Thunga C, Mitra S, Babbar A, Lal R, Pal A, Kakkar N, Lal SB. Clinical spectrum and genotype-phenotype correlation of ABCB4 mutations in children: Insights from a North Indian cohort. World J Hepatol 2026; 18(1): 113485 [DOI: 10.4254/wjh.v18.i1.113485]
Corresponding Author of This Article
Sadhna Bhasin Lal, Head, Professor, Department of Paediatric Gastroenterology and Hepatology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India. sadhnalal2014@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jan 27, 2026 (publication date) through Jan 27, 2026
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Journal Information of This Article
Publication Name
World Journal of Hepatology
ISSN
1948-5182
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Thunga C, Mitra S, Babbar A, Lal R, Pal A, Kakkar N, Lal SB. Clinical spectrum and genotype-phenotype correlation of ABCB4 mutations in children: Insights from a North Indian cohort. World J Hepatol 2026; 18(1): 113485 [DOI: 10.4254/wjh.v18.i1.113485]
Chennakeshava Thunga, Alisha Babbar, Sadhna Bhasin Lal, Department of Paediatric Gastroenterology and Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
Suvradeep Mitra, Raghav Lal, Nandita Kakkar, Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
Arnab Pal, Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
Co-first authors: Chennakeshava Thunga and Suvradeep Mitra.
Author contributions: Thunga C and Mitra S were responsible for patient recruitment, intellectual content, acquisition and analysis of data, initial draft of the manuscript, histopathology reporting, and co-draft of the original manuscript as co-first authors; Babbar A was responsible for patient recruitment, acquisition and analysis of data; Lal R was responsible for histopathology documentation, and intellectual inputs; Pal A was responsible for biochemistry and laboratory reporting, and intellectual inputs; Kakkar N was responsible for histopathology reporting and intellectual inputs; Lal SB was responsible for conception and design of study, supervision of study, interpretation of data, critical intellectual content, revision, and editing; all of the authors read and approved the final version of the manuscript to be published.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee, No. IEC-INT/2023/DM-1452.
Informed consent statement: All participants provided informed consent.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sadhna Bhasin Lal, Head, Professor, Department of Paediatric Gastroenterology and Hepatology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India. sadhnalal2014@gmail.com
Received: August 28, 2025 Revised: September 28, 2025 Accepted: December 8, 2025 Published online: January 27, 2026 Processing time: 153 Days and 21.9 Hours
Abstract
BACKGROUND
Progressive familial intrahepatic cholestasis type 3, caused by mutations in the ABCB4 gene, is a rare genetic disorder. Although severe phenotypes due to biallelic mutations are well described, emerging data seem to suggest the clinical relevance of monoallelic variants.
AIM
To describe the clinical spectrum and genotype-phenotype correlation of ABCB4 mutations in children in a cohort of North Indian children.
METHODS
This is a retrospective analysis of a prospectively maintained database from a single tertiary care centre. Children (≤ 18 years) with ABCB4 mutations between January 2021 and March 2025 were analysed. The clinical presentation, laboratory investigations, genetic sequencing and outcomes were recorded. Patients were stratified into group 1 (homozygous/compound heterozygous) and group 2 (heterozygous). Variant pathogenicity was assessed using the American College of Medical Genetics guidelines and available predictive tools.
RESULTS
Of the 26 patients, 16 had biallelic mutations, and 10 had monoallelic mutations. Group 1 exhibited higher rates of positive family history (75% vs 30%, P = 0.04), ascites (43.2% vs 0%, P = 0.02), larger varices (40% vs 0%, P = 0.009), higher gamma glutamyl transferase levels (171 U/L vs 38 U/L, P = 0.007), and lower platelet counts (162 × 109/L vs 415 × 109/L, P = 0.007). Notably, two-thirds of patients in group 1 experienced disease progression, and one-third died during follow-up. Certain missense variants (e.g., c.2860T>C) and all nonsense variants were linked to rapid deterioration. Most children in group 2 had transient cholestasis with a good outcome, but two older children succumbed.
CONCLUSION
Mutations in the ABCB4 gene contribute significantly to pediatric chronic liver disease. Patients with severe biallelic mutations frequently experience a progressive disease course, whereas those with monoallelic mutations may progress slowly. Genetic testing for ABCB4 should be considered in children with cryptogenic chronic liver disease, especially those with high gamma-glutamyltransferase cholestasis and portal hypertension.
Core Tip: Patients with ABCB4 mutations continue to pose an enigma for clinicians, and understanding of the varied manifestations continues to evolve. Children with biallelic mutations had a progressive disease with ascites, larger varices and decompensation. Children with monoallelic mutations fare better with significantly better liver function in follow-up; however, the risk of disease progression and decompensation remains and needs close monitoring. Protein-truncating mutations and missense mutations in highly conserved domains are associated with early disease progression. Early genetic testing and family screening may help in tailoring treatment and prognostication.
