Submission Details

The ABCB4 gene was first reported in relation to progressive familial intrahepatic cholestasis, an autosomal recessive condition, with the 1998 publication of affected patients harboring variants in the homozygous state (PMID: 9419367). Affected individuals harboring homozygous or compound heterozygous variants are typically diagnosed with progressive familial intrahepatic cholestasis type 3, and generally present between infancy and late adolescence with jaundice, pruritus, bile duct proliferation, cholestasis, hepatosplenomegaly, elevated serum gamma-glutamyltransferase, and/or increased serum bile acids. The disease progresses in many cases to develop portal hypertension, fibrosis, cirrhosis, and eventually liver failure and transplantation, although some cases respond positively to ursodeoxycholate treatment (PMID: 17726488). Neoplasm of the liver can develop in some cases as well. Heterozygous ABCB4 variants have also been reported in association with cholestasis, typically with a diagnosis of either intrahepatic cholestasis of pregnancy 3 or gallbladder disease 1. Although these presentations can occur in carriers in families with recessive progressive familial intrahepatic cholestasis, their adult onset, low penetrance and monoallelic state constitute a different disease. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism of loss of function has been found to be consistent between cases harboring biallelic and monoallelic variants in ABCB4. However, the dramatic difference in phenotypic severity between the biallelic and monoallelic cases distinguishes them as two different conditions rather than a single broad spectrum disease. Therefore, cases caused by biallelic ABCB4 variants have been separately curated here for progressive familial intrahepatic cholestasis type 3 (MONDO:0011214, MIM #614972).

Twelve suspected pathogenic variants have been scored as part of this curation (six missense, two nonsense, three frameshift, and one disrupting a canonical splice site). These have been collectively reported in ten probands in four publications (PMID: 9419367, PMID: 26474921, PMID: 32793533, PMID: 11313315). The mechanism of pathogenicity appears to be biallelic loss of ABCB4 function conferred by null and/or hypomorphic variants. Eight out of ten probands were homozygous for their respective variants, while two probands were compound heterozygous. Segregation evidence has not contributed to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but was not included in this curation as the maximum score for this category of evidence had already been reached.

This gene-disease association is also supported by experimental evidence that the expression pattern of ABCB4 across human tissues is highly restricted to the liver (PMID: 23715323). Biochemical studies indicate that ABCB4 encodes a transporter of the ATP-binding cassette family that localizes to the canalicular membrane of hepatocytes, consistent with a role in transporting phospholipid into bile secretions that form at this site (PMID: 7734012). Reduced expression of ABCB4 has been detected in a subset of progressive familial intrahepatic cholestasis cases characterized by elevated serum levels of gamma-glutamyltransferase activity (PMID: 8666348). Homozygous disruption of the mouse ortholog of ABCB4 recapitulates human patient features such as the absence of phospholipids from bile, hyperbilirubinemia, nonsuppurative inflammatory cholangitis, bile duct proliferation, portal inflammation, neoplasm of the liver, hepatocyte degeneration, portal fibrosis, and widening and tortuosity of the bile canaliculi (PMID: 7977654). Some of these phenotypes can be rescued by injection of lipid nanoparticles delivering wild-type ABCB4 mRNA (PMID: 33340584).

In summary, ABCB4 is definitively associated with progressive familial intrahepatic cholestasis type 3, an autosomal recessive condition. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Gene Curation Expert Panel on November 23rd, 2022 (SOP Version 9).