Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

作者：Sanna Gudmundsson, Moriel Singer‐Berk, Sarah L. Stenton, Julia K. Goodrich, Michael W. Wilson, Jonah Einson, Nicholas A. Watts, María T. Abreu, Amina Abubakar, Rolf Adolfsson, Carlos A. Aguilar‐Salinas, Tariq Ahmad, Christine M. Albert, Jessica Alföldi, Matthieu Allez, Celso Arango López, Diego Ardissino, Irina M. Armean, Elizabeth G. Atkinson, Gil Atzmon, Eric Banks, J. A. Barnard, Samantha Baxter, Laurent Beaugerie, David Benjamin, Emelia J. Benjamin, Louis Bergelson, Çharles N. Bernstein, Douglas Blackwood, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Böttinger, Donald W. Bowden, Matthew J. Bown, Harrison Brand, Steven R. Brant, Ted Brookings, Sam Bryant, Shawneequa Callier, Hannia Campos, John C. Chambers, Juliana C.N. Chan, Katherine R. Chao, Sinéad B. Chapman, Daniel I. Chasman, Lea Ann Chen, Siwei Chen, Rex L. Chisholm, Judy H. Cho, Rajiv Chowdhury, Mina K. Chung, Wendy K. Chung, Kristian Cibulskis, Bruce M. Cohen, Ryan L. Collins, Kristen M. Connolly, Adolfo Correa, Aiden Corvin, Miguel Covarrubias, Nick Craddock, Beryl B. Cummings, Dana Dabelea, Mark J. Daly, John Danesh, Dawood Darbar, Phil Darnowsky, Joshua C. Denny, Stacey Donnelly, Richard H. Duerr, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosúa, James Emery, Eleina England, Jeanette Erdmann, Tõnu Esko, Emily Evangelista, Yossi Farjoun, Diane Fatkin, William A. Faubion, Steven Ferriera, Gemma A. Figtree, Kelly Flannagan, José C. Florez, Laurent C. Francioli, André Franke, Adam Frankish, Jack Fu, Martti Färkkilâ, Stacey Gabriel, Kiran Garimella, Laura D. Gauthier, Jeff Gentry, Michel Georges, Gad Getz, David C. Glahn, Benjamin Gläser, Stephen J. Glatt, Fernando S. Goes, David B. Goldstein, Clicerio González, Julia K. Goodrich, Riley Grant, Leif Groop, Sanna Gudmundsson, Namrata Gupta, Andrea Haessly, Christopher A. Haiman, Ira M. Hall, Craig L. Hanis, James Hanyok, Matthew Harms, Qin He, Mikko Hiltunen, Matti Holi, Christina M. Hultman, Steve Jahl, Chaim Jalas, Thibault Jeandet, Mikko Kallela, Diane Kaplan, Jaakko Kaprio, Konrad J. Karczewski, Elizabeth W. Karlson, Sekar Kathiresan, Eimear E. Kenny, Bong‐Jo Kim, Young J. Kim, Daniel King, George Kirov, Zan Koenig, Jaspal S. Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Juozas Kupčinskas, Soo Heon Kwak, Markku Laakso, Nicole J. Lake, Mikael Landén, Trevyn Langsford, Kristen M. Laricchia, Terho Lehtimäki, Monkol Lek, James D. Lewis, Cecilia M. Lindgren, Emily Lipscomb, Christopher Llanwarne, Ruth J. F. Loos, Édouard Louis, Chelsea Lowther, Wenhan Lu, Steven A. Lubitz, Tom Lyons, C. W. Ronald, Daniel G. MacArthur, Dara S. Manoach, Gregory M. Marcus, Jaume Marrugat, Nicholas Marston, Daniel Marten, Alicia R. Martin, Kari M. Mattila, Steven McCarroll, Mark I. McCarthy, Jacob L. McCauley, Dermot McGovern, Ruth McPherson, Andrew MacQuillin, James B. Meigs, Olle Melander, Andres Metspalu, Deborah A. Meyers, Eric Vallabh Minikel, Braxton D. Mitchell, Paul Moayyedi, Sanghamitra Mohanty, Andrés Moreno‐Estrada, Nicola Mulder, Ruchi Munshi, Aliya Naheed, Andrea Natale, Saman Nazarian, Benjamin M. Neale, Charles Newton, Peter M. Nilsson, Sam Novod, Anne O’Donnell‐Luria, Michael O‘Donovan, Yukinori Okada, Döst Öngür, Roel A. Ophoff, Lorena Orozco, Willem H. Ouwehand, Michael J. Owen, Nick Owen, Colin Palmer, Nicholette D. Palmer, Aarno Palotie, Mara Parellada, Kyong Soo Park, Carlos N. Pato, Nancy L. Pedersen, Tina Pesaran, Nikelle Petrillo, William Phu, Sharon E. Plon, Danielle Posthuma, Timothy Poterba, Ann E. Pulver, Aaron R. Quinlan, Dan Rader, Nazneen Rahman, Heidi L. Rehm, Andreas Reif, Alex Reiner, Anne M. Remes, Dan Rhodes, Stephen S. Rich, John D. Rioux, Samuli Ripatti, David Roazen, Jason Roberts, Elise Robinson, Dan M. Roden, Jerome I. Rotter, Guy A. Rouleau, Valentín Ruano-Rubio, Christian T. Ruff, Heiko Runz, Marc S. Sabatine, Nareh Sahakian, Danish Saleheen, Veikko Salomaa, Andrea Saltzman, Nilesh J. Samani, Kaitlin E. Samocha, Alba Sanchis-Juan, Akira Sawa, Jeremiah M. Scharf, Molly Schleicher, Patrick Schultz, Heribert Schunkert, Sebastian Schönherr, Eleanor G. Seaby, Cotton Seed, Svati H. Shah, Megan Shand, Ted Sharpe, Moore B. Shoemaker, Tai E. Shyong, Edwin K. Silverman, Jurgita Skiecevičienė, Pamela Sklar, J. G. Smith, Jonathan T. Smith, Jordan W. Smoller, Hilkka Soininen, Harry Sokol, Matthew Solomonson, Rachel G. Son, José Soto, Tim D. Spector, David St Clair, Christine Stevens, Nathan O. Stitziel, Patrick F. Sullivan, Jaana Suvisaari, E Shyong Tai, Michael E. Talkowski, Yekaterina Tarasova, Kent D. Taylor, Yik Ying Teo, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Ming T. Tsuang, Tiinamaija Tuomi, Dan Turner, Teresa Tusié‐Luna, Erkki Vartiainen, Marquis P. Vawter, Séverine Vermeire, Elisabet Vilella, Christopher Vittal, Gordon Wade, Mark S. Walker, Arcturus Wang, Lily Wang, Qingbo S. Wang, James S. Ware, Hugh Watkins, Nicholas A. Watts, Rinse K. Weersma, Ben Weisburd, Maija Wessman, Christopher W. Whelan, Nicola Whiffin, James G. Wilson, Lauren Witzgall, Ramnik J. Xavier, Mary T. Yohannes, Robert H. Yolken, Xuefang Zhao, Tuuli Lappalainen, Heidi L. Rehm, Daniel G. MacArthur, Anne O’Donnell‐Luria · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61698-x · 被引用次数：15 · 研究领域：Genomics and Rare Diseases、Genetic Associations and Epidemiology、Hereditary Neurological Disorders

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.