2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A Plot Twist: When RNA Evidence Challenges Our Expectations of DNA Results

Pdf Summary

This document discusses the importance of RNA evidence in challenging our expectations of DNA results. The process of RNA splicing is complex and can result in unexpected outcomes that differ from predictions made by in silico splicing algorithms. The document highlights seven unanticipated RNA findings that were discovered through paired DNA and RNA testing (DGT-RGT) in a clinical diagnostic laboratory. These findings demonstrate the significant impact of RNA functional data on variant interpretation.<br /><br />The document includes several case examples to illustrate the variability of splicing events and their effect on variant interpretation. For example, one case involved a variant in the NF1 gene that was classified as pathogenic due to the presence of an NMD-prone transcript detected through DGT-RGT. Another case involved a variant in the ATM gene that resulted in the activation of a cryptic acceptor site in some individuals, leading to an uncertain significance classification.<br /><br />The document also discusses the impact of novel donor and acceptor sites, as well as the creation of pseudo-introns and cryptic pyrimidine tract modifications on splicing outcomes. It highlights the importance of considering RNA evidence in addition to DNA evidence to accurately interpret genetic variants.<br /><br />In conclusion, the document emphasizes the need for RNA functional data, obtained through techniques like DGT-RGT, to challenge and refine our understanding of genetic variant interpretation. RNA evidence can reveal unexpected splicing events that can greatly impact the classification of variants, leading to unexpected benign or pathogenic results.

Asset Subtitle

Co-Author - Alexandra Richardson, MS; Co-Author - Terra Brannan, PhD; Presenting Author - Colin C. Young, PhD; Co-Author - Jessica Grzybowski, MS; Co-Author - Marcy E. Richardson, BS, PhD; Co-Author - Carolyn Horton; Co-Author - Rachid Karam, MD, PhD; Co-Author - Heather Zimmermann, PhD;

Meta Tag

Biochemical genetics

Cancer Syndromes

Genetic Testing

Co-Author Alexandra Richardson, MS

Co-Author Terra Brannan, PhD

Co-Author Jessica Grzybowski, MS

Co-Author Marcy E. Richardson, BS, PhD

Co-Author Carolyn Horton

Co-Author Rachid Karam, MD, PhD

Co-Author Heather Zimmermann, PhD

Presenting Author Colin C. Young, PhD

Keywords

RNA evidence

DNA results

RNA splicing

DGT-RGT

variant interpretation

splicing events

NMD-prone transcript

uncertain significance classification

genetic variants

RNA functional data