Interpretative Information

Cholestatic liver disease is often multifactorial, resulting from a combination of metabolic, genetic, and environmental factors (Santos et al. 2010. PubMed ID: 20425482). Mendelian forms of cholestasis are most often inherited in an autosomal recessive (AR) manner, but may also be inherited in an autosomal dominant (AD) manner, or arise de novo. This test includes genes identified through literature, OMIM, and HGMD searches that have been reported to be associated with cholestasis.

An example of hereditary cholestatic liver disease due to defective hepatocyte transport includes progressive familial intrahepatic cholestasis (PFIC). Five types of PFIC have been classified in terms of causative genes involved in the hepatocellular transport system. Progressive familial intrahepatic cholestasis-1 (PFIC1) and progressive familial intrahepatic cholestasis-2 (PFIC2) are caused by hepatocyte membrane phospholipid asymmetry due to defects in the ATP8B1 and ABCB11 genes, respectively (Sticova et al. 2018. PubMed ID: 30148122). Progressive familial intrahepatic cholestasis-3 (PFIC3) is caused by reduced biliary phospholipid secretion due to pathogenic variants in the ABCB4 gene. Progressive familial intrahepatic cholestasis-4 (PFIC4) is caused by abnormal tight junctions between adjacent hepatocytes and biliary canaliculi in liver tissue due to TJP2 defects (Sambrotta et al. 2014. PubMed ID: 24614073). Progressive familial intrahepatic cholestasis-5 (PFIC5) is caused by defects in the NR1H4 gene, a key regulator of bile salt metabolism (Sticova et al. 2018. PubMed ID: 30148122). PFIC is estimated to occur in 1/50,000 to 1/100,000 births (Davit-Spraul et al. 2009. PubMed ID: 19133130), and while de novo variants have been reported, the majority of causative variants are inherited (Francalanci et al. 2013. PubMed ID: 23437912).

Alagille syndrome, an autosomal dominant disorder caused by defects in the JAG1 and NOTCH2 genes, is an example of hereditary cholestatic liver disease due to disordered bile duct development. The JAG1 and NOTCH2 genes both encode components of the Notch signaling pathway, which is critical for proper development of the biliary tree (Adams and Jafar-Nejad. 2019. PubMed ID: 31615106). Alagille syndrome is estimated to occur in 1/70,000 births and 1/30,000 individuals overall (Turnpenny and Ellard. 2012. PubMed ID: 21934706; Hartley et al. 2013. PubMed ID: 23540503). Approximately 50-70% of cases have a de novo pathogenic variant (Spinner et al. 1993. PubMed ID: 20301450).