Biallelic pathogenic TULP3 variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations

Jia-Qi Li; Yan Li; Ruida He; Zaisheng Lin; Jiayan Feng; Bin Yang; Qing-Wen Shan; Sixing Chen; Ye Cheng; Qinghe Xing; Muqing Cao; Jian-She Wang

doi:10.1136/jmg-2025-110658

Biallelic pathogenic TULP3 variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations

J Med Genet. 2025 Jun 27:jmg-2025-110658. doi: 10.1136/jmg-2025-110658. Online ahead of print.

Authors

Jia-Qi Li¹, Yan Li², Ruida He², Zaisheng Lin², Jiayan Feng³, Bin Yang⁴, Qing-Wen Shan⁵, Sixing Chen⁵, Ye Cheng¹, Qinghe Xing⁶, Muqing Cao⁷, Jian-She Wang⁸

Affiliations

¹ The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, Shanghai, China.
² Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China.
³ The Department of Pathology, Children's Hospital of Fudan University, Shanghai, Shanghai, China.
⁴ The Department of Radiology, Children's Hospital of Fudan University, Shanghai, Shanghai, China.
⁵ Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
⁶ Children's Hospital of Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, Shanghai, China.
⁷ Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China jshwang@shmu.edu.cn muqingcao@sjtu.edu.cn.
⁸ The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, Shanghai, China jshwang@shmu.edu.cn muqingcao@sjtu.edu.cn.

PMID: 40579123
DOI: 10.1136/jmg-2025-110658

Abstract

Background: Biallelic pathogenic TULP3 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.

Methods: Patients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of TULP3 were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.

Results: Two unrelated children carrying biallelic rare variants in TULP3 were identified. Patient 1 had variants c.666T>G, p. (Tyr222Ter) and c.1291G>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>T, p. (Gln25Ter) and c.1211T>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>T and c.666T>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.

Conclusion: Severe neonatal cholestasis and/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous TULP3 variants. Missense variants in TULP3 may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.

Keywords: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Liver Diseases.