Undiagnosed Diseases Network Grand Rounds 2025: Clinical Insights and Lessons Learned from Implementing Diagnostic Transcriptome Sequencing (RECORDING)

Internet Enduring Material sponsored by Stanford University School of Medicine.

The Undiagnosed Diseases Network hosts a quarterly lecture on lessons learned from the rare disease population, protocols, or novel technologies related to rare disease. In this session recorded on January 9, 2025, Pengfei Liu, PhD delved into the diagnostic applications of RNA sequencing, highlighting its role in detecting aberrant splicing and aberrant expression to enhance the understanding of genetic variants. Viewers will gain practical strategies for integrating RNA sequencing into clinical workflows, from test validation to data interpretation, and learn to identify key components of clinical reports for effective communication of findings. This presentation was designed to provide both theoretical insights and actionable approaches for advancing patient care through RNA sequencing.

  Release Date: January 24, 2025
  Expiration Date: January 23, 2028
  Estimated Time to Complete: 55 minutes
  Registration Fee: FREE

*Originally recorded on 01/09/2025 as part of the quarterly Undiagnosed Diseases Network Grand Rounds.

Click the Begin tab to launch this course. 

1. Explore the utility of RNA sequencing in identifying aberrant splicing, allele-specific expression, and other RNA-level events, enhancing comprehension of genetic variants and their pathogenicity.
2. Utilize practical strategies for integrating RNA sequencing into clinical workflows, including laboratory test validation, technical considerations, and data interpretation to optimize diagnostic accuracy and improve patient care.
3. Identify key components of clinical reports for diagnostic RNA sequencing.

In support of improving patient care, Stanford Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Credit Designation 
American Medical Association (AMA) 
Stanford Medicine designates this Enduring Material for a maximum of 1.00 AMA PRA Category 1 Credits^TM.  Physicians should claim only the credit commensurate with the extent of their participation in the activity. 

Accessibility Statement
 Stanford University School of Medicine is committed to ensuring that its programs, services, goods and facilities are accessible to individuals with disabilities as specified under Section 504 of the Rehabilitation Act of 1973 and the Americans with Disabilities Amendments Act of 2008.  If you have needs that require special accommodations, please contact the coordinator.

Cultural and Linguistic Competency
The planners and speakers of this CME activity have been encouraged to address cultural issues relevant to their topic area for the purpose of complying with California Assembly Bill 1195. Moreover, the Stanford University School of Medicine Multicultural Health Portal contains many useful cultural and linguistic competency tools including culture guides, language access information and pertinent state and federal laws.  You are encouraged to visit the Multicultural Health Portal: https://laneguides.stanford.edu/multicultural-health

References/Bibliography

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (Eds.). (2002). Molecular Biology of the Cell, 4th Edition. Garland Science, New York: New York.

Cummings, B. B., Marshall, J. L., Tukiainen, T., Lek, M., Donkervoort, S., Foley, A. R., Bolduc, V., Waddell, L. B., Sandaradura, S. A., O'Grady, G. L., Estrella, E., Reddy, H. M., Zhao, F., Weisburd, B., Karczewski, K. J., O'Donnell-Luria, A. H., Birnbaum, D., Sarkozy, A., Hu, Y., Gonorazky, H., … MacArthur, D. G. (2017). Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Science translational medicine, 9(386), eaal5209. https://doi.org/10.1126/scitranslmed.aal5209

Dekker, J., Schot, R., Bongaerts, M., de Valk, W. G., van Veghel-Plandsoen, M. M., Monfils, K., Douben, H., Elfferich, P., Kasteleijn, E., van Unen, L. M. A., Geeven, G., Saris, J. J., van Ierland, Y., Verheijen, F. W., van der Sterre, M. L. T., Sadeghi Niaraki, F., Smits, D. J., Huidekoper, H. H., Williams, M., Wilke, M., … van Ham, T. J. (2023). Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders. American journal of human genetics, 110(2), 251–272. https://doi.org/10.1016/j.ajhg.2022.12.015

Deshwar, A. R., Yuki, K. E., Hou, H., Liang, Y., Khan, T., Celik, A., Ramani, A., Mendoza-Londono, R., Marshall, C. R., Brudno, M., Shlien, A., Meyn, M. S., Hayeems, R. Z., McKinlay, B. J., Klentrou, P., Wilson, M. D., Kyriakopoulou, L., Costain, G., & Dowling, J. J. (2023). Trio RNA sequencing in a cohort of medically complex children. American journal of human genetics, 110(5), 895–900. https://doi.org/10.1016/j.ajhg.2023.03.006

Frésard, L., Smail, C., Ferraro, N. M., Teran, N. A., Li, X., Smith, K. S., Bonner, D., Kernohan, K. D., Marwaha, S., Zappala, Z., Balliu, B., Davis, J. R., Liu, B., Prybol, C. J., Kohler, J. N., Zastrow, D. B., Reuter, C. M., Fisk, D. G., Grove, M. E., Davidson, J. M., … Montgomery, S. B. (2019). Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nature medicine, 25(6), 911–919. https://doi.org/10.1038/s41591-019-0457-8

Gonorazky, H. D., Naumenko, S., Ramani, A. K., Nelakuditi, V., Mashouri, P., Wang, P., Kao, D., Ohri, K., Viththiyapaskaran, S., Tarnopolsky, M. A., Mathews, K. D., Moore, S. A., Osorio, A. N., Villanova, D., Kemaladewi, D. U., Cohn, R. D., Brudno, M., & Dowling, J. J. (2019). Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease. American journal of human genetics, 104(3), 466–483. https://doi.org/10.1016/j.ajhg.2019.01.012

Jaramillo Oquendo, C., Wai, H. A., Rich, W. I., Bunyan, D. J., Thomas, N. S., Hunt, D., Lord, J., Douglas, A. G. L., & Baralle, D. (2024). Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach. Genome medicine, 16(1), 110. https://doi.org/10.1186/s13073-024-01381-w

Kremer, L. S., Bader, D. M., Mertes, C., Kopajtich, R., Pichler, G., Iuso, A., Haack, T. B., Graf, E., Schwarzmayr, T., Terrile, C., Konaríková, E., Repp, B., Kastenmüller, G., Adamski, J., Lichtner, P., Leonhardt, C., Funalot, B., Donati, A., Tiranti, V., Lombes, A., … Prokisch, H. (2017). Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature communications, 8, 15824. https://doi.org/10.1038/ncomms15824

Lee, H., Huang, A. Y., Wang, L. K., Yoon, A. J., Renteria, G., Eskin, A., Signer, R. H., Dorrani, N., Nieves-Rodriguez, S., Wan, J., Douine, E. D., Woods, J. D., Dell'Angelica, E. C., Fogel, B. L., Martin, M. G., Butte, M. J., Parker, N. H., Wang, R. T., Shieh, P. B., Wong, D. A., … Nelson, S. F. (2020). Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genetics in medicine : official journal of the American College of Medical Genetics, 22(3), 490–499. https://doi.org/10.1038/s41436-019-0672-1

Li, S., Zhao, S., Sinson, J. C., Bajic, A., Rosenfeld, J. A., Neeley, M. B., Pena, M., Worley, K. C., Burrage, L. C., Weisz-Hubshman, M., Ketkar, S., Craigen, W. J., Clark, G. D., Lalani, S., Bacino, C. A., Machol, K., Chao, H. T., Potocki, L., Emrick, L., Sheppard, J., … Liu, P. (2024). The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing. American journal of human genetics, 111(5), 841–862. https://doi.org/10.1016/j.ajhg.2024.03.007

Murdock, D. R., Dai, H., Burrage, L. C., Rosenfeld, J. A., Ketkar, S., Müller, M. F., Yépez, V. A., Gagneur, J., Liu, P., Chen, S., Jain, M., Zapata, G., Bacino, C. A., Chao, H. T., Moretti, P., Craigen, W. J., Hanchard, N. A., Undiagnosed Diseases Network, & Lee, B. (2021). Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing. The Journal of clinical investigation, 131(1), e141500. https://doi.org/10.1172/JCI141500

Smirnov, D., Schlieben, L. D., Peymani, F., Berutti, R., & Prokisch, H. (2022). Guidelines for clinical interpretation of variant pathogenicity using RNA phenotypes. Human mutation, 43(8), 1056–1070. https://doi.org/10.1002/humu.24416

Yépez, V. A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N. H., Alston, C. L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S. J., Hempel, M., Itkis, Y. S., Kishita, Y., Klopstock, T., Krylova, T. D., … Prokisch, H. (2022). Clinical implementation of RNA sequencing for Mendelian disease diagnostics. Genome medicine, 14(1), 38. https://doi.org/10.1186/s13073-022-01019-9

Zhao, S., Macakova, K., Sinson, J. C., Dai, H., Rosenfeld, J., Zapata, G. E., Li, S., Ward, P. A., Wang, C., Qu, C., Maywald, B., Undiagnosed Diseases Network, Lee, B., Eng, C., & Liu, P. (2025). Clinical validation of RNA sequencing for Mendelian disorder diagnostics. American journal of human genetics, 112(4), 779–792. https://doi.org/10.1016/j.ajhg.2025.02.006

For activity related questions, please contact
     Name: Holly Meyer
     Title: Compliance Coordinator
     Email: [email protected]

For CME general questions, please contact 
     Email: [email protected]

Mitigation of Relevant Financial Relationships

Stanford Medicine adheres to the Standards for Integrity and Independence in Accredited Continuing Education.

There are no relevant financial relationships with ACCME-defined ineligible companies for anyone who was in control of the content of this activity, except those listed in the table below. All of the relevant financial relationships listed for these individuals have been mitigated.