#303 RNA Analysis with Ambry Genetics

We have wanted to explore the role of RNA analysis in genetic testing for a long time on DNA Today, but waited until we could get THE leader in the space, Ambry Genetics. The Vice President of Research and Development and head of their Translational Genomics lab, Dr. Rachid Karam, was kind enough to come on to have this long awaited conversation.

We'll discuss Ambry Genetics' history of innovation in RNA testing, how it has increased diagnostic yield and reduced Variants of Uncertain Significance in hereditary cancer testing, and its role in closing health disparity gaps. We'll also introduce ExomeReveal, Ambry’s new exome testing product that includes RNA analysis, extending our expertise to rare diseases.

Dr. Rachid Karam obtained his M.D. in 2003 at UFCSPA in Brazil, and his Ph.D. in Oncogenetics in 2008 at the University of Porto, Portugal. During his Ph.D. he studied the role of the tumor suppressor gene CDH1 in cancer predisposition. He did his postdoctoral fellowship at the University of California San Diego (UCSD) from 2009 to 2014 where he studied the role of the NMD mRNA surveillance pathway in cancer. He joined Ambry Genetics in 2014 and is now Ambry’s Vice President of Research & Development. His work focuses on strategies to improve the positive yield of clinical genetic testing, including the clinical implementation of new technologies such as RNA-seq and Long-Read sequencing. He also actively participates in several ClinGen committees dedicated to creating guidelines for the interpretation of genetic testing results, such as the BRCA1 and BRCA2 Variant Curation Expert Panel (VCEP) and is currently the co-chair of the ClinGen CDH1 VCEP.

Discussion Topics:

• Ambry Genetics' Leadership in RNA Analysis:
  • The journey of Ambry Genetics in becoming a pioneer in RNA testing.
  • Initial challenges and breakthroughs in RNA analysis.
• Mechanics and Benefits of RNA Testing:
  • How RNA testing works and its role in accurately classifying genetic variants.
  • The impact of RNA testing on increasing diagnostic yield and reducing VUS in hereditary cancer testing.
  • The process of reclassifying variants from VUS to likely pathogenic or benign using RNA analysis.
• Concurrent DNA/RNA Analysis:
  • The rationale behind Ambry's preference for concurrent DNA/RNA analysis.
  • Potential future shifts in the necessity of concurrent analysis as RNA evidence accumulates.
• Addressing Health Disparities:
  • Benefits of RNA testing for non-white patients in hereditary cancer testing.
• Introducing ExomeReveal:
  • Integration of RNA analysis into Ambry's new exome testing product, ExomeReveal.
  • Importance of RNA analysis for splice site variants identified during exome testing.
  • Comparison of ExomeReveal to standard exome tests in terms of diagnostic yield.
• Case Studies and Future Directions:
  • Example case demonstrating the clarity and diagnosis provided by RNA analysis.
  • Expectations and anticipated outcomes for extending RNA expertise to rare diseases.
• Implications for Genetic Counseling and Patient Management:
  • Integration of RNA testing into exome and hereditary cancer testing and its impact on genetic counseling.
  • Evolution of patient management as RNA testing integration improves.

During the episode we referenced three other episodes of DNA Today…

#95 Kieger Family on Familial Adenomatous Polyposis

#297 Exome Reanalysis with Ambry Genetics