An optimized variant prioritization process for rare disease diagnostics: recommendations for Exomiser and Genomiser

作者：Isabelle Cooperstein, Shruti Marwaha, Alistair Ward, Shilpa N. Kobren, Jennefer N. Carter, Undiagnosed Diseases Network, Aaron R. Quinlan, Abdul Elkadri, Adeline Vanderver, Adriana Rebelo, Alan H. Beggs, Albert R. La Spada, Alden Huang, Alex Paul, Alexander Miller, Alistair Ward, A. Bale, Allyn McConkie‐Rosell, Alyson Krokosky, Alyssa A. Tran, Andrea Gropman, Andres Vargas, Andrew B. Crouse, Andrew B. Stergachis, Anna Hurst, Anna Raper, Anne Slavotinek, Arian Nouraee, Arjun Tarakad, Ashley Andrews, Ashley McMinn, Ashok Balasubramanyam, Ayuko Iverson, Barbara N. Pusey Swerdzewski, Beatriz Anguiano, Ben Afzali, Ben Solomon, Beth A. Martin, Bianca Russell, Brandon Wilk, B.D. Mitchell, Brendan C. Lanpher, Brendan Lee, Brent L. Fogel, Brett J. Bordini, Brett H. Graham, Brianna M. Tucker, Bruce D. Gelb, Bruce R. Korf, Calum A. MacRae, Camilo Toro, Cara Skraban, Carlos A. Bacino, Carlos Pardo‐Villamizar, Carlos Prada, Carol Oladele, Caroline Hendry, Carson Smith, Cathy Shyr, Cecilia Esteves, Changrui Xiao, Charlotte Cunningham‐Rundles, Chloe M. Reuter, Christine M. Eng, Christopher N. Mayhew, Chun‐Hung Chan, Colleen E. Wahl, Corrine K. Welt, Cynthia J. Tifft, Dana Kiley, Dana Sayer, Daniel J. Rader, Daniel Wegner, Danny E. Miller, Daryl A. Scott, Dave Viskochil, David A. Sweetser, David R. Adams, Deborah Barbouth, Deepak A. Rao, Devin Oglesbee, Devon Bonner, Donald Basel, Donna Novacic, Francisco Bustos velasq, Dustin Baldridge, Edward M. Behrens, Edwin K. Silverman, Elaine Seto, Elijah Kravets, Elisabeth A. Rosenthal, Elizabeth A. Worthey, Elizabeth A. Burke, Elizabeth Blue, Elizabeth Chao, Elizabeth L. Fieg, Elizabeth Wohler, Ellen F. Macnamara, Elsa Balton, Emily Glanton, Emily Shelkowitz, Emily Wang, Eneida A. Mendonça, Eric J. Allenspach, Eric R. Gamazon, E. Woloschak Gayle, Eric W. Klee, Éric Vilain, Erica E. Davis, Erin Conboy, Erin E. Baldwin, Erin McRoy, Esteban C. Dell’Angelica, Euan A. Ashley, F. Sessions Cole, Filippo Pinto e Vairo, Frances A. High, Francesco Vetrini, Francis Rossignol, Fuki M. Hisama, Gábor Marth, Gail P. Jarvik, Gary Clark, George Carvalho, Gerard T. Berry, Ghayda Mirzaa, Giorgio Sirugo, Gonench Kilich, Güney Bademci, Hector Rodrigo Mendez, Heidi Wood, Herman A. Taylor, Holly K. Tabor, Hongzheng Dai, Hsiao‐Tuan Chao, Hua Xu, Hugo J. Bellen, Hui Zhang, I. S. Glass, Ian R. Lanza, Ingrid A. Holm, Isaac S. Kohane, Isum Ward, Iván K. Chinn, J. Carl Pallais, Jacinda B. Sampson, James P. Orengo, James Verbsky, Jared A. Sninsky, Jason Hom, Jason Schend, Jennefer N. Kohler, Jennifer Morgan, Jennifer C. Schymick, Jennifer Tousseau, Jennifer Wambach, Jessica Douglas, Jiayu Fu, Jill A. Rosenfeld, Jimann Shin, Joan M. Stoler, Joanna C. Jen, Joanna M. Gonzalez, John A. Phillips, John C. Carey, John E. Gorzynski, John J. Mulvihill, Joie Davis, Jonathan A. Bernstein, Jordan Whitlock, José E. Abdenur, Joseph Loscalzo, Joy D Cogan, Julián A. Martínez-Agosto, Julie Hoover‐Fong, Julie McCarrier, Justin Alvey, Kahlen Darr, Kai Lee Yap, Kaitlin Callaway, Kathleen A. Leppig, Kathleen Page, Kathleen Sullivan, Kathy Sisco, Katrina M. Dipple, Kayla M. Treat, Kelly Hassey, Kelly Regan-Fendt, Kelly Schoch, Kevin S. Smith, Khurram Liaqat, Kim C. Worley, Kimberly Ezell, Kimberly LeBlanc, Kirsten Blanco, Kumarie Latchman, Lakshitha Perera, Lance H. Rodan, Laura Keehan, Laurel A. Cobban, Lauren S. Blieden, Lauren C. Briere, Lauren Jeffries, Laurens Wiel, Layal F. Abi Farraj, Leoyklang Petcharet, LéShon Peart, Lili Mantcheva, Lilianna Solnica-Krezel, Lindsay C. Burrage, Lindsay A. Mulvihill, Lisa Bastarache, Lisa A. Schimmenti, Lisa Emrick, Lorenzo Botto, Lorraine Potocki, Louise Bier, Lynette Rives, Lynne A. Wolfe, Mafalda Barbosa, Maija Steenari, Manish J. Butte, Manisha Balwani, Margaret Delgado, María José Ortuño Romero, María Paula Silva, Maria T. Acosta, Marie Morimoto, Mariko Nakano‐Okuno, Mariya Shadrina, Mark Gerstein, Mark H. Wener, Marla Sabaii, Martha Horike‐Pyne, Martín G. Martín, Martín A. Rodríguez, Mary Koziura, Matt Velinder, Matthew Coggins, Matthew Might, Matthew Robinson, Matthew T. Wheeler, May Christine V. Malicdan, Megan Bell, Meghan C. Halley, Melissa Walker, Mia Levanto, Michael Bamshad, Michael F. Wangler, Michael Muriello, Michael T. Zimmermann, Michele Spencer‐Manzon, Miranda Leitheiser, Mohamad A. Mikati, Mohamad Saifeddine, Monika Weisz Hubshman, Monkol Lek, Monte Westerfield, Mustafa Tekin, Nada Derar, Naghmeh Dorrani, Nara Sobreira, Neil H. Parker, Neil A. Hanchard, Nicholas A. Borja, Nicola Longo, Nicole M Walley, Nitsuh Dargie, Odelya Kaufman, Oguz Kanca, Orpa Jean-Marie, Pagé C. Goddard, Paolo Moretti, Patricia A. Ward, Patricia Dickson, Patrick D. McMullen, Paul G. Auwaerter, Paul Berger, Paul G. Fisher, Pengfei Liu, Peter H. Byers, P. Dane Witmer, Pınar Bayrak‐Toydemir, Pongtawat Lertwilaiwittaya, Precilla D’Souza, Queenie Shu Woon Tan, Rachel A. Ungar, Rachel Evard, Rachel Li, Rakale C. Quarells, Ramakrishnan Rajagopalan, Raquel L. Alvarez, Reaford Blackburn, Rebecca C. Spillmann, Rebecca Ganetzky, Rebecca S. Overbury, Rebekah Barrick, Richard A. Lewis, Richard Chang, Richard L. Maas, Rizwan Hamid, Rong Mao, Ronit Marom, Rosario I. Corona, Runjun D. Kumar, Russell J. Butterfield, Sanaz Attaripour, Sandesh C.S. Nagamani, Sara Emami, Saskia Shuman, Seema R. Lalani, Seth J. Perlman, Shamika Ketkar, Shamil R. Sunyaev, Shilpa N. Kobren, Shinya Yamamoto, Shrikant Mane, Shruti Marwaha, Sirisak Chanprasert, Stanley F. Nelson, Stephan Züchner, Stephanie Bivona, Stephanie M. Ware, Stephen B. Montgomery, Stephen C. Pak, Steven E. Boyden, Suha Bachir, Surendra Dasari, Susan Korrick, Susan Shin, Suzanne Sandmeyer, Tahseen Mozaffar, Tammi Skelton, Tanner Jensen, Tarun Karthik Kumar Mamidi, Taylor Beagle, Taylor Maurer, Teneasha Washington, Teodoro Jerves Serrano, Terra R. Coakley, Thomas Cassini, T. Nicholas, Timothy Schedl, Tiphanie P. Vogel, Vaidehi Jobanputra, Valerie V. Maduro, Vandana Shashi, Vasilis S. Vasiliou, Virginia P. Sybert, Vishnu Anand Cuddapah, Wendy J. Introne, Wendy H. Raskind, Willa Thorson, William A. Gahl, William E. Byrd, William J. Craigen, W. K. Halstead, Winston Timp, Yan Huang, Yigit Karasozen, Yong‐hui Jiang, Yuka Manabe, Zackary Berger, Ziyuan Guo, Matthew T. Wheeler, Gábor Marth · 发表于：Genome Medicine · 年份：2025 · DOI：10.1186/s13073-025-01546-1 · 被引用次数：10 · 研究领域：Genomics and Rare Diseases、Genetic Associations and Epidemiology、Hereditary Neurological Disorders

BACKGROUND: Exome sequencing (ES) and genome sequencing (GS) are increasingly used as standard genetic tests to identify diagnostic variants in rare disease cases. However, prioritizing these variants to reduce the time and burden of manual interpretation by clinical teams remains a significant challenge. The Exomiser/Genomiser software suite is the most widely adopted open-source software for prioritizing coding and noncoding variants. Despite its ubiquitous use, limited data-driven guidelines currently exist to optimize its performance for diagnostic variant prioritization. Based on detailed analyses of Undiagnosed Diseases Network (UDN) probands, this study presents optimized parameters and practical recommendations for deploying the Exomiser and Genomiser tools. We also highlight scenarios where diagnostic variants may be missed and propose alternative workflows to improve diagnostic success in such complex cases. METHODS: We analyzed 386 diagnosed probands from the UDN, including cases with coding and noncoding diagnostic variants. We systematically evaluated how tool performance was affected by key parameters, including gene:phenotype association data, variant pathogenicity predictors, phenotype term quality and quantity, and the inclusion and accuracy of family variant data. RESULTS: Parameter optimization significantly improved Exomiser's performance over default parameters. For GS data, the percentage of coding diagnostic variants ranked within the top 10 candidates ...