Enhancing Exome Sequencing with RNA Analysis

This white paper discusses the integration of RNA analysis into exome sequencing (ES) to improve the classification of genetic variants, particularly those of uncertain significance (VUS). It outlines how RNA analysis supplements DNA testing by providing functional insights that are critical for determining the pathogenicity of variants. The document details the role of RNA in identifying splicing variants, which can affect gene expression and lead to various consequences, including aberrant protein production. It emphasizes the importance of RNA analysis in clinical settings, particularly for rare diseases, where it can enhance the diagnostic yield and reduce misclassification of variants. The paper also highlights the guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) that advocate for the use of RNA evidence in variant classification. Additionally, it presents the ExomeReveal bioinformatics pipeline, which leverages RNA data to improve the accuracy of genetic variant interpretation and patient care.