A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant

Claudia Mandato,Monica Gelzo,Brunella Franco,Manuela Morleo,Maria Anna Siano,Pietro Vajro,Ylenia D’Agostino,Francesca Rizzo,Paola Francalanci,Lucia Nazzaro,Simona Brillante,Alessandro Weisz

doi:10.1186/s13023-021-01775-8

Abstract

BackgroundZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation.ResultsA now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities.ConclusionsOur findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.

Highlights

zinc finger FYVE-type containing 19 (ZFYVE19) (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction
In this patient mutations were found in the ZFYVE19 transcript which is ubiquitously expressed
Analysis of cilia morphology revealed a significantly increased number of cilia with non-canonical ciliary structure in fibroblasts obtained from patient compared to controls: the ciliary phenotype was mainly defined by a discontinuous axoneme, marked by gaps in ARL13b staining in all z-planes

Summary

Introduction

ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. While obstacles on the extrahepatic biliary tree [e.g. surgical emergencies such as Biliary Atresia (OMIM #210500)] are quite regularly characterized by high levels of gamma-glutamyl transpeptidase (GGT), assessment of intrahepatic cholestasis is more difficult. In this respect, patients can be usefully categorized by whether levels of serum GGT remain in normal ranges despite hyperbilirubinemia activity or rise together with serum concentrations of conjugated bilirubin [1]. Cholangiocyte cilia extending from the apical plasma membrane to the lumen of the bile duct are ideally positioned to detect changes in bile flow, composition and osmolality These mechanosensory, osmosensory and chemosensory organelles have been proposed to control cholangiocytes’ functions such as the formation of ductal bile [6]. While this may result from the same severe cholestasis or inflammation themselves, it has been suggested that it may reflect common mechanistic pathways in different forms of biliary atresia and may have implications for understanding the progression of the disease [7]

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