ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations associated with cholestasis with Different phenotypes and Outcomes.

Objectives To characterize the clinical, laboratory, histological, molecular features and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for “genotype-phenotype correlations.” Study design We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid (UDCA) and ultimate outcome, into mild (complete response), intermediate (partial response, non-progressive), and severe (progression to end-stage liver disease). Results Overall, 27 different mutations were identified [ATP8B1, n= 5; ABCB11, n= 11; ABCB4, n= 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n=2; ABCB11, n=4) had transient cholestasis. Of the remaining 3 PFIC1 patients, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 PFIC2 patients, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 PFIC3 patients, 10 developed severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than Patients with PFIC3 (P Conclusion We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in PFIC3 patients could be favorably modified by UDCA therapy.