Utility of RNA Sequencing Analysis in the Context of Genetic Testing
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COUNSELING AND TESTING (C WALTON AND C REISER, SECTION EDITORS)
Utility of RNA Sequencing Analysis in the Context of Genetic Testing Jackie Tahiliani 1 & Jeanne Leisk 1 & Kerry Aradhya 1 & Karen Ouyang 1 & Swaroop Aradhya 1 & Keith Nykamp 1 Accepted: 20 October 2020 / Published online: 12 November 2020 # The Author(s) 2020
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. Keywords Genetic counseling . RNA analysis . RNA sequencing . Splicing . Variant discovery . Variant interpretation
Introduction Research over the past decade has illuminated the dramatic extent of variation in the human genome. Any two unrelated individuals have millions of DNA sequence changes that differ between them [1]. Amid this natural variation, individuals may carry certain sequence changes that cause or predispose them to monogenic hereditary disease. Identifying and correctly classifying these variants are central to clinical genetic testing. In recent years, the ability to identify and classify diseasecausing variants has dramatically improved owing to advances in next-generation sequencing (NGS) technologies; data from large-scale sequencing studies, such as those included in the Genome Aggregation Database (gnomAD); better tools for assessing the functional effects of variants; and advances in functional genomics, computational biology, and predictive algorithms. In addition, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular This article is part of the Topical Collection on Counseling and Testing * Jackie Tahiliani [email protected] 1
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Pathology (AMP) have provided useful guidelines for evaluating evidence for the clinical interpretation of DNA sequence variants [2]. As a result, diagnostic laboratories have been able to classify variants more consistently. Even with these recent advances, the clinical
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