{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:56:49Z","timestamp":1793692609513,"version":"4.5.1"},"reference-count":27,"publisher":"BMJ","issue":"10","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32322021"],"award-info":[{"award-number":["32322021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2700800"],"award-info":[{"award-number":["2021YFC2700800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,6,15]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Biallelic pathogenic <jats:italic>TULP3<\/jats:italic> variants have been associated with a novel ciliopathy named hepatorenocardiac degenerative fibrosis, which is characterised by hepatic fibrosis in childhood or early adulthood, fibrocystic kidney disease later in life and hypertrophic cardiomyopathy in the elderly. Its genotype and phenotype spectrum are largely unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children\u2019s Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of <jats:italic>TULP3<\/jats:italic> were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Two unrelated children carrying biallelic rare variants in <jats:italic>TULP3<\/jats:italic> were identified. Patient 1 had variants c.666T&gt;G, p. (Tyr222Ter) and c.1291G&gt;C, p. (Gly431Arg). She initially presented with neonatal cholestasis, which rapidly progressed to liver fibrosis, with liver transplantation at 2 years of age. She also had intellectual disability and attention deficit hyperactivity disorder. Patient 2 had variants c.73C&gt;T, p. (Gln25Ter) and c.1211T&gt;G, p. (Met404Arg). He was found to have liver fibrosis, portal hypertension and abnormal cranial imaging at the age of 7.5 years. Both non-sense variants, c.73C&gt;T\u2009and c.666T&gt;G, were predicted to result in non-sense-mediated mRNA decay. Missense variant Met404Arg abolished TULP3 expression, while Gly431Arg reduced the localisation of TULP3 in cilia. Both Met404Arg and Gly431Arg impaired ciliogenesis and the trafficking of ARL13B and INPP5E into cilia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Severe neonatal cholestasis and\/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous <jats:italic>TULP3<\/jats:italic> variants. Missense variants in <jats:italic>TULP3<\/jats:italic> may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2025-110658","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T13:20:25Z","timestamp":1751030425000},"page":"631-640","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Biallelic pathogenic <i>TULP3<\/i> variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-3212","authenticated-orcid":false,"given":"Jia-Qi","family":"Li","sequence":"first","affiliation":[{"name":"The Center for Pediatric Liver Diseases, Children\u2019s Hospital of Fudan University, Shanghai, Shanghai, 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