Intrahepatic Cholestasis via the ABCB11 Gene

Jaundice and pruritus are the hallmark features of progressive familial intrahepatic cholestasis (PFIC). PFIC is a group of autosomal recessive liver disorders due to defects in bile secretion. Disease onset is usually in infancy or childhood (Srivastava 2014; Davit-Spraul et al. 2009). Four types of PFIC have been established in terms of causative genes involved in the hepatocellular transport system. FIC1 (familial intrahepatic cholestasis protein 1) deficiency (PFIC1) is caused by pathogenic variants in ATP8B1. BSEP (bile salt export pump) deficiency (PFIC2) is caused by pathogenic variants in ABCB11. PFIC3 is caused by reduced biliary phospholipid secretion due to pathogenic variants in ABCB4. The most recently identified PFIC4 is caused by abnormal tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue due to TJP2 defects (Sambrotta et al. 2014). PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyl transferase (GGT) activity is normal in PFIC1 and PFIC2 patients, elevated in PFIC3 patients and low in PFIC4 patients. Defects in PFIC-associated genes ATP8B1 and ABCB11 can also cause a milder type of liver disease called benign recurrent intrahepatic cholestasis (BRIC) (Klomp et al. 2004; Beauséjour et al. 2011). BRIC is an autosomal recessive disorder characterized by intermittent episodes of cholestasis without progression to liver failure.

Progressive familial intrahepatic cholestasis (PFIC) is inherited in an autosomal recessive manner. Defects in four genes to date encoding proteins associated with hepatocellular transport have been found to cause PFIC: ATP8B1, ABCB11, ABCB4 and TJP2 (Srivastava et al. 2014; Davit-Spraul et al. 2009; Sambrotta et al. 2014). The ABCB11 (27 coding exons) gene encodes the bile salt export pump protein (BSEP), which is a member of the superfamily of ATP-binding cassette (ABC) transporters. Pathogenic defects in ABCB11 include missense, nonsense, splicing site pathogenic variants, small indels and exon-level large deletions (Human Gene Mutation Database). In addition to PFIC2, recessive ABCB11 pathogenic variants can also cause benign recurrent intrahepatic cholestasis-2 (BRIC2).

In a study of 51 subjects with cholestasis of undefined etiology, Matte et al. found causative variants in JAG1, ATP8B1, ABCB11, or ABCB4 genes in 14 patients (27%) (Matte et al. 2010). ATP8B1 and ABCB11 causative variants were found in 12 (21%) and 36 (63%) respectively of 57 families affected by PFIC with normal GGT activity (Davit-Spraul et al. 2010).

This test provides full coverage of all coding exons of the ABCB11 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.