Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis

Objectives: The study aimed to describe the clinical course, outcomes, and analyze genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. Methods: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into three genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation (PPTM) on the other), and TJP2-C (PPTMs on both alleles). Results: A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2. TJP2-A genotype were identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p=0.033), less likely to clear jaundice (12.5% vs. 52.2%, p=0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (LT) (native liver survival: 12.5% vs. 78.6%, p<0.001), with a median age at death/LT of 2.5 years. Cox regression analysis revealed that TJP2-C mutations (p=0.003) and failure to resolve jaundice (p=0.049) were independent predictors of poor outcome. Conclusion: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely LT.