{
  "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.",
  "authors": [
    {
      "affiliations": [
        "The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Jia-Qi Li"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Yan Li"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Ruida He"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Zaisheng Lin"
    },
    {
      "affiliations": [
        "The Department of Pathology, Children’s Hospital of Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Jiayan Feng"
    },
    {
      "affiliations": [
        "The Department of Radiology, Children’s Hospital of Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Bin Yang"
    },
    {
      "affiliations": [
        "Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Qing-Wen Shan"
    },
    {
      "affiliations": [
        "Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China"
      ],
      "name": "Sixing Chen"
    },
    {
      "affiliations": [
        "The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Ye Cheng"
    },
    {
      "affiliations": [
        "Children’s Hospital of Fudan University and Institutes of Biomedical Sciences, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Qinghe Xing"
    },
    {
      "affiliations": [
        "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"
      ],
      "name": "Muqing Cao"
    },
    {
      "affiliations": [
        "The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Jian-She Wang"
    }
  ],
  "title": "Biallelic pathogenic TULP3 variants presenting as neonatal cholestasis, liver fibrosis and neurological manifestations",
  "uid": "c9699b9e-d0cb-5677-a944-30fff07859b4"
}