Skin Sample Success Story

More than 70 percent of rare diseases are of genetic origin, yet only half of such individuals receive a diagnosis following a genetic test. To tackle the imbalance, researchers at the University of Adelaide developed a method that leans on Nobel-prize-winning discoveries to make “silent” genes accessible through more accessible samples. (1).

We connected with corresponding author Lachlan Jolly to learn more about this initiative.

How does your new method help find genetic variants?
 

About one-third of disease-related genes aren’t active in blood or skin samples, making their RNA unavailable without invasive biopsies. We call these “silent” Mendelian genes. We developed two methods based on Nobel Prize-winning discoveries: gene transactivation and cellular transdifferentiation. Both start by growing a small skin sample from the patient in the lab. In gene transactivation, we modify the skin cells to activate the silent gene. In cellular transdifferentiation, we transform the skin cell into another type, like a brain cell, where the silent gene is naturally active. Both methods allow us to study RNA from these silent genes and assess genetic variants.

Specifically, we can see how gene variants affect mRNA processing, leading to two key outcomes. First, it can enable a diagnosis. If a variant disrupts mRNA processing, it suggests that the variant harms gene function and supports its role in causing disease. Second, it opens the door to personalized treatments. Understanding how the variant mRNA is processed can help in designing therapies, such as antisense oligonucleotide treatments like nusinersen (Spinraza), which is approved for spinal muscular atrophy in countries like the US and Australia.

How might your findings change the way we diagnose genetic disorders?
 

Variants of uncertain significance in silent disease genes make up 22.2 percent of all such variants in ClinVar, a database of human genetic variations and their clinical significance hosted by the National Center for Biotechnology Information. This leaves hundreds of thousands of people worldwide without a genetic diagnosis for their disorder, and this is likely just the tip of the iceberg. Though RNA-based tests can help in around 30 percent of cases, obtaining variant RNA has been difficult because it usually requires invasive biopsies – for example, of the brain. Our new method to obtain variant RNA from silent genes using skin samples offers a less invasive way to conduct RNA-based tests, improving the chances of diagnosis for many patients.

And though more than 90 percent of rare diseases currently have no precision therapies, there are over 14,000 clinical trials underway for such treatments. Access to these trials depends on having a genetic diagnosis. 

Beyond diagnosis, our research highlights the potential to develop new therapies to reverse the harmful effects of gene variants on mRNA. These could include antisense oligonucleotide therapies to change RNA splicing or drugs that modify mRNA decay and translation.

^{Teaser Image Credit: Olivia Robinson}