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Original research
Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis
  1. Weisha Luan1,2,
  2. Chen-Zhi Hao2,
  3. Jia-Qi Li1,2,
  4. Qing Wei3,
  5. Jing-Yu Gong1,
  6. Yi-Ling Qiu1,2,
  7. Yi Lu2,
  8. Cong-Huan Shen4,
  9. Qiang Xia5,
  10. Xin-Bao Xie2,
  11. Mei-Hong Zhang1,
  12. Kuerbanjiang Abuduxikuer2,
  13. Zhong-Die Li2,
  14. Li Wang2,
  15. Qing-He Xing6,
  16. A S Knisely7,
  17. Jian-She Wang2
  1. 1 Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China
  2. 2 The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, China
  3. 3 Laboratory for Reproductive Health, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
  4. 4 Department of Surgery, Huashan Hospital Affiliated to Fudan University, Shanghai, China
  5. 5 Department of Liver Surgery and Liver Transplantation Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  6. 6 Institutes of Biomedical Sciences, Fudan University, Shanghai, China
  7. 7 Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
  1. Correspondence to Dr Jian-She Wang, The Center for Pediatric Liver Diseases, Children's Hospital, Fudan University, Shanghai, Shanghai, China; jshwang{at}


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.

  • clinical genetics
  • genetic screening/counselling
  • liver disease
  • molecular genetics
  • portal hypertension

Data availability statement

Data are available upon reasonable request from J-SW (

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Data availability statement

Data are available upon reasonable request from J-SW (

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  • WL, C-ZH and J-QL contributed equally.

  • Contributors Acquisition of data with analysis and interpretation of data involved W-SL (immunohistochemical and immunofluorescence studies), J-QL (genetic analysis), C-ZH (western blotting) and QW (immunofluorescence studies). W-SL and C-ZH were involved in the drafting of the manuscript; J-QL and C-ZH were involved in statistical analysis; J-YG, YQ, YL, C-HS, QX, XX, M-HZ and KA were involved in patient collection; QX was involved in study concept and design; ASK was involved in histopathological analysis, immunohistochemical studies and critical revision of the manuscript; and J-SW was involved in obtaining funding, study concept and design, and study supervision.

  • Funding Support for this study was provided by the National Natural Science Foundation of China (grant numbers 81570468 and 81873543, to JW).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.