RNA-4RD: Disease-agnostic, nationally-accessible pipelines of clinical RNA Diagnostics

Context 1: Splicing VUS (75/100 cases). 

• presumed monogenic disorder; AND 
• putative splicing variant(s) classified VUS in a phenotypically concordant gene; AND 
• variant allele frequency consistent with disease incidence; AND preferably 
• variant segregates with disease; AND 
• associated gene amenable to examination by RNA-Seq or RT-PCR in an available biospecimen 

Context 2: No hit or single hit with another test strongly indicative of a known associated gene (25/100 cases). 

• presumed monogenic disorder; AND 
• no identified variant; OR monoallelic variant in a phenotypically concordant recessive gene with an allele frequency consistent with disease incidence; AND 
• another biochemical or diagnostic test, or a reliable functional assay, is strongly indicative of a genetic disorder with one (or only a few) associated genes; AND 
• associated gene(s) are amenable to examination by RNA-Seq or RT-PCR in an available biospecimen 

Genotype-phenotype concordance  

a. Phenotype highly specific for a disease with a single genetic aetiology

b. Phenotype highly specific for a disease with only a few associated disease genes   

c. Phenotype strongly consistent with gene but high genetic heterogeneity of disorder   

d. Phenotype consistent with gene, but not highly specific, and condition can be heterogeneous 

e. Phenotype not wholly consistent with gene 

Recruitment pathway 

1. Automatic Triage: Context 1 cases with genotype-phenotype concordance rated a, b, or c are eligible for automatic triage into RNA testing.   
2. We have priority access for Aboriginal and Torres Strait Islander peoples. Context 1 or 2 cases with phenotypic concordance rated a, b, or c are eligible for automatic triage into RNA testing. 
3. Clinical Consult: Context 1 cases with genotype-phenotype concordance rated d or e are referred to an RNA4RD ‘Investigator pod’ (2x Clinical Geneticists + 1x Diagnostic Laboratory Representative) to assess clinical merit of RNA testing, or another diagnostic investigation, as best next step.   
4. Multi-disciplinary Team discussion for Context 2 cases and Context 1 cases where there is some complexity. 

1. No clinically accessible tissue with sufficient expression for RNA studies
2. Non monogenic disorder
3. No rationale for how RNA testing may inform diagnosis or clinical management of the affected individual.

The sample requirements for RNA testing vary depending on expression of the gene of interest in clinically accessible tissues. When you submit a case to us, we analyse expression data to determine the most suitable tissue for RNA studies.  

For further details please click here.

We take referrals from clinicians across Australia. Please submit patient details and variant information (if known) to our submission portal. 

We review these weekly and will respond to the referring clinician with our initial assessment within the week. Please note we have halted variant review from June 1st – July 31st 2023.