Advancements in research and technology have shown us that many cholestatic liver diseases that were once deemed “idiopathic” do in fact have a genetic cause. Researchers have identified various mutations that can give rise to the cholestatic phenotype.

In a review article published in Hepatology, Ibrahim and colleagues presented in great detail what we know about the genetics of cholestatic liver diseases. Broadly speaking, there are a few key defects that can lead to cholestasis:

  • Transporter membrane defects
  • Bile acid synthesis disorders
  • Cholangiopathies
  • Biliary atresia.

Over the last few decades, genomic diagnostics have advanced tremendously. The results are twofold: their availability has increased and their cost has decreased. The turnaround time for genetic testing results has also sped up. Some physicians may be accustomed to treating the cholestatic phenotype without further investigating its genetic cause. All of these factors should incentivize physicians to determine whether a cholestatic condition has a genetic cause.

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“In the next few years, it is likely that we will see wider implementation of WGS [wide genome sequencing] as a first-line diagnostic test,“ Ibrahim and colleagues wrote. “Novel technology is also being developed for long-read sequencing that will improve the ability to detect copy number variants and structural rearrangements.” Also, genetic testing is increasingly being incorporated into decision algorithms, which can improve our diagnostic capabilities and help in the development of targeted therapies. 

Taken together, this means that most diseases that have a genetic cause will be identified as such in the near future. The obvious implication in therapeutics is that this will hasten the production of gene-specific treatment, potentially changing the treatment landscape of cholestatic diseases altogether. 

The Genetics Behind Alagille Syndrome 

In Ibrahim et al’s review, the “cholangiopathies” category of diseases includes Alagille syndrome (ALGS), which occurs in about 1 in 30,000 live births. We will look at the disease in detail, from a genetic point of view. 

ALGS is inherited in an autosomally dominant manner. It is caused by the heterozygous mutations in either JAG1 (accounting for around 94% of cases) or NOTCH2 (accounting for around 2% to 4% of cases). 

Read more about Alagille syndrome etiology

There is great variability in expression between individuals with ALGS, and the heterogeneity of clinical presentation can hinder the clinical investigation and diagnosis of the condition. “Disease severity is highly variable, even within families where multiple individuals have inherited the same mutation, suggesting that genetic modifiers are likely to play a role,” Ibrahim and colleagues wrote.

In Diagnostics, Ayoub and colleagues provided a brief historical overview of how JAG1 was linked to ALGS. In 1986, a child with a classical Alagille syndrome phenotype was found to have a deletion in the short arm of chromosome 20. A decade later, in 1997, researchers discovered that the JAG1 mutations were responsible for ALGS in 4 different families. “Since then, 696 JAG1 pathogenic variants have been described in patients with ALGS,” Ayoub et al wrote. 

NOTCH2 was identified as a gene that causes ALGS after a study on mice models. The study revealed that JAG1/NOTCH2 double heterozygous mice went on to develop an ALGS phenotype. Further research in the years following would fully reveal the association between NOTCH2 mutations and ALGS (keeping in mind that NOTCH2 mutations account for only less than 5% of cases). 

Ayoub and colleagues summed up their findings this way: “Overall, the observation that similar ALGS clinical phenotypes can be caused by different pathogenic mutations (protein-truncating, intragenic, whole gene deletions) suggest that haploinsufficiency of JAG1 and NOTCH2 is the primary mechanism for disease pathobiology, rather than a dominant negative mechanism.” 

Read more about Alagille syndrome treatment 

Scientists have also pinpointed the exact mutation that causes the cholangiopathy phenotype in ALGS. They have discovered that the only candidate genetic modifier of liver disease severity in patients with ALGS is THSB2, which encodes the secreted matricellular protein thrombospondin 2. THSB2 has been discovered to be an excellent biomarker for severe liver disease in ALGS caused by cholestasis or hepatic fibrosis (or both conditions present together). 

In addition, studies demonstrated that the thrombospondin 2 protein was expressed in portal vessels and bile ducts. This protein can then inhibit JAG1-NOTCH2 interactions in vitro. 

The Ongoing Hunt for Targeted Therapies

We are cracking the genetic code that causes ALGS and aggravates its pathological phenotype. What next?

“The discovery of genetic modifiers in ALGS raises the question of whether this knowledge could be applied to the development of novel therapeutics,” Ibrahim and colleagues wrote. “It is theoretically possible that targeting a genetic modifier could shift the balance and augment Notch pathway signaling just enough to result in postnatal bile duct development or growth of hypoplastic blood vessels.” 

It is important, when discussing advancements in genetic research, to keep an eye firmly on the prize: the development of more targeted therapeutics that can improve the quality of life of our patients and possibly cure the disease altogether. The persistence of medical researchers in digging deep into the genetic workings of a disease gives us hope that this knowledge can become immensely useful in the therapeutic field, sooner or later. 


Ibrahim SH, Kamath BM, Loomes KM, Karpen SJ. Cholestatic liver diseases of genetic etiology: advances and controversiesHepatology. 2022;10.1002/hep.32437. doi:10.1002/hep.32437

Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in managementDiagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907