Nineteen-year-old Declan was in his early teenage years when his legs began failing him.

While the cause was not apparent, his symptoms were consistent with unknown leukodystrophy, a degenerative condition affecting the brain, spinal cord and nerves. By the time he reached his late teens, it was expected Declan would start to experience cognitive delay, loss to his speech and motor function, and seizures.

DNA testing found a suspicious genetic variant, however was unable to provide a clear genetic answer, as is the case for 30-50 per cent of patients who undertake DNA testing.

With his family and clinicians searching for answers, Declan became one of the early pioneering patients to enrol in a RNA testing research project, aiming to help diagnose rare disorders. The results were lifechanging.

RNA testing revealed Declan had an ultra-rare genetic condition known as VPS13D Spinocerebellar Ataxia. Declan is believed to be the first in Australia to receive this diagnosis, which would not have been picked up without the RNA technology.

It was through the success of the RNA testing research project involving Declan and 87 other committed patients and their families that the SpliceVault project was born.

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. It was created by Professor Sandra Cooper, Scientific Director of the Kids Neuroscience Centre (KNC) at The Children’s Hospital at Westmead and the University of Sydney, and Adjunct Research Scientist at Children’s Medical Research Institute (CMRI),

“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,” Prof Cooper said.

Unlike DNA, which is the source of genetic information in the body, RNA is the intermediate “blueprint” copied from DNA in small pieces, which are used to make proteins. 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.

These errors can be harmless, or utterly devastating.

For Declan, the error means that while his condition is rare, it is not fatal nor degenerative, meaning he is not at risk of experiencing any of the devastating symptoms initially laid out for his future.

“When you have a rare disease and you can discover what it is through RNA testing, you can take another step forward,” said Angela, Declan’s mum.

“Even if there’s no treatment, you know where to begin. Declan is in such a good space today because of the pioneering work of Sandra and her team.”

SpliceVault is the first method that helps clinicians either make an outright diagnosis about a splicing variant, or make an informed decision to recommend an RNA test. The trial that Declan participated in paved the way for clinical use of both SpliceVault and RNA as a new diagnostic test.

“Through our research, 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,” Prof Cooper said.

“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.’’

“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 she is proud of the leading efforts of her team, and she hopes that SpliceVault will transform clinical practice for rare inherited disorders, helping patients receive a diagnosis more quickly, and improving their access to therapies.

Professor Cooper has attracted $3 million in grant funding from the Medical Research Future Fund Genomic Health Futures Mission for RNA Clinical Implementation Study, and hopes to implement SpliceVault into clinical practice across Australia to increase diagnostic rates from between 30 to 50 percent to between 50 to 70 percent.

“Patients can’t access a therapy or pathways for newborn disease-prevention if they don’t have a genetic diagnosis. We want to give families answers so they will be able to get a molecular diagnosis, find the genetic cause of their disease and have access to any available therapy or clinical trial.”

“SpliceVault will empower clinicians to confidently make a diagnostic decision about genetic errors called splicing variants, or recommend an RNA test. We are quite far ahead of the world in this field, and I truly believe SpliceVault will change clinical practice.’’

For Declan, the results have now opened up the possibility of exploring precision treatment and therapies to target his specific genetic fault. It has also opened enormous possibilities for his future, with the ambitious teen currently studying Science and Astrophysics at university.

A paper on the SpliceVault research project has been published in the prestigious journal, Nature Genetics.

SpliceVault was developed by Professor Cooper and PhD students Ruby Dawes and Adam Bournazos, together with her team of data scientists led by Mr Himanshu Joshi at CMRI, with research supported by Sydney Health Partners, the NHMRC, Luminesce Alliance, Lenity Australia and Sydney Children’s Hospitals Foundation.