Clinical spectrum and genotype-phenotype correlation of ABCB4 mutations in children: Insights from a North Indian cohort

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.