Intrahepatic Cholestasis via the ABCB4 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.

Progressive familial intrahepatic cholestasis (PFIC) is inherited in an autosomal recessive manner. Defects in four genes to date encoding proteins associated with hepatocellular transport system 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 ABCB4 gene (27 coding exons) encodes the multi-drug resistant 3 protein (MDR3), which is also a member of the superfamily of ATP-binding cassette (ABC) transporters. Genetic defects in ABCB4 include missense, nonsense, splicing site mutations, small indels and exon-level large deletions (Human Gene Mutation Database).

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). In a cohort study of 68 unrelated PFIC3 patients, ABCB4 mutations were found at both alleles in 13 patients (19%) and only one allele in 5 patients (7%), respectively (Degiorgio et al. 2007).

This test provides full coverage of all coding exons of the ABCB4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).