Utility of RNA Sequencing Analysis in the Context of Genetic Testing

Tahiliani, Jackie; Leisk, Jeanne; Aradhya, Kerry; Ouyang, Karen; Aradhya, Swaroop; Nykamp, Keith

doi:10.1007/s40142-020-00195-7

Cited by 9 publications

(7 citation statements)

References 24 publications

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“…RNA-seq is on its way to be integrated into clinical laboratory genomics, since it holds the promise to facilitate the interpretation of variants of unclear significance [36]. Previous studies have touched on the potential of RNA-seq to enable rare disease diagnosis as well as novel gene discovery [11,12,14], but the extent to which RNA-seq is useful and when alternative approaches are needed remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

et al. 2021

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Background RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology. Results We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses. Conclusions PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at https://bioinf.eva.mpg.de/PTEE/

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Section: Discussionmentioning

confidence: 99%

Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

et al. 2021

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“…For patients with suspected genetic disorders, the addition of other ‘omics, such as transcriptomics, to clinical genetic testing, can help reclassify variants of uncertain significance [ 97 ] and elucidate pathogenic mechanisms [ 98 ]. Identifying the pathogenic variant underlying the disease may enable more personalised therapies for rare genetic disorders [ 99 ].…”

Section: Multi-omics Technologies and The Discovery Of Novel Causal M...mentioning

confidence: 99%

From ‘Omics to Multi-omics Technologies: the Discovery of Novel Causal Mediators

Mohammadi-Shemirani

Sood

Paré

2023

Curr Atheroscler Rep

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Purpose of Review ‘Omics studies provide a comprehensive characterisation of a biological entity, such as the genome, epigenome, transcriptome, proteome, metabolome, or microbiome. This review covers the unique properties of these types of ‘omics and their roles as causal mediators in cardiovascular disease. Moreover, applications and challenges of integrating multiple types of ‘omics data to increase predictive power, improve causal inference, and elucidate biological mechanisms are discussed. Recent Findings Multi-omics approaches are growing in adoption as they provide orthogonal evidence and overcome the limitations of individual types of ‘omics data. Studies with multiple types of ‘omics data have improved the diagnosis and prediction of disease states and afforded a deeper understanding of underlying pathophysiological mechanisms, beyond any single type of ‘omics data. For instance, disease-associated loci in the genome can be supplemented with other ‘omics to prioritise causal genes and understand the function of non-coding variants. Alternatively, techniques, such as Mendelian randomisation, can leverage genetics to provide evidence supporting a causal role for disease-associated molecules, and elucidate their role in disease pathogenesis. Summary As technologies improve, costs for ‘omics studies will continue to fall and datasets will become increasingly accessible to researchers. The intrinsically unbiased nature of ‘omics data is well-suited to exploratory analyses that discover causal mediators of disease, and multi-omics is an emerging discipline that leverages the strengths of each type of ‘omics data to provide insights greater than the sum of its parts.

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“…Standards must be created for test thresholds and normalized reporting, and databases must be established (Tahiliani et al, 2020;Wang et al, 2020). These databases must be designed to not fall prey to any logical fallacies (e.g.…”

Section: Fragmentation Of Rna-seq Databases and Standardsmentioning

confidence: 99%

“…These challenges include the need for scientific rigor, reproducibility, accuracy, precision, clinical validity, and clinical utility. Standards must be created for test thresholds and normalized reporting, and databases must be established (Tahiliani et al, 2020 ; Wang et al, 2020 ). These databases must be designed to not fall prey to any logical fallacies (e.g.…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Transcriptome analysis provides critical answers to the “variants of uncertain significance” conundrum

et al. 2022

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While whole‐genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA‐level data fails to identify the underlying genetic etiology. Specifically, patients of non‐White race and non‐European ancestry are disproportionately affected by “variants of unknown/uncertain significance” (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non‐neoplastic diseases.

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Utility of RNA Sequencing Analysis in the Context of Genetic Testing

Cited by 9 publications

References 24 publications

Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

From ‘Omics to Multi-omics Technologies: the Discovery of Novel Causal Mediators

Transcriptome analysis provides critical answers to the “variants of uncertain significance” conundrum

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