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

Progressive familial intrahepatic cholestasis (PFIC) is a rare group of genetic disorders that typically presents in infants and children, often progressing to end-stage liver disease. We used whole genome sequencing (WGS) for diagnosis to assess phenotypic features and outcomes in Pakistani children with different types of PFIC. The study included 116 pediatric participants with five PFIC types: PFIC1, ATP8B1 gene (n = 19); PFIC2, ABCB11 (n = 28); PFIC3, ABCB4 (n = 52); PFIC4 TJP2 (n = 15); and PFIC5 NR1H4 (n = 2). Seventy unique variants were identified across the five genes. The age at genetic diagnosis was higher in patients with PFIC3. Clinical and laboratory findings showed significant overlap among all PFIC types. PFIC3 had a less aggressive course and better survival outcomes than PFIC1, PFIC2, and PFIC4. The cumulative survival rate was significantly higher at 89% (95% CI 43–98%) for patients who underwent liver transplantation, compared to 9% (95% CI 1–29%) for those who did not (p = 0.016). The study provided the first comprehensive analysis of PFIC in Pakistani children, highlighting significant clinical overlap and the critical need for early genetic diagnosis using WGS. The findings underscore the importance of personalized treatment approaches, including early consideration for liver transplantation, to improve patient outcomes.