Abstracts/Presentation Description
Sandra T. Cooper1,2,3
1The University of Sydney; 2The Children's Hospital at Westmead; 3The Children's Medical Research Institute
DNA variants that alter pre-messenger RNA splicing are increasingly recognised as a common cause of genetic rare disorders and inherited cancer predisposition. Faulty RNA splicing creates a faulty genetic blueprint for proteins, which are encoded incorrectly or not built at all, causing disease.
1The University of Sydney; 2The Children's Hospital at Westmead; 3The Children's Medical Research Institute
DNA variants that alter pre-messenger RNA splicing are increasingly recognised as a common cause of genetic rare disorders and inherited cancer predisposition. Faulty RNA splicing creates a faulty genetic blueprint for proteins, which are encoded incorrectly or not built at all, causing disease.
Most splicing variants affect non-coding DNA, which remains poorly understood. Often, genetic sequencing identifies a “high clinical suspicion” splicing variant, but it is deemed as uninterpretable, due to absence of specific evidence to confidently support or refute an impact to RNA splicing. This limits the diagnostic return on investment into genomic sequencing and leaves an affected individual undiagnosed and without tailored clinical care, despite identifying a probable or plausible genetic cause.
This talk will:
1. Explain how pre-mRNA splicing works and specific features that distinguish strong, weak, and unusable splice sites - making the understanding of mis-splicing more accessible.
2. Reveal outcomes from five years of clinical RNA testing used to benchmark the predictive accuracy of contemporary in silico splicing tools.
3. Update progress being made by Prof Cooper’s RNA for Rare Disease (RNA4RD) MRFF GHFM project to embed RNA testing into clinical practice for rare disorder diagnostics.
4. Highlight how clinical-grade RNA Diagnostics can advance and support individualised and variant-agnostic RNA Therapeutics.
Synthesising evidence from empirical RNA testing data for 1191 variants across 536 genes, we offer recommendations for clinical use of in silico tools for splice-region variant curation, classification, and triage into RNA sequencing.
Our overarching goals are to: a) Enlighten pathology workforces about RNA splicing and how mis-splicing can cause disease. b) Provide an evidence base to inform and maximise the detection of candidate pathogenic splicing variants in genetic pathology. c) Develop standardised practices and quality standards for the comprehensive integration of RNA testing into clinical practice. Collectively, these efforts aim to enhance the diagnosis of rare disorders, enabling opportunities for personalised clinical care and disease prevention.
Speaker/Presenting Authors
Authors
Submitting/Presenting Authors
Professor Sandra Cooper - The University of Sydney, the Children's Hospital at Westmead and the Children's Medical Research Institute. (New South Wales, Australia)