Alagille Syndrome Etiology

In a way, the COVID-19 pandemic has given the world a crash course in basic medical practices and terminology. For example, most of the world now knows how to wear a surgical mask correctly, and medical words such as “quarantine” and “pulse oximetry” have become ingrained in our collective vocabulary. 

Another pair of terms that has become familiar to us all is “false positives” and “false negatives.” As COVID-19 tests become mandated in most parts of the world prior to one boarding a flight, home self-test kits have boomed, with varying degrees of accuracy. A “false positive” means that your test shows that you are positive for a disease when in fact you are not; the opposite is true for a “false negative.” 

Beyond the pandemic, anything less than an accurate diagnosis of an illness based on currently available diagnostic measures has become the bane of modern medicine. This is especially true when the treatment course bifurcates drastically depending on the initial diagnostic result. 

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In a study published in Genetics in Medicine. Rajagopalan and colleagues discussed how genome sequencing “increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results” – in other words, correcting false negative tests. They carried out a clinical trial using genome sequencing to identify pathogenic variants in 18 individuals who met the threshold for a clinical diagnosis of Alagille syndrome but were tested negative or inconclusive. We will look at some of their findings in this article.

The Superiority of Genome Sequencing 

The results of this study by Rajagopalan et al demonstrated that out of the 18 patients recruited for the study, “2 were found to have a pathogenic variant that was missed by Sanger sequencing, 2 had breakpoint mapping of complex rearrangements involving JAG1 to a resolution that was not attainable by MLPA [multiplex ligation-dependent probe amplification], and 4 were found to have novel variants that could not be detected by previous testing methods.”

This means that genome sequencing identified 8 patients out of the 18 studied with Alagille syndrome where standard-of-care testing failed. Among the 8 patients, 4 were identified to have a variant that could have only been detected through genome sequencing. 

Read more about Alagille syndrome epidemiology

Through the means of genome sequencing, the research team observed an additional diagnostic yield of 0.9%. In addition, the researchers remarked that “genome sequencing can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.” 

However, the promising findings of this study may not so easily translate to the more widespread use of gene sequencing in actual clinical practice. This is because genome sequencing is considered a first-tier genomic test and is therefore rather expensive. In addition, it carries with it a huge burden of data analysis. However, genome sequencing has the ability to eliminate the need for serial testing since it is able to detect all major classes of Alagille syndrome variants. 

The Next Dilemma 

It would be remiss to discuss genome sequencing without spending a bit of time talking about the ethical dilemma that it invites, namely genetic counseling. Spinner et al discussed the utility of genetic counseling specifically in the case of Alagille syndrome in a study published in Gene Reviews. 

The study offered a clear definition of genetic counseling: “Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.” 

Read more about Alagille syndrome patient education

There are many aspects that we can potentially discuss on genetic counseling, but we will focus our attention on a few key facts as they relate to Alagille syndrome. First and foremost, Alagille syndrome is inherited in an autosomal dominant manner. The percentage of patients with Alagille syndrome have a 30% to 50% chance of having an affected parent.

In addition, studies have shown that around 50% to 70% of patients are affected with Alagille syndrome as a result of a de novo genetic alteration. The children of a patient with Alagille syndrome have a 50% chance of inheriting the genetic alteration relating to Alagille syndrome. 

In the case of fetuses that have a 50% risk of developing Alagille syndrome, a fetal echocardiogram may detect the presence of cardiac structural defects, which strongly suggests that the fetus has inherited the disease. However, even if the echocardiogram appears normal, it neither rules out Alagille syndrome nor the presence of cardiac structural defects. 

With regards to family planning, Spinner et al recommended that genetic counseling be offered to young adults who are affected by Alagille syndrome. Discussions should involve the potential risks to offspring as well as the reproductive options available. Spinner and colleagues wrote, “The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.” 

Difficult Decisions 

In this article, we have demonstrated the utility of genomic testing for diagnosing Alagille syndrome and also presented some of the practical dilemmas they bring to patients who are affected. A close and open relationship between patient and physician should be able to smooth out some of the difficulties mentioned.


Rajagopalan R, Gilbert MA, McEldrew DA, et al. Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results. Published online October 20, 2020. doi:10.1038/s41436-020-00989-8

Spinner NB, Gilbert MA, Loomes KM, et al. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington; 2019. Accessed October 10, 2021.