New Data-tool Will Help Patients with Genetic Diseases

In a world-first, a team led by the Scientific Director of the Kids Neuroscience Centre at the Children’s Hospital at Westmead and the University of Sydney, Professor Sandra Cooper, has developed a data-tool called SpliceVault.

SpliceVault aims to solve a problem increasingly experienced by clinicians and researchers where, despite huge advances being made in precision medicine, it can still be difficult to find the genetic cause for a family’s inherited medical condition. Without a specific genetic answer, affected families cannot access therapies or pathways for newborn disease-prevention.

A paper just published in the prestigious journal Nature Genetics, shows that SpliceVault predicts with 92% accuracy exactly how a splicing mistake in a person’s genetic code (DNA) will affect the next step - their RNA.

While DNA is the source of genetic information in the body, RNA is the intermediate “blueprint” copied from the DNA in small pieces, which are used to make proteins. Before RNA is used to make proteins, it is edited through “splicing” and errors in this process can lead to genetic diseases.

In 2019 Sydney Health Partners provided seed funding to help Professor Cooper’s team to scale up a diagnostic program testing for RNA splicing variants.

This led to further financial support from the National Health and Medical Research Council, Luminesce Alliance and Lenity Australia.

Between 2019 and 2022, Professor Cooper studied the splicing mistakes in 74 genes at the root cause of disease in 88 families who received a genetic disease diagnosis. The core clinical data it acquired led to the development of SpliceVault.

“The trouble is that splicing mistakes can be harmless, or utterly devastating” Professor Cooper said. “In the past, there has been a large element of Russian Roulette, ‘guessing’ whether a splicing mistake in the genetic code could be the cause of a patient’s disorder.

“SpliceVault takes a lot of the guesswork out of splicing mistake interpretation. We looked at millions of splicing events in 335,301 cells and tissues from general population and found the same splicing mistakes recur in different people and tissues.”

“SpliceVault is a catalogue of all natural splicing mistakes. By knowing what splicing mistakes can happen, we can predict the splicing mistakes that will happen with a genetic variant. Essentially, it’s a story of past behaviour predicting future behaviour.’’

“We think SpliceVault will change clinical practice. Simply, SpliceVault means clinicians no longer have to ‘guess’ how a DNA variant will muck up the RNA.”

Professor Cooper, who is an Adjunct Research Scientist at Children’s Medical Research Institute (CMRI), worked with PhD students Ruby Dawes and Adam Bournazos, and a team of data scientists led by Mr Himanshu Joshi at CMRI to develop SpliceVault.

She said it was incredibly satisfying for the team to have produced a database that could significantly change outcomes for patients.

“Patients can’t access a therapy if they don’t have a genetic diagnosis,’’ she said. “SpliceVault will empower clinicians to confidently make a diagnostic decision about genetic errors called splicing variants, or recommend an RNA test. We want to give families answers so they don’t end up being told ‘your child’s condition is caused by a fault of unknown origin. Hopefully more people will now be able to get that molecular diagnosis, find the genetic cause of their disease and have access to any available therapy or clinical trial.”

“We are quite far ahead of the world in this field, and I think SpliceVault will be used a lot. It was such a terrific team effort which makes me feel so proud. I think this will really change clinical practice for rare disorders and inherited cancer predisposition’’.