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

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.

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Journal
Nature Communications
Published
2025-10-31
DOI
https://doi.org/10.1038/s41467-025-61698-x
Citations
4
Primary Topic
Genomics and Rare Diseases
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article
Field-Weighted Citation Impact
7.27

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article

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

Christopher W. Whelan, Nareh Sahakian, Aiden Corvin, James Emery et al.
4 citations
Nature Communications
Genomics and Rare Diseases
7.27
article

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

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

Abstract

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.

Nature CommunicationsVol. 16(1)
Rutgers, The State University of New Jersey (US), Broad Institute (US), Boston University (US), Northwestern University (US), University of North Carolina at Chapel Hill (US), Goethe University Frankfurt (DE), James S. McDonnell Foundation (US), Universitat de Vic - Universitat Central de Catalunya (ES), University of Southern California (US), Universidad Complutense de Madrid (ES), University of Copenhagen (DK), University of Parma (IT), Western University (CA), University of Maryland, Baltimore (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), Montreal Neurological Institute and Hospital (CA), The University of Sydney (AU), Biogen (United States) (US), National Institutes of Health (US), Albert Einstein College of Medicine (US), European Bioinformatics Institute (GB), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Lithuanian University of Health Sciences (LT), Yale New Haven Hospital (US), University Medical Center Groningen (NL), Children's Hospital of Philadelphia (US), Texas A&M University – San Antonio (US), Centre for Human Genetics (GB), University of Helsinki (FI), University College London Hospitals NHS Foundation Trust (GB), Harvard University (US), Garvan Institute of Medical Research (AU), University of Arizona (US), Seoul National University (KR), Institute of Cancer Research (GB), Innsbruck Medical University (AT), Johns Hopkins University (US), University of Miami (US), Emory University (US), Tampere University of Applied Sciences (FI), Colorado School of Public Health (US), Imperial College Healthcare NHS Trust (GB), University of Leicester (GB), University of Ottawa (CA), Inserm (FR), University of Cape Town (ZA), University of Liège (BE), University of California, Los Angeles (US), National University of Singapore (SG), Tampere University (FI), University of Groningen (NL), University of Pittsburgh (US), Duke University (US), City University of New York (US), University of Eastern Finland (FI), University of Dundee (GB), Chinese University of Hong Kong (HK), University of California, San Francisco (US), Baylor College of Medicine (US), Malmö University (SE), King's College London (GB), Lund University (SE), George Washington University (US), Victor Chang Cardiac Research Institute (AU), University of Aberdeen (GB), Hebrew University of Jerusalem (IL), Vanderbilt University (US), University of Washington (US), SUNY Upstate Medical University (US), University of California, Irvine (US), Washington University in St. Louis (US), Université Paris Cité (FR), Trinity College Dublin (IE), International Centre for Diarrhoeal Disease Research (BD), University of Utah (US), University of Cambridge (GB), University of Michigan (US), Oulu University Hospital (FI), Columbia University Irving Medical Center (US), Ealing Hospital (GB), Johns Hopkins Medicine (US), Hadassah Medical Center (IL), Ionis Pharmaceuticals (United States) (US), Royal North Shore Hospital (AU), Science for Life Laboratory (SE), Montreal Heart Institute (CA), Helsinki University Hospital (FI), Hong Kong Science and Technology Parks Corporation (HK), Government of Victoria (AU), Sahlgrenska University Hospital (SE), Novo Nordisk Foundation (DK), McLean Hospital (US), Churchill Hospital (GB), Instituto de Salud Carlos III (ES), UCLA Medical Center (US), Institut Pere Mata (ES), Jewish General Hospital (CA), Erasmus MC (NL), Shaare Zedek Medical Center (IL), Glenfield Hospital (GB), Johnson University (US), WinnMed (US), Ninewells Hospital (GB), John Radcliffe Hospital (GB), Population Health Research Institute (CA), Seoul National University Hospital (KR), Jackson Memorial Hospital (US), Kingsbrook Jewish Medical Center (US), Open Data Institute (GB), Karolinska Institutet (SE), Kenya Medical Research Institute (KE), Hospital General Universitario Gregorio Marañón (ES), University of Mississippi Medical Center (US), Microbiologie de l’alimentation au service de la santé (FR), UNSW Sydney (AU), Christian-Albrechts-Universität zu Kiel (DE), Yale University (US), University of California San Diego (US), Cleveland Clinic Lerner College of Medicine (US), University of Illinois Chicago (US), Swansea University (GB), Finnish Institute for Health and Welfare (FI), Sorbonne Université (FR), University of Oxford (GB), St Vincent's Hospital Sydney (AU), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), National Human Genome Research Institute (US), Centro de Investigación Biomédica en Red de Salud Mental (ES), Joint Center for Structural Genomics (US), Kuopio University Hospital (FI), Instituto Nacional de Investigaciones Nucleares (MX), Fulcrum Therapeutics (United States) (US), Centro de Investigación en Red en Enfermedades Cardiovasculares (ES), Korea National Institute of Health (KR), Assistance Publique – Hôpitaux de Paris (FR), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Lung Institute (US), Institut de Recerca Biomèdica Catalunya Sud (ES), Nashville VA Medical Center (US), National University Cancer Institute, Singapore (SG), National Energy Research Center (JO), Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine (FR), Aga Khan University Nairobi (KE), Amsterdam Neuroscience (NL), National Institute of Genomic Medicine (MX), University Hospital Schleswig-Holstein (DE), Centro de Investigación Biomédica en Red (ES), Wisdom Health (United States) (US), St David's Medical Center (US), Framingham Heart Study (US), Instituto Nacional de Salud (PE), Duke Medical Center (US), Duke-NUS Medical School (SG), Technical University of Applied Sciences Lübeck (DE), German Centre for Cardiovascular Research (DE), Instituto Nacional de Salud Pública (MX), Oxford Centre for Diabetes, Endocrinology and Metabolism (GB), Hospital Del Mar (ES), Dr. John T. Macdonald Foundation (US), Child, Adolescent and Family Mental Health (CA), University Hospital Frankfurt (DE), Tampere University (FI), Institute for Molecular Medicine Finland (FI), Fimlab (Finland) (FI), Fulcrum Corporation (United States) (US), Centre Hospitalier Universitaire de Liège (BE), Centre de Recherche Saint-Antoine (FR), Advanced Medical Institute (Australia) (AU), Skåne University Hospital (SE), College of Law and Business (IL), Hôpital Saint-Louis (FR), Scripps Clinic (US), Texas Cardiac Arrhythmia (US), Oxford BioMedica (United Kingdom) (GB), Science Oxford (GB), National University Hospital (SG), Mayo Clinic in Florida (US), Deutsches Herzzentrum München (DE), National University Health System (SG), Murdoch Children's Research Institute (AU), Ambry Genetics (United States) (US), New York Genome Center (US), Institute of Genetics (HU), Hospital del Mar Research Institute (ES), Center for Non-Communicable Diseases (PK), MetroHealth Medical Center (US), Statistical Research (United States) (US), Centro de Investigación Biomédica en Red de Cáncer (ES), Thrombolysis in Myocardial Infarction Study Group (US), Institute of Coal Chemistry (CN), Alzheimer's Association of Israel (IL), Genomic Health (United States) (US), MRC London Institute of Medical Sciences (GB), Daiichi Sankyo (United States) (US), Ealing Hospital NHS Trust (GB), Universidad Americana (CR), Folkhälsans Forskningscentrum (FI), Harbor–UCLA Medical Center (US), NIHR Leicester Biomedical Research Centre (GB), University of Southampton (GB), Estonian Biocentre (EE), University College London (GB), University of Manitoba (CA), Wake Forest University (US), Imperial College London (GB), McGill University (CA), University of Virginia (US), University of Tartu (EE), Case Western Reserve University (US), Technical University of Munich (DE), Clalit Health Services (IL), Université de Montréal (CA), Hamilton Health Sciences (CA), Columbia University (US), Cardiff University (GB), University of Pennsylvania (US), Peninsula College of Medicine and Dentistry (GB), Vrije Universiteit Amsterdam (NL), KTH Royal Institute of Technology (SE), University of Gothenburg (SE), Vanderbilt University Medical Center (US), Umeå University (SE), University of Haifa (IL), The University of Texas Health Science Center at Houston (US), University of Lübeck (DE), McMaster University (CA), The University of Osaka (JP), University of Oulu (FI), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
Broad Institute, Knut och Alice Wallenbergs Stiftelse, National Institutes of Health, Manton Center for Orphan Disease Research, Boston Children's Hospital, Medical Research Council, National Health and Medical Research Council, National Human Genome Research Institute
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Genomics and Rare Diseases
7.27
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