RT Journal Article SR Electronic T1 Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 514 OP 525 DO 10.1136/jmedgenet-2019-106706 VO 58 IS 8 A1 Weisha Luan A1 Chen-Zhi Hao A1 Jia-Qi Li A1 Qing Wei A1 Jing-Yu Gong A1 Yi-Ling Qiu A1 Yi Lu A1 Cong-Huan Shen A1 Qiang Xia A1 Xin-Bao Xie A1 Mei-Hong Zhang A1 Kuerbanjiang Abuduxikuer A1 Zhong-Die Li A1 Li Wang A1 Qing-He Xing A1 A S Knisely A1 Jian-She Wang YR 2021 UL http://jmg.bmj.com/content/58/8/514.abstract AB 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>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, 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).