Portal de Periódicos da CAPES

Enriched phenotypes in rare variant carriers suggest pathogenic mechanisms in rare disease patients

2025; BioMed Central; Volume: 18; Issue: 1 Linguagem: Inglês

10.1186/s13040-024-00418-5

1756-0381

Lane Fitzsimmons, Maria T. Acosta, David R. Adams, Ben Afzali, Ali Al-Beshri, Eric J. Allenspach, Aimee Allworth, Raquel L. Alvarez, Mahshid S. Azamian, Ashley Andrews, Euan A. Ashley, Carlos A. Bacino, Güney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Erin Baldwin, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak‐Toydemir, Anita Beck, Alan H. Beggs, Edward M. Behrens, Gill Bejerano, Hugo J. Bellen, Jimmy Bennett, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Nicholas A. Borja, Lorenzo Botto, Lauren C. Briere, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter H. Byers, William E. Byrd, Kaitlin Callaway, John M. Carey, George Carvalho, Thomas Cassini, Sirisak Chanprasert, Hsiao‐Tuan Chao, Iván K. Chinn, Gary Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Brian Corner, Rosario I. Corona, William J. Craigen, Andrew B. Crouse, Vishnu Anand Cuddapah, Precilla D’Souza, Hongzheng Dai, Kahlen Darr, Surendra Dasari, Joie Davis, Margaret Delgado, Esteban C. Dell’Angelica, Katrina M. Dipple, Daniel Doherty, Naghmeh Dorrani, Jessica Douglas, Emilie D. Douine, Dawn Earl, Lisa Emrick, Christine M. Eng, Cecilia Esteves, Kimberly Ezell, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Jiayu Fu, William A. Gahl, Rebecca Ganetzky, Emily Glanton, Ian A. Glass, Pagé C. Goddard, Joanna M. Gonzalez, Andrea Gropman, Meghan C. Halley, Rizwan Hamid, Neal Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike‐Pyne, Alden Huang, Yan Huang, Anna Hurst, Wendy J. Introne, Gail P. Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Oguz Kanca, Yigit Karasozen, Shamika Ketkar, Dana Kiley, Gonench Kilich, Eric W. Klee, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Bruce R. Korf, Susan Korrick, Deborah Krakow, Elijah Kravets, Seema R. Lalani, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Kumarie Latchman, Kimberly LeBlanc, Brendan Lee, Kathleen A. Leppig, Richard A. Lewis, Pengfei Liu, Nicola Longo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, AudreyStephannie Maghiro, Rachel Mahoney, May Christine V. Malicdan, Rong Mao, Ronit Marom, Gábor Marth, Beth A. Martin, Martín G. Martín, Julián A. Martínez-Agosto, Shruti Marwaha, Allyn McConkie‐Rosell, Andrew McMinn, Matthew Might, Mohamad A. Mikati, Danny E. Miller, Ghayda Mirzaa, B.D. Mitchell, Paolo Moretti, Marie Morimoto, John J. Mulvihill, Lindsay A. Mulvihill, Mariko Nakano‐Okuno, Stanley F. Nelson, Serena Neumann, Dargie Nitsuh, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen C. Pak, J. Carl Pallais, Neil H. Parker, LéShon Peart, Leoyklang Petcharet, John A. Phillips, Filippo Pinto e Vairo, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey Swerdzewski, 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 A. Rodríguez, Jill A. Rosenfeld, Elizabeth M. Rosenthal, Francis Rossignol, Maura Ruzhnikov, Marla Sabaii, Jacinda B. Sampson, Timothy Schedl, Lisa A. Schimmenti, Kelly Schoch, Daryl A. Scott, Elaine Seto, Vandana Shashi, Emily Shelkowitz, Sam Sheppeard, Jimann Shin, Edwin K. Silverman, A. Compston, Kathy Sisco, Tammi Skelton, Cara Skraban, Carson Smith, Kevin S. Smith, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Andrew B. Stergachis, Joan M. Stoler, Kathleen Sullivan, Shamil R. Sunyaev, Shirley Sutton, David A. Sweetser, 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, Rachel A. Ungar, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Sophie Nicole, Jennifer Wambach, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz Hubshman, Mark H. Wener, Tara Wenger, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Heidi Wood, Kim C. Worley, Shinya Yamamoto, Zhe Zhang, Stephan Züchner, Brett K. Beaulieu‐Jones, Shilpa N. Kobren,

Genetics and Neurodevelopmental Disorders

The mechanistic pathways that give rise to the extreme symptoms exhibited by rare disease patients are complex, heterogeneous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional series of interrelated symptoms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common and extreme phenotype that can result from diverse and often elusive pathways in patients with ultrarare or undiagnosed disorders. In this pilot study, we present an approach to understand the underlying pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient's recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing mechanisms at play in rare disease UDN patients. We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition. For each patient, we analyze a gene of interest: MPO, P2RX7, SQSTM1, COL27A1, PIGQ, or CACNA2D2, and find relevant symptoms associated with UKB participants. We discuss the potential mechanisms by which the digestive, skeletal, circulatory, and immune system abnormalities found in the UKB patients may contribute to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems. Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general. Continued research in this area could lead to more precise diagnostics and personalized treatment strategies for patients with rare and undiagnosed conditions.