 deficiency in cultured cells by immunofluorescence microscopy.Results Nine Han Chinese children harboured biallelic, predictedly complete loss-of-function pathogenic mutations in ZFYVE19 (c.314C&gt;G, p.S105X; c.379C&gt;T, p.Q127X; c.514C&gt;T, p.R172X; c.547C&gt;T, p.R183X; c.226A&gt;G, p.M76V). All had portal hypertension and, at liver biopsy, histopathological features of the ductal plate malformation (DPM)/congenital hepatic fibrosis (CHF). Four children required liver transplantation for recurrent gastrointestinal haemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. Immunostaining for two primary-cilium axonemal proteins found expression that was deficient intraluminally and ectopic within cholangiocyte cytoplasm. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme.Conclusion Biallelic ZFYVE19 mutations can lead to high-GGT cholestasis and DPM/CHF in vivo. In vitro, they can lead to centriolar and axonemal abnormalities. These observations indicate that mutation in ZFYVE19 results, through as yet undefined mechanisms, in a ciliopathy.Data are available upon reasonable request from J-SW (jshwang@shmu.edu.cn). ER -