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1,377 results on '"Renieri, Alessandra"'

101. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, Elisabeth; https://orcid.org/0000-0002-4952-2016, Popp, Bernt; https://orcid.org/0000-0002-3679-1081, Güse, Esther, Skinner, Cindy, van der Sluijs, Pleuntje J; https://orcid.org/0000-0002-1174-2806, Maystadt, Isabelle, Pinto, Anna Maria, Renieri, Alessandra, Bruno, Lucia Pia, Granata, Stefania, Marcelis, Carlo, Baysal, Özlem, Hartwich, Dewi, Holthöfer, Laura, Isidor, Bertrand, Cogné, Benjamin; https://orcid.org/0000-0002-5503-6292, Wieczorek, Dagmar, Capra, Valeria, Scala, Marcello, De Marco, Patrizia, Ognibene, Marzia, Abou Jamra, Rami; https://orcid.org/0000-0002-1542-1399, Platzer, Konrad, Carter, Lauren B, Kuismin, Outi, van Haeringen, Arie, Maroofian, Reza; https://orcid.org/0000-0001-6763-1542, Valenzuela, Irene, Cuscó, Ivon, Martinez-Agosto, Julian A, et al, Zweier, Markus; https://orcid.org/0000-0001-8290-0413, Bosch, Elisabeth; https://orcid.org/0000-0002-4952-2016, Popp, Bernt; https://orcid.org/0000-0002-3679-1081, Güse, Esther, Skinner, Cindy, van der Sluijs, Pleuntje J; https://orcid.org/0000-0002-1174-2806, Maystadt, Isabelle, Pinto, Anna Maria, Renieri, Alessandra, Bruno, Lucia Pia, Granata, Stefania, Marcelis, Carlo, Baysal, Özlem, Hartwich, Dewi, Holthöfer, Laura, Isidor, Bertrand, Cogné, Benjamin; https://orcid.org/0000-0002-5503-6292, Wieczorek, Dagmar, Capra, Valeria, Scala, Marcello, De Marco, Patrizia, Ognibene, Marzia, Abou Jamra, Rami; https://orcid.org/0000-0002-1542-1399, Platzer, Konrad, Carter, Lauren B, Kuismin, Outi, van Haeringen, Arie, Maroofian, Reza; https://orcid.org/0000-0001-6763-1542, Valenzuela, Irene, Cuscó, Ivon, Martinez-Agosto, Julian A, et al, and Zweier, Markus; https://orcid.org/0000-0001-8290-0413

Abstract

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.

Published
2023

102. ENIGMA CHEK2gether Project:A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk

Author

Stolarova, Lenka, Kleiblova, Petra, Zemankova, Petra, Stastna, Barbora, Janatova, Marketa, Soukupova, Jana, Achatz, Maria Isabel, Ambrosone, Christine, Apostolou, Paraskevi, Arun, Banu K., Auer, Paul, Barnard, Mollie, Bertelsen, Birgitte, Japan, Biobank, Blok, Marinus J., Boddicker, Nicholas, Brunet, Joan, Burnside, Elizabeth S., Calvello, Mariarosaria, Campbell, Ian, Chan, Sock Hoai, Chen, Fei, Chiang, Jian Bang, Coppa, Anna, Cortesi, Laura, Crujeiras-González, Ana, Czecanca, Consortium, De Leeneer, Kim, De Putter, Robin, DePersia, Allison, Devereux, Lisa, Domchek, Susan, Efremidis, Anna, Engel, Christoph, Ernst, Corinna, Evans, Gareth D.R., Feliubadaló, Lidia, Fostira, Florentia, Fuentes-Ríos, Olivia, Gómez-García, Encarna B., González, Sara, Haiman, Christopher, van Overeem Hansen, Thomas, Hauke, Jan, Hodge, James, Hu, Chunling, Huang, Hongyan, Binte Ishak, Nur Diana, Iwasaki, Yusuke, Konstantopoulou, Irene, Kraft, Peter, Lacey, James, Lázaro, Conxi, Li, Na, Lim, Weng Khong, Lindstrom, Sara, Lori, Adriana, Martinez, Elana, Martins, Alexandra, Matsuda, Koichi, Matullo, Giuseppe, McInerny, Simone, Michailidou, Kyriaki, Montagna, Marco, Monteiro, Alvaro N.A., Mori, Luigi, Nathanson, Katherine, Neuhausen, Susan L., Nevanlinna, Heli, Olson, Janet E., Palmer, Julie, Pasini, Barbara, Patel, Alpa, Piane, Maria, Poppe, Bruce, Radice, Paolo, Renieri, Alessandra, Resta, Nicoletta, Richardson, Marcy E., Rosseel, Toon, Ruddy, Kathryn J., Santamariña, Marta, Dos Santos, Elizabeth Santana, Teras, Lauren, Toland, Amanda E., Trentham-Dietz, Amy, Vachon, Celine M., Volk, Alexander E., Weber-Lassalle