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

Gudmundsson, Sanna, Singer-Berk, Moriel, Stenton, Sarah L., Goodrich, Julia K., Wilson, Michael W., Einson, Jonah, Watts, Nicholas A., Abreu, Maria, Abubakar, Amina, Adolfsson, Rolf, Aguilar Salinas, Carlos A., Ahmad, Tariq, Albert, Christine M., Alföldi, Jessica, Allez, Matthieu, López, Celso Arango, Ardissino, Diego, Armean, Irina M., Atkinson, Elizabeth G., Atzmon, Gil, Banks, Eric, Barnard, John, Baxter, Samantha M., Beaugerie, Laurent, Benjamin, David, Benjamin, Emelia J., Bergelson, Louis, Bernstein, Charles, Blackwood, Douglas, Boehnke, Michael, Bonnycastle, Lori L., Bottinger, Erwin P., Bowden, Donald W., Bown, Matthew J., Brand, Harrison, Brant, Steven, Brookings, Ted, Bryant, Sam, Callier, Shawneequa L., Campos, Hannia, Chambers, John C., Chan, Juliana C., Chao, Katherine R., Chapman, Sinéad, Chasman, Daniel I., Chen, Lea A., Chen, Siwei, Chisholm, Rex, Cho, Judy, Chowdhury, Rajiv, Chung, Mina K., Chung, Wendy K., Cibulskis, Kristian, Cohen, Bruce, Collins, Ryan L., Connolly, Kristen M., Correa, Adolfo, Corvin, Aiden, Covarrubias, Miguel, Craddock, Nick ORCID: https://orcid.org/0000-0003-2171-0610, Cummings, Beryl B., Dabelea, Dana, Daly, Mark J., Danesh, John, Darbar, Dawood, Darnowsky, Phil, Denny, Joshua C., Donnelly, Stacey, Duerr, Richard H., Duggirala, Ravindranath, Dupuis, Josée, Ellinor, Patrick T., Elosua, Roberto, Emery, James, England, Eleina, Erdmann, Jeanette, Esko, Tõnu, Evangelista, Emily, Farjoun, Yossi, Fatkin, Diane, Faubion, William, Ferriera, Steven, Figtree, Gemma, Flannagan, Kelly, Florez, Jose, Francioli, Laurent, Franke, Andre, Frankish, Adam, Fu, Jack, Färkkilä, Martti, Gabriel, Stacey, Garimella, Kiran, Gauthier, Laura D., Gentry, Jeff, Georges, Michel, Getz, Gad, Glahn, David C., Glaser, Benjamin, Glatt, Stephen J., Goes, Fernando S., Goldstein, David, Gonzalez, Clicerio, Goodrich, Julia, Grant, Riley H., Groop, Leif, Gudmundsson, Sanna, Gupta, Namrata, Haessly, Andrea, Haiman, Christopher, Hall, Ira, Hanis, Craig L., Hanyok, James, Harms, Matthew, He, Qin, Hiltunen, Mikko, Holi, Matti M., Hultman, Christina M., Jahl, Steve, Jalas, Chaim, Jeandet, Thibault, Kallela, Mikko, Kaplan, Diane, Kaprio, Jaakko, Karczewski, Konrad J., Karlson, Elizabeth W., Kathiresan, Sekar, Kenny, Eimear E., Kim, Bong-Jo, Kim, Young Jin, King, Daniel, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Koenig, Zan, Kooner, Jaspal, Koskinen, Seppo, Krumholz, Harlan M., Kugathasan, Subra, Kupcinskas, Juozas, Kwak, Soo Heon, Laakso, Markku, Lake, Nicole, Landén, Mikael, Langsford, Trevyn, Laricchia, Kristen M., Lehtimäki, Terho, Lek, Monkol, Lewis, James, Lindgren, Cecilia M., Lipscomb, Emily, Llanwarne, Christopher, Loos, Ruth J. F., Louis, Edouard, Lowther, Chelsea, Lu, Wenhan, Lubitz, Steven A., Lyons, Tom, Ma, Ronald C. W., MacArthur, Daniel G., Manoach, Dara S., Marcus, Gregory M., Marrugat, Jaume, Marston, Nicholas, Marten, Daniel M., Martin, Alicia R., Mattila, Kari M., McCarroll, Steven, McCarthy, Mark