A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant
Abstract Background 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. Herein, we report a new...
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doaj-f7df835d169b48d499c236df0dd1e0c72021-04-18T11:11:04ZengBMCOrphanet Journal of Rare Diseases1750-11722021-04-011611910.1186/s13023-021-01775-8A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variantClaudia Mandato0Maria Anna Siano1Lucia Nazzaro2Monica Gelzo3Paola Francalanci4Francesca Rizzo5Ylenia D’Agostino6Manuela Morleo7Simona Brillante8Alessandro Weisz9Brunella Franco10Pietro Vajro11Department of Pediatrics, Santobono-Pausilipon Children’s HospitalPostgraduate School of Pediatrics Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of SalernoPediatric Clinic, “SS. Giovanni Di Dio and Ruggi D’Aragona” University of Salerno HospitalDepartment of Molecular Medicine and Medical Biotechnology, Faculty of Medicine, University of Naples Federico IIPathology Unit. Department of Laboratories, IRCCS Bambino Gesù Pediatric HospitalMedical Genomics Program, “SS. Giovanni Di Dio and Ruggi D’Aragona” University of Salerno HospitalLaboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno and Genome Research Center for Health (CRGS)Telethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Medical Genomics Program, “SS. Giovanni Di Dio and Ruggi D’Aragona” University of Salerno HospitalTelethon Institute of Genetics and Medicine (TIGEM)Postgraduate School of Pediatrics Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of SalernoAbstract Background 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. 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. Results A 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. Conclusions Our 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.https://doi.org/10.1186/s13023-021-01775-8CholestasisCiliopathyZFYVE19Children |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claudia Mandato Maria Anna Siano Lucia Nazzaro Monica Gelzo Paola Francalanci Francesca Rizzo Ylenia D’Agostino Manuela Morleo Simona Brillante Alessandro Weisz Brunella Franco Pietro Vajro |
spellingShingle |
Claudia Mandato Maria Anna Siano Lucia Nazzaro Monica Gelzo Paola Francalanci Francesca Rizzo Ylenia D’Agostino Manuela Morleo Simona Brillante Alessandro Weisz Brunella Franco Pietro Vajro A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant Orphanet Journal of Rare Diseases Cholestasis Ciliopathy ZFYVE19 Children |
author_facet |
Claudia Mandato Maria Anna Siano Lucia Nazzaro Monica Gelzo Paola Francalanci Francesca Rizzo Ylenia D’Agostino Manuela Morleo Simona Brillante Alessandro Weisz Brunella Franco Pietro Vajro |
author_sort |
Claudia Mandato |
title |
A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
title_short |
A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
title_full |
A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
title_fullStr |
A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
title_full_unstemmed |
A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
title_sort |
zfyve19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2021-04-01 |
description |
Abstract Background 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. 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. Results A 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. Conclusions Our 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. |
topic |
Cholestasis Ciliopathy ZFYVE19 Children |
url |
https://doi.org/10.1186/s13023-021-01775-8 |
work_keys_str_mv |
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