The mutational landscape of genetic cholestatic diseases in Pakistani children

Objective: To report the mutational landscape of a clinically diagnosed cohort paediatric patients with cholestasis liver diseases. Method: The retrospective study was conducted at University Child Health Sciences, Children Hospital, Lahore, Pakistan, from December 10, 2021, to March 31, 2022, and comprised data collected Paediatric Gastroenterology Hepatology unit on demographics, clinical laboratory findings related children either gender aged <12 years cholestatic disease July 2018 June 2021. diagnosis based biochemical findings, no evidence biliary atresia metabolic disease. Molecular characterisation done through whole exome sequencing. Results: Of 171 evaluated, 92(53.8%) were genetic disorders. There 52(56%) boys 41(44%) girls. median age presentation 19.5 months (interquartile range: 51 months). Consanguinity found in 82(88.1%) cases, positive family history one or more affected siblings noted 60(64.5%). Exome sequencing identified pathogenic mutations 13 genes underlying hereditary cholestasis; ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, DCDC2, ACOX2, AKR1D1, HSD3B7, ABCC2, USP53, SLC10A1, SLC51A. 70 variants identified, 50(71.4%) novel variants. ABCB11-related most frequent 27(29%), followed by ABCB4 (26(27.9%). Homozygosity frequently seen all except 8(8.6%) children, who had compound heterozygous phenotypic expression carrier parents despite severe nature respective patients. Conclusions: Genetic heterogeneity intrahepatic showed recurrent mutations. Key Words: Cholestasis, Progressive familial cholestasis, Neonatal sclerosing cholangitis, mutation, Bile acid synthetic defects, CLD.