DOI: 10.1097/hep.0000000000000828 ISSN: 0270-9139

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

Bikrant Bihari Lal, Seema Alam, Anupam Sibal, Karunesh Kumar, Somashekara Hosaagrahara Ramakrishna, Vaibhav Shah, Nirmala Dheivamani, Ashish Bavdekar, Aabha Nagral, Nishant Wadhwa, Arjun Maria, Aashay Shah, Ira Shah, Zahabiya Nalwalla, Pandey Snehavardhan, K.P. Srikanth, Subhash Gupta, Viswanathan M. Sivaramakrishnan, Yogesh Waikar, Arya Suchismita, A. Ashritha, Vikrant Sood, Rajeev Khanna,
  • Hepatology
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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.

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