Sandra T. Cooper^1,2,3
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. 

 

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.

Matilda Haas

Australian Genomics is an Australian Government initiative supporting genomic research and its translation into clinical practice. Through broad engagement and a national collaborative approach, Australian Genomics achieves two key objectives: to improve efficiency, reach and timeliness of genomic research projects, and to support Commonwealth, State and Territory health departments in the implementation of genomics research outcomes by refining and communicating evidence to inform policy development.

Australian Genomics engages with current and emerging government policy and priorities to identify gaps and opportunities, to support policy and action for integrating genomic technologies into the health system. By interfacing with consumers, government, industry and global genomics initiatives, Australian Genomics drives change and growth in the sector.

In this presentation, we will journey together across the decade since the establishment of Australian Genomics in 2016, and explore the collaboration’s changing priorities and activities in the context of the growth and change in the sector. We will also discuss the establishment of a new national genomics body, Genomics Australia, and consider plans to ensure the momentum of health genomics efforts in Australia is maintained into the future.