{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:16:37Z","timestamp":1789654597239,"version":"4.0.1"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003852","name":"Regione Campania","doi-asserted-by":"publisher","award":["Grant GENOMAeSALUTE, CUP: B41C17000080007"],"award-info":[{"award-number":["Grant GENOMAeSALUTE, CUP: B41C17000080007"]}],"id":[{"id":"10.13039\/501100003852","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"crossref","award":["Grant PerMedNet cod. ARS01_01226, CUP: D26C18000260005)"],"award-info":[{"award-number":["Grant PerMedNet cod. ARS01_01226, CUP: D26C18000260005)"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59\u00a0days 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-01775-8","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T20:34:50Z","timestamp":1618432490000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant"],"prefix":"10.1186","volume":"16","author":[{"given":"Claudia","family":"Mandato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Anna","family":"Siano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Nazzaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Gelzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Francalanci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ylenia","family":"D\u2019Agostino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Morleo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Brillante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Weisz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunella","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9418-5880","authenticated-orcid":false,"given":"Pietro","family":"Vajro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"1775_CR1","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s13052-019-0679-x","volume":"45","author":"C Mandato","year":"2019","unstructured":"Mandato C, Zollo G, Vajro P. Cholestatic jaundice in infancy: struggling with many old and new phenotypes. Ital J Pediatr. 2019;45:83.","journal-title":"Ital J Pediatr"},{"key":"1775_CR2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3389\/fped.2014.00065","volume":"2","author":"A Hoerning","year":"2014","unstructured":"Hoerning A, Raub S, Dech\u00eane A, Brosch MN, Kathemann S, Hoyer PF, Gerner P. Diversity of disorders causing neonatal cholestasis\u2014the experience of a tertiary pediatric center in Germany. Front Pediatr. 2014;2:65.","journal-title":"Front Pediatr"},{"key":"1775_CR3","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1097\/MPG.0000000000001334","volume":"64","author":"R Fawaz","year":"2017","unstructured":"Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for pediatric gastroenterology, hepatology, and nutrition and the European Society for pediatric gastroenterology, hepatology, and nutrition. J Pediatr Gastroenterol Nutr. 2017;64:154\u201368.","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"1775_CR4","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/lt.24964","volume":"24","author":"E Nicastro","year":"2018","unstructured":"Nicastro E, D\u2019Antiga L. Next generation sequencing in pediatric hepatology and liver transplantation. Liver Transpl. 2018;24:282\u201393.","journal-title":"Liver Transpl"},{"key":"1775_CR5","doi-asserted-by":"crossref","unstructured":"Luan W, Hao CZ, Li JQ, Wei Q, Gong JY, Qiu YL et al. Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis. J Med Genet. 2020 (Epub ahead of print).","DOI":"10.2139\/ssrn.3439573"},{"issue":"44","key":"1775_CR6","first-page":"12451253","volume":"1864","author":"AP Mansini","year":"2018","unstructured":"Mansini AP, Peixoto E, Thelen KM, Gaspari C, Jin S, Gradilone SA. The cholangiocyte primary cilium in health and disease. Biochim Biophys Acta Mol Basis Dis. 2018;1864(44):1245\u201353.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"1775_CR7","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/modpathol.2011.212","volume":"25","author":"AS Chu","year":"2012","unstructured":"Chu AS, Russo PA, Wells RG. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol. 2012;25:751\u20137.","journal-title":"Mod Pathol"},{"key":"1775_CR8","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1080\/17474124.2017.1359538","volume":"11","author":"A Catzola","year":"2017","unstructured":"Catzola A, Vajro P. Management options for cholestatic liver disease in children. Expert Rev Gastroenterol Hepatol. 2017;11:1019\u201330.","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"1775_CR9","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.mcn.2016.01.004","volume":"72","author":"F Rizzo","year":"2016","unstructured":"Rizzo F, Ambrosino P, Guacci A, Chetta M, Marchese G, Rocco T, et al. Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci. 2016;72:54\u201363.","journal-title":"Mol Cell Neurosci"},{"key":"1775_CR10","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1093\/hmg\/ddy380","volume":"28","author":"F Massa","year":"2019","unstructured":"Massa F, Tammaro R, Prado MA, Cesana M, Lee B-H, Finley D, et al. The deubiquitinating enzyme USP14 controls ciliogenesis and Hedgehog signalling. Hum Mol Genet. 2019;28:764\u201377.","journal-title":"Hum Mol Genet"},{"issue":"6","key":"1775_CR11","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1093\/hmg\/ddaa029","volume":"29","author":"D Iaconis","year":"2020","unstructured":"Iaconis D, Crina C, Brillante S, Indrieri A, Morleo M, Franco B. The HOPS complex subunit VPS39 controls ciliogenesis through autophagy. Hum Mol Genet. 2020;29(6):1018\u201329.","journal-title":"Hum Mol Genet"},{"key":"1775_CR12","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1038\/s41436-018-0288-x","volume":"21","author":"S Maddirevula","year":"2019","unstructured":"Maddirevula S, Alhebbi H, Alqahtani A, et al. Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet Med. 2019;21:1164\u201372.","journal-title":"Genet Med"},{"key":"1775_CR13","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1177\/1093526619881541","volume":"23","author":"S Kulkarni","year":"2020","unstructured":"Kulkarni S, Abro B, Duque Lasio ML, Stoll J, Grange DK, He M. Clinical and pathological features of a newborn with compound heterozygous ANKS6 variants. Pediatr Dev Pathol. 2020;23:235\u20139.","journal-title":"Pediatr Dev Pathol"},{"key":"1775_CR14","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/ng.2681","volume":"45","author":"S Hoff","year":"2013","unstructured":"Hoff S, Halbritter J, Epting D, et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat Genet. 2013;45:951\u20136.","journal-title":"Nat Genet"},{"issue":"2","key":"1775_CR15","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.celrep.2017.06.045","volume":"20","author":"H Shimada","year":"2017","unstructured":"Shimada H, Lu Q, Insinna-Kettenhofen C, Nagashima K, English MA, Semler EM, et al. In vitro modeling using ciliopathy patient-derived cells reveals distinct cilia dysfunctions caused by CEP290 mutations. Cell Rep. 2017;20(2):384\u201396.","journal-title":"Cell Rep"},{"issue":"6","key":"1775_CR16","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1002\/hep.30982","volume":"71","author":"R Shaheen","year":"2020","unstructured":"Shaheen R, Alsahli S, Ewida N, Alzahrani F, Shamseldin HE, Patel N, et al. Biallelic mutations in tetratricopeptide repeat domain 26 (intraflagellar transport 56) cause severe biliary ciliopathy in humans. Hepatology. 2020;71(6):2067\u201379.","journal-title":"Hepatology"},{"key":"1775_CR17","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1053\/j.gastro.2005.10.022","volume":"130","author":"TA Miettinen","year":"2006","unstructured":"Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB. Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology. 2006;130:542\u20137.","journal-title":"Gastroenterology"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01775-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-021-01775-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01775-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T20:44:32Z","timestamp":1618433072000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-01775-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,14]]},"references-count":17,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1775"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-01775-8","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,14]]},"assertion":[{"value":"24 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures followed were in accordance with the ethical standards of the responsible Institutional Committee on Human Experimentation and with the Helsinki Declaration of 1975 (revised in 2000). The study was approved by the Ethics Committee of the University Hospital of Salerno.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent was written by the parents of our patient to participate in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"179"}}