Unlocking Comprehensive Genetic Insights with RNAseq for WGS and WES
Whole genome sequencing (WGS) and whole exome sequencing (WES) are comprehensive genetic tests that help improve patient care by enabling a more complete analysis of an individual’s genetic makeup. However, certain variants can be difficult to interpret, and may lengthen the diagnostic odyssey for patients. With RNA sequencing (RNAseq) for Whole Genome Sequencing and Whole Exome Sequencing, Baylor Genetics has the potential to reclassify and resolve 10-15% of qualified variants, providing clinicians and patients with vital diagnostic clarity, ensuring quicker and actionable insights.
Understanding Qualified Variants in Genomic Sequencing
Genomic sequencing analyzes a patient’s DNA for variants that might be present. These variants are typically classified into categories based on their predicted clinical impact: benign, likely benign, likely pathogenic, pathogenic and a qualifying variant. Benign variants are not expected to impact an individual’s health, whereas pathogenic variants are expected to have an impact. For variants with fewer pieces of evidence to support them being benign or pathogenic, the likely benign and likely pathogenic classifications are used. Certain variants can lack sufficient evidence to definitively categorize as benign or pathogenic, and often complicates how clinicians interpret results for their patients. Resolving the clinical significance of qualified variants is a critical step in translating even more genomic data into insights to inform patient care.
The Role of RNA Sequencing
RNA sequencing (RNAseq) is a technique that provides insights into understanding the functional consequences of qualified genetic variants. Like DNA sequencing, RNA sequencing involves reading through sequences of RNA transcribed from an individual’s genes to look for changes that might guide classification efforts. This type of analysis is part of what is known as transcriptomics.
Here’s how RNAseq can aid in the classification of qualifying variants:
- Gene Expression Profiling: RNAseq enables expression levels of genes in different cell types to be quantified. By comparing the gene expression profiles of patients with and without a specific qualifying variant, it is possible to identify genes that may be dysregulated due to these variants. If a qualifying variant is associated with altered gene expression in a known disease-related gene, it can provide evidence of its pathogenicity.
- Splicing Aberrations: One common mechanism by which qualifying variants can disrupt gene function is by affecting RNA splicing, the process by which “mature” messenger RNA (mRNA) is generated from precursors (pre-mRNA). RNAseq can detect changes in splicing patterns caused by qualifying variants, such as exon skipping or intron retention. Deviations from normal splicing patterns can indicate the potential pathogenicity of a variant.
- Allelic Imbalance: RNAseq can reveal whether a qualifying variant results in an allelic imbalance in gene expression, where one allele is expressed at a significantly higher or lower level than the other. Such imbalances can be indicative of a functional impact and help classify qualifying variants.
RNAseq with WGS and WES
RNAseq can help reclassify qualifying variants to provide a deeper understanding of a patient’s condition and greater diagnostic clarity helping to impact treatment options and personalize health management. For this reason, RNAseq has been adopted as a reflex test for WGS and WES to help with the reclassification of qualified variants for patients with multisystemic conditions, neurological disorders, muscular dystrophy, epilepsy, multiple congenital anomalies, ID/DD, and many others.
RNAseq from Baylor Genetics
In May 2024, Baylor Genetics announced the addition of RNAseq testing for all new WGS and WES orders. RNAseq from Baylor Genetics is performed at the lab director’s discretion as a reflex from WGS or WES after a qualified variant has been reported. By enhancing both our Whole Genome and Exome Sequencing tests with the addition of RNA sequencing, we increase the potential to reclassify qualified variants for a more comprehensive analysis, because we’re committed to findings answers for you and your patients. Read more in the press release here.
Conclusion
The integration of RNA sequencing provides insights into gene expression patterns, splicing alterations, allelic imbalances, and tissue-specific effects, resulting in a more comprehensive understanding of the functional impact of genetic variants. This aids in the clinical interpretation of qualifying variants, to help determine treatment options and improve patient care. As technology and analytical methods continue to evolve, Baylor Genetics continues to be a pioneer of precision medicine at the forefront of diagnostic genomics.
If you would like to discuss our testing capabilities and how we can help, contact us here.
Scientific contributions from Rob Rigobello, CGC
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