Media release

From: Children's Medical Research Institute (CMRI)

A new RNA datatool aims to help patients with genetic diseases to receive a quicker diagnosis and improve their access to therapies.

This world-first work has been published in the prestigious journal, Nature Genetics. The database, called SpliceVault, was created by Professor Sandra Cooper, Scientific Director of the Kids Neuroscience Centre at the Children’s Hospital at Westmead and the University of Sydney, and Adjunct Research Scientist at Children’s Medical Research Institute (CMRI).  

PhD students Ruby Dawes and Adam Bournazos in Professor Cooper’s lab, together with her team of data scientists led by Mr Himanshu Joshi at CMRI, developed SpliceVault, with financial support from Sydney Health Partners, the NHMRC, Luminesce Alliance and Lenity Australia.

SpliceVault aimed 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.

Professor Cooper is a specialist in 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.

Proteins are the ‘building blocks of life’, necessary for healthy functioning of our cells, tissues and organs. Before RNA is used to make proteins, it is edited through a process called “splicing” and errors in RNA splicing can lead to genetic diseases.

Professor Cooper studied the splicing mistakes in 74 genes at the root cause of disease in 88 families who received a genetic disease diagnosis from 2019 to 2022.

“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 msitakes that will happen with a genetic variant.  Essentially, it’s a story of past behaviour predicting future behaviour.’’

SpliceVault is an evidence-based method that predicts with 92% accuracy exactly how a splicing mistake in a person’s genetic code (DNA) will affect the next step - their RNA.

“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.

After two years on this project, Professor Cooper said it was incredibly satisfying 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 inherited disorders’’.