I., McCauley, Jacob L., McGovern, Dermot, McPherson, Ruth, MacQuillin, Andrew, Meigs, James B., Melander, Olle, Metspalu, Andres, Meyers, Deborah, Minikel, Eric V., Mitchell, Braxton D., Moayyedi, Paul, Mohanty, Sanghamitra, Estrada, Andrés Moreno, Mulder, Nicola J., Munshi, Ruchi, Naheed, Aliya, Natale, Andrea, Nazarian, Saman, Neale, Benjamin M., Newton, Charles, Nilsson, Peter M., Novod, Sam, O’Donnell-Luria, Anne H., O’Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Okada, Yukinori, Ongur, Dost, Ophoff, Roel, Orozco, Lorena, Ouwehand, Willem, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Owen, Nick, Palmer, Colin, Palmer, Nicholette D., Palotie, Aarno, Parellada, Mara, Park, Kyong Soo, Pato, Carlos, Pedersen, Nancy L., Pesaran, Tina, Petrillo, Nikelle, Phu, William, Plon, Sharon, Posthuma, Danielle, Poterba, Timothy, Pulver, Ann E., Quinlan, Aaron, Rader, Dan, Rahman, Nazneen, Rehm, Heidi, Reif, Andreas, Reiner, Alex, Remes, Anne M., Rhodes, Dan, Rich, Stephen, Rioux, John D., Ripatti, Samuli, Roazen, David, Roberts, Jason, Robinson, Elise, Roden, Dan M., Rotter, Jerome I., Rouleau, Guy, Ruano-Rubio, Valentin, Ruff, Christian T., Runz, Heiko, Sabatine, Marc S., Sahakian, Nareh, Saleheen, Danish, Salomaa, Veikko, Saltzman, Andrea, Samani, Nilesh J., Samocha, Kaitlin E., Sanchis-Juan, Alba, Sawa, Akira, Scharf, Jeremiah, Schleicher, Molly, Schultz, Patrick, Schunkert, Heribert, Schönherr, Sebastian, Seaby, Eleanor G., Seed, Cotton, Shah, Svati H., Shand, Megan, Sharpe, Ted, Shoemaker, Moore B., Shyong, Tai, Silverman, Edwin K., Skieceviciene, Jurgita, Sklar, Pamela, Smith, J. Gustav, Smith, Jonathan T., Smoller, Jordan, Soininen, Hilkka, Sokol, Harry, Solomonson, Matthew, Son, Rachel G., Soto, Jose, Spector, Tim, Clair, David St, Stevens, Christine, Stitziel, Nathan O., Sullivan, Patrick F., Suvisaari, Jaana, Tai, E. Shyong, Talkowski, Michael E., Tarasova, Yekaterina, Taylor, Kent D., Teo, Yik Ying, Tiao, Grace, Tibbetts, Kathleen, Tolonen, Charlotte, Tsuang, Ming, Tuomi, Tiinamaija, Turner, Dan, Tusie-Luna, Teresa, Vartiainen, Erkki, Vawter, Marquis, Vermeire, Severine, Vilella, Elisabet, Vittal, Christopher, Wade, Gordon, Walker, Mark, Wang, Arcturus, Wang, Lily, Wang, Qingbo, Ware, James S., Watkins, Hugh, Watts, Nicholas A., Weersma, Rinse K., Weisburd, Ben, Wessman, Maija, Whelan, Christopher, Whiffin, Nicola, Wilson, James G., Witzgall, Lauren, Xavier, Ramnik J., Yohannes, Mary T., Yolken, Robert, Zhao, Xuefang, Lappalainen, Tuuli, Rehm, Heidi L., MacArthur, Daniel G. and O’Donnell-Luria, Anne 2025. Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database. Nature Communications 16 , 9623. 10.1038/s41467-025-61698-x

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB)

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Nature Research
Date of First Compliant Deposit:	10 December 2025
Date of Acceptance:	23 June 2025
Last Modified:	10 Dec 2025 16:31
URI:	https://orca.cardiff.ac.uk/id/eprint/183116

Actions (repository staff only)

Edit Item