Oral Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

RNA for Rare Disease (RNA4RD): revolutionising rare disease diagnosis with RNA testing (129902)

Sandra Cooper 1 2 3
  1. Kids Neuroscience Centre, The Children's Hospital at Westmead, Sydney, NSW, Australia
  2. Functional Neuromics Group, The Children's Medical Research Institute, Sydney, NSW, Australia
  3. School of Medical Sciences, University of Sydney, Sydney, NSW, Australia

DNA variants that disrupt RNA splicing are increasingly recognised as a major cause of rare genetic disorders and inherited cancer predispositions. These variants often occur in non-coding regions of the genome, which are poorly understood and frequently overlooked in standard diagnostic pipelines.

In Prof Cooper’s large neurological cohort (n = 257), a targeted approach to splicing variant detection and RNA testing nearly doubled the diagnostic yield, from 34% with exome sequencing alone to 63%. To scale this impact, she founded the Australasian Consortium for RNA Diagnostics (SpliceACORD), uniting multidisciplinary expertise to develop a pragmatic strategy to integrate RNA testing into routine care. 

Over 300 families have participated in pioneering research shaping the RNA for Rare Disease (RNA4RD) program. Reportable RNA test results are achieved in over 95% of cases, with variant reclassification rates between 70–75% over four years; meaning nearly three-quarters of participants receive an actionable diagnosis.

This presentation will:

  1. Update progress from the MRFF GHFM RNA4RD project, embedding RNA testing into routine diagnostics for rare disorders.
  2. Introduce the Australian “RNA Cloud”: a secure, scalable platform delivering standardised RNA-Seq analytics for rare disease diagnostics – with wider application for monitoring RNA biomarkers of disease progression, allele-specific expression and imprinting, or response to RNA or gene therapies.
  3. Highlight advances in evidence-based splice variant interpretation, including a validated framework for distinguishing strong, weak, and unusable splice sites. Clinically tested on 1,191 variants across 546 genes, this model delivers: 99.8% sensitivity, 96.0% specificity and 99.2% positive and negative predictive value.

Together, innovations in splicing variant detection, splicing effect prediction and functional RNA Testing are reshaping the genomic diagnostic landscape to unlock diagnosis-drive precision care for rare disorders.