Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

作者：Shilpa N. Kobren, Mikhail A. Moldovan, Rebecca Reimers, Daniel Traviglia, Xinyun Li, Danielle Barnum, Alexander Veit, Rosario I. Corona, Gabriel Andrade Bonanno Carvalho, Julian Willett, Michele Berselli, William Ronchetti, Stanley F. Nelson, Julián A. Martínez-Agosto, Richard I. Sherwood, Joel B. Krier, Isaac S. Kohane, Undiagnosed Diseases Network, Jose Abdenur, Maria T. Acosta, David R. Adams, Ben Afzali, Ali Al-Beshri, Eric J. Allenspach, Raquel L. Alvarez, Justin Alvey, Ashley Andrews, Beatriz Anguiano, Euan A. Ashley, Sanaz Attaripour, Suha Bachir, Carlos A. Bacino, Güney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Erin E. Baldwin, A. Bale, Elsa Balton, Manisha Balwani, Michael J. Bamshad, Mafalda Barbosa, Deborah Barbouth, Rebekah Barrick, Donald Basel, Pınar Bayrak‐Toydemir, Taylor Beagle, Alan H. Beggs, Edward M. Behrens, Megan Bell, Hugo J. Bellen, Paul Berger, Jonathan A. Bernstein, Gerard T. Berry, Louise Bier, Stephanie Bivona, Kirsten Blanco, Lauren S. Blieden, Elizabeth Blue, Devon Bonner, Brett J. Bordini, Nicholas A. Borja, Lorenzo D. Botto, Steven E. Boyden, Lauren C. Briere, Elizabeth A. Burke, Lindsay C. Burrage, Francisco Bustos, Manish J. Butte, Russell J. Butterfield, Peter H. Byers, William E. Byrd, Kaitlin Callaway, John C. Carey, Thomas Cassini, Chun‐Hung Chan, Richard Chang, Sirisak Chanprasert, Hsiao‐Tuan Chao, Elizabeth Chao, Iván K. Chinn, Gary Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Erin Conboy, Brian Corner, William J. Craigen, Andrew B. Crouse, Vishnu Anand Cuddapah, Charlotte Cunningham‐Rundles, Precilla D’Souza, Hongzheng Dai, Nitsuh Dargie, Kahlen Darr, Surendra Dasari, Joie Davis, Margaret Delgado, Esteban C. Dell’Angelica, Nada Derar, Patricia Dickson, Katrina M. Dipple, Naghmeh Dorrani, Jessica Douglas, Abdul Elkadri, Sara Emami, Lisa Emrick, Christine M. Eng, Cecilia Esteves, Rachel Evard, Kimberly Ezell, Layal F. Abi Farraj, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Jiayu Fu, William A. Gahl, Rebecca Ganetzky, E. Woloschak Gayle, Bruce D. Gelb, Mark Gerstein, Emily Glanton, I. S. Glass, Pagé C. Goddard, Joanna M. Gonzalez, John E. Gorzynski, Brett H. Graham, Andrea Gropman, Meghan C. Halley, W. K. Halstead, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Caroline Hendry, Frances A. High, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike‐Pyne, Yan Huang, Alden Huang, Monika Weisz Hubshman, Anna Hurst, John A. Phillips, Wendy J. Introne, Ayuko Iverson, Gail P. Jarvik, Orpa Jean-Marie, Lauren Jeffries, Joanna C. Jen, Tanner Jensen, Yong‐hui Jiang, Vaidehi Jobanputra, Oguz Kanca, Yigit Karasozen, Odelya Kaufman, Laura Keehan, Shamika Ketkar, Dana Kiley, Gonench Kilich, Eric W. Klee, Jennefer N. Kohler, Bruce R. Korf, Susan Korrick, Elijah Kravets, Runjun D. Kumar, Seema R. Lalani, Brendan C. Lanpher, Ian R. Lanza, Kumarie Latchman, Kimberly LeBlanc, Brendan Lee, Miranda Leitheiser, Monkol Lek, Kathleen A. Leppig, Mia Levanto, Richard A. Lewis, Rachel Li, Khurram Liaqat, Pengfei Liu, Nicola Longo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Rachel Mahoney, May Christine V. Malicdan, Tarun Karthik Kumar Mamidi, Shrikant Mane, Lili Mantcheva, Rong Mao, Ronit Marom, Gábor Marth, Beth A. Martin, Martı́n G. Martı́n, Julián A. Martínez-Agosto, Shruti Marwaha, Taylor Maurer, Julie