Utility of RNA Sequencing Analysis in the Context of Genetic Testing

Abstract

Purpose of Review RNA analysis is beginning to be integrated into clinical laboratory genomics, and a review of its current uses and limitations is warranted. Here, we summarize the scope and utility of RNA analysis in the context of clinical genetic testing, including considerations for genetic counseling. Recent Findings RNA analysis is a powerful approach for interpreting some variants of uncertain significance, for analyzing splicing alterations, for providing additional functional evidence for sequence and structural variants, and for discovering novel variants. However, a review of RNA sequencing methods has noted variability in both laboratory processes and findings. Genetic counseling related to RNA analysis has to take into account nonstandardized laboratory processes, sample-type limitations, and differences in variant-interpretation outcomes. Summary RNA analysis is an important complement to DNA testing, although limitations still exist. Maximizing the utility of RNA analysis will require appropriate patient referrals and standardization of laboratory processes as the practice continues to expand the ability to identify and resolve molecular diagnoses.

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

“…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.…”

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

“…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 ].…”

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

“…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.…”

“…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.…”