Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Beryl B. Cummings, Jamie L. Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, A. Reghan Foley, Veronique Bolduc, Leigh B. Waddell, Sarah A. Sandaradura, Gina L. O'Grady, Elicia Estrella, Hemakumar M. Reddy, Fengmei Zhao, Ben Weisburd, Konrad J. Karczewski, Anne H. O'Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky & 226 others Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily C. Oates, Roula Ghaoui, Mark Davis, Nigel G. Laing, Ana Topf, Peter B. Kang, Alan H. Beggs, Kathryn N. North, Volker Straub, James J. Dowling, Francesco Muntoni, Nigel F. Clarke, Sandra T. Cooper, Carsten G. Bönnemann, Daniel G. MacArthur, Kristin G. Ardlie, Gad Getz, Ellen T. Gelfand, Ayellet V. Segrè, François Aguet, Timothy J. Sullivan, Xiao Gang Li, Jared L. Nedzel, Casandra A. Trowbridge, Kane Hadley, Katherine H. Huang, Michael S. Noble, Duyen T. Nguyen, Andrew B. Nobel, Fred A. Wright, Andrey A. Shabalin, John J. Palowitch, Yi Hui Zhou, Emmanouil T. Dermitzakis, Mark I. McCarthy, Anthony J. Payne, Tuuli Lappalainen, Stephane Castel, Sarah Kim-Hellmuth, Pejman Mohammadi, Alexis Battle, Princy Parsana, Sara Mostafavi, Andrew Brown, Halit Ongen, Olivier Delaneau, Nikolaos Panousis, Cedric Howald, Martijn Van De Bunt, Roderic Guigo, Jean Monlong, Ferran Reverter, Diego Garrido, Manuel Munoz, Gireesh Bogu, Reza Sodaei, Panagiotis Papasaikas, Anne W. Ndungu, Stephen B. Montgomery, Xin Li, Laure Fresard, Joe R. Davis, Emily K. Tsang, Zachary Zappala, Nathan S. Abell, Michael J. Gloudemans, Boxiang Liu, Farhan N. Damani, Ashis Saha, Yungil Kim, Benjamin J. Strober, Yuan He, Matthew Stephens, Jonathan K. Pritchard, Xiaoquan Wen, Sarah Urbut, Nancy J. Cox, Dan L. Nicolae, Eric R. Gamazon, Hae Kyung Im, Christopher D. Brown, Barbara E. Engelhardt, Yo Son Park, Brian Jo, Ian C. McDowell, Ariel Gewirtz, Genna Gliner, Don Conrad, Ira Hall, Colby Chiang, Alexandra Scott, Chiara Sabatti, Eleazar Eskin, Christine Peterson, Farhad Hormozdiari, Eun Yong Kang, Serghei Mangul, Buhm Han, Jae Hoon Sul, Andrew P. Feinberg, Lindsay F. Rizzardi, Kasper D. Hansen, Peter Hickey, Joshua Akey, Manolis Kellis, Jin Billy Li, Michael Snyder, Hua Tang, Lihua Jiang, Shin Lin, Barbara E. Stranger, Marian Fernando, Meritxell Oliva, John Stamatoyannopoulos, Rajinder Kaul, Jessica Halow, Richard Sandstrom, Eric Haugen, Audra Johnson, Kristen Lee, Daniel Bates, Morgan Diegel, Brandon L. Pierce, Lin Chen, Muhammad G. Kibriya, Farzana Jasmine, Jennifer Doherty, Kathryn Demanelis, Kevin S. Smith, Qin Li, Rui Zhang, Concepcion R. Nierras, Helen M. Moore, Abhi Rao, Ping Guan, Jimmie B. Vaught, Philip A. Branton, Latarsha J. Carithers, Simona Volpi, Jeffery P. Struewing, Casey G. Martin, Lockhart C. Nicole, Susan E. Koester, Anjene M. Addington, A. Roger Little, William F. Leinweber, Jeffrey A. Thomas, Gene Kopen, Alisa McDonald, Bernadette Mestichelli, Saboor Shad, John T. Lonsdale, Michael Salvatore, Richard Hasz, Gary Walters, Mark Johnson, Michael Washington, Lori E. Brigham, Christopher Johns, Joseph Wheeler, Brian Roe, Marcus Hunter, Kevin Myer, Barbara A. Foster, Michael T. Moser, Ellen Karasik, Bryan M. Gillard, Rachna Kumar, Jason Bridge, Mark Miklos, Scott D. Jewell, Daniel C. Rohrer, Dana Valley, Robert G. Montroy, Deborah C. Mash, David A. Davis, Anita H. Undale, Anna M. Smith, David E. Tabor, Nancy V. Roche, Jeffrey A. McLean, Negin Vatanian, Karna L. Robinson, Leslie Sobin, Mary E. Barcus, Kimberly M. Valentino, Liqun Qi, Stephen Hunter, Pushpa Hariharan, Shilpi Singh, Ki Sung Um, Takunda Matose, Maria M. Tomadzewski, Laura A. Siminoff, Heather M. Traino, Maghboeba Mosavel, Laura K. Barker, Daniel R. Zerbino, Thomas Juettmann, Kieron Taylor, Magali Ruffier, Dan Sheppard, Steven Trevanion, Paul Flicek, W. James Kent, Kate R. Rosenbloom, Maximilian Haeussler, Christopher M. Lee, Benedict Paten, John Vivan, Jingchun Zhu, Mary Goldman, Brian Craft, Gen Li, Pedro G. Ferreira, Esti Yeger-Lotem, Matthew T. Maurano, Ruth Barshir, Omer Basha, Hualin S. Xi, Jie Quan, Michael Sammeth, Judith B. Zaugg

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017

Original languageEnglish
Article numbereaal5209
JournalScience Translational Medicine
Volume9
Issue number386
DOIs
Publication statusPublished - 19 Apr 2017

    Fingerprint

Cite this

Cummings, B. B., Marshall, J. L., Tukiainen, T., Lek, M., Donkervoort, S., Foley, A. R., ... Zaugg, J. B. (2017). Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Science Translational Medicine, 9(386), [eaal5209]. https://doi.org/10.1126/scitranslmed.aal5209