PT  - JOURNAL ARTICLE
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
TI  - Biallelic loss-of-function <em>ZFYVE19</em> mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis
AID  - 10.1136/jmedgenet-2019-106706
DP  - 2021 Aug 01
TA  - Journal of Medical Genetics
PG  - 514--525
VI  - 58
IP  - 8
4099  - http://jmg.bmj.com/content/58/8/514.short
4100  - http://jmg.bmj.com/content/58/8/514.full
SO  - J Med Genet2021 Aug 01; 58
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).