A novel compound heterozygous mutation in ABCB4 gene in a pedigree with progressive familial intrahepatic cholestasis 3: a case report

Abstract

Progressive familial intrahepatic cholestasis (PFIC) includes a group of genetic autosomal recessive disorders that predominantly affects young children and results in early-onset progressive liver damage. Variations in ABCB4 have been shown to cause PFIC3. However, the association between ABCB4 genotype and clinical manifestations remains unclear. We investigated the clinical manifestations and genetic features of a Chinese Han pedigree with PFIC3. A 15-year-old boy, with high-serum gamma-glutamyl transferase (γ-GT) cholestatic cirrhosis, was diagnosed with PIFC3. After ursodeoxycholic acid (UDCA) treatment, the boy stayed in a relatively stable state with mild itching, and elevated γ-GT exhibited a remarkable decrease. Genetic testing identified a novel compound heterozygous mutation L842P/V1051A in ABCB4, which was inherited from his mother and father, respectively. Several predictive software suggested that these two mutations are pathogenic. Interestingly, the same compound heterozygous mutation was also found in his two sisters, one of whom had a history of intrahepatic cholestasis of pregnancy (ICP) and the other had asymptomatic gallstones. Therefore, this novel compound heterozygous mutation L842P/V1051A caused a continuum of ABCB4-related diseases including ICP, cholelithiasis and PFIC3 in our pedigree. The inconsistency between genotypes and phenotypes may be influenced by other factors. Genetic testing will be useful for diagnosis and genetic counseling.

Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures

“…The clinical and molecular genetic data of 82 pediatric PFIC3 patients, who were definitely diagnosed with biallelic ABCB4 variants and had relatively complete clinical information in 20 official literatures [11][12][13][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], were summarized in Additional file 2: Table S1. Together with the 13 new PFIC3 patients in this study, a total of 95 patients (38 females, 39 males and 18 gender undescribed) were in-depth analyzed in terms of the phenotypic and genotypic features.…”

Case Report: A rare case of young adult progressive familial intrahepatic cholestasis-type 3 with a novel heterozygous pathogenic variant of ABCB4

“…FXR's downstream targets include the genes responsible for PFIC 2 and 3— ABCB11 encoding the BSEP and ABCB4 encoding MDR3, respectively ( 15 ). PFIC-6 is caused by genetic variants in MYO5B gene ( 16 ). There are few specific reports of PFIC-6, so further research is needed.…”

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

“…Defects in this protein have been studied and functionally characterized, with multiple types of mutations resulting in low levels of biliary PC and destabilized micelles, as well as toxic bile leading to damage to the biliary epithelial cells and hepatocytes [3,4]. A wide-spectrum of rare liver diseases is caused by mutations in the ABCB4 gene including progressive familial intrahepatic cholestasis type 3 (PFIC3), low-phospholipid associated cholelithiasis (LPAC) syndrome, and other rare biliary diseases (e.g., primary biliary cirrhosis) [5][6][7][8][9]. Moreover, variants in this transporter could play a role in driving liver fibrosis in patients with chronic liver diseases [10].…”