Clinical Diversity and Outcomes of Progressive Familial Intrahepatic Cholestasis Diagnosed by Whole Genome Sequencing in Pakistani Children

This study analyzes 116 Pakistani children with Progressive Familial Intrahepatic Cholestasis (PFIC), diagnosed with whole genome sequencing. PFIC3 was the predominant type (44.8%), followed by PFIC2 (24.1%), PFIC1 (16.4%), PFIC4 (12.9%), and PFIC5 (1.7%). Diverging from prior studies, we found a notable absence of pruritus in a quarter of PFIC1 and PFIC3 patients, and in one-third of those with PFIC2 and PFIC4; diarrhea in 6.7% of PFIC4; hearing loss in 13.3% of PFIC4 and some PFIC3; elevated GGT levels in about half the patients with PFIC1, PFIC2, and PFIC4; anemia in 84.2%-89.3% of cases; no liver tumors observed in PFIC patients even into the second decade. Survival analysis revealed a grim 20-year cumulative survival rate of 20%. However, liver transplantation significantly improved survival to 89%, compared to 9% with standard medical treatment. PFIC3 patients showed a less aggressive disease course and better survival. This study, highlighting the genetic and phenotypic diversity within PFIC and the poor outcomes with conventional treatment, underscores the critical need for revising medical management strategies for PFIC patients. ### Competing Interest Statement Aliaksandr Skrahin, Arndt Rolfs, Ahmad Malik and Volha Skrahina declared employment in a rare disease consulting company. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Ethics Committee of Rostock University (Germany), A2022-0072, 25.04 2022. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The variant from this study have been submitted to the NCBI ClinVar database (http://www.clinvar.com/) under accession numbers SCV004232458 - SCV004232527