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

• Published in: Human mutation Vol. 43; no. 11; pp. 1590 - 1608
• Main Authors: Postel, Mackenzie D., Culver, Julie O., Ricker, Charité, Craig, David W.
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.11.2022; John Wiley and Sons Inc
• Subjects: deep intronic variants; Etiology; Gene Expression Profiling; genetic ancestry; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genomes; Humans; Introns; Precision medicine; Reclassification; Review; Reviews; RNA; splicing variants; Transcriptomes; variants of uncertain significance; variants of unknown significance; splicing variants; genetic ancestry; variants of unknown significance; deep intronic variants; variants of uncertain significance
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.24394

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. RNA data tips the scales of molecular evidence, clarifying variants as benign or pathogenic.