McCarrier, Allyn McConkie‐Rosell, Ashley McMinn, Erin McRoy, Hector Rodrigo Mendez, Matthew Might, Mohamad A. Mikati, Danny E. Miller, Alexander Miller, Ghayda Mirzaa, B.D. Mitchell, Stephen B. Montgomery, Paolo Moretti, Jennifer C. Morgan, Marie Morimoto, Tahseen Mozaffar, Lindsay A. Mulvihill, John J. Mulvihill, Michael Muriello, Sandesh C. Sreenath Nagamani, Mariko Nakano‐Okuno, Serena Neumann, T. Nicholas, Donna Novacic, Devin Oglesbee, Carol Oladele, James P. Orengo, Rebecca S. Overbury, Laura Pace, Stephen C. Pak, J. Carl Pallais, Neil H. Parker, Alex Paul, LéShon Peart, Seth J. Perlman, Leoyklang Petcharet, Jennifer E. Posey, Lorraine Potocki, Rakale C. Quarells, Aaron R. Quinlan, Daniel J. Rader, Ramakrishnan Rajagopalan, Deepak A. Rao, Anna Raper, Wendy H. Raskind, Adriana Rebelo, Chloe M. Reuter, Lynette Rives, Lance H. Rodan, Martín Rodríguez, María José Ortuño Romero, Jill A. Rosenfeld, Elisabeth A. Rosenthal, Francis Rossignol, Bianca Russell, Marla Sabaii, Mohamad Saifeddine, Jacinda B. Sampson, Suzanne Sandmeyer, Timothy Schedl, Jason Schend, Lisa A. Schimmenti, Kelly Schoch, Jennifer C. Schymick, Daryl A. Scott, Teodoro Jerves Serrano, Elaine Seto, Mariya Shadrina, Vandana Shashi, Emily Shelkowitz, Susan Shin, Jimann Shin, Saskia Shuman, Edwin K. Silverman, Giorgio Sirugo, Kathy Sisco, Tammi Skelton, Cara Skraban, Carson Smith, Kevin S. Smith, Jared A. Sninsky, Lilianna Solnica-Krezel, Ben Solomon, Albert R. La Spada, Michele Spencer‐Manzon, Rebecca C. Spillmann, Maija Steenari, Andrew B. Stergachis, Joan M. Stoler, Kathleen E. Sullivan, David A. Sweetser, Barbara N. Pusey Swerdzewski, Virginia P. Sybert, Holly K. Tabor, Queenie Shu Woon Tan, Arjun Tarakad, Herman A. Taylor, Mustafa Tekin, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Kayla M. Treat, Brianna M. Tucker, Rachel A. Ungar, Filippo Pinto e Vairo, Adeline Vanderver, A Ramírez Vargas, Vasilis S. Vasiliou, Matt Velinder, James Verbsky, Francesco Vetrini, Éric Vilain, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Nicole M. Walley, Jennifer Wambach, Emily Wang, Michael F. Wangler, Patricia A. Ward, Isum Ward, Alistair Ward, Stephanie M. Ware, Daniel Wegner, Corrine K. Welt, Mark H. Wener, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Laurens Wiel, Brandon Wilk, Lynne A. Wolfe, Heidi Wood, Kim C. Worley, Elizabeth A. Worthey, Changrui Xiao, Hua Xu, Shinya Yamamoto, Hui Zhang, Michael T. Zimmermann, Stephan Züchner, Shamil Sunyaev · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61712-2 · 被引用次数：5 · 研究领域：Genomics and Rare Diseases、Genetic factors in colorectal cancer、Genomic variations and chromosomal abnormalities

Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform in-depth analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development. The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale case-based diagnostic analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We further release a software package, RaMeDiES, enabling automated cross-analysis of deidentified sequenced cohorts for new diagnostic and research discoveries. Gene-level findings and variant-level information across the cohort are available in a public-facing browser ( https://dbmi-bgm.github.io/udn-browser/ ). These results show that case-level diagnostic efforts should be supplemented by a joint genomic analysis across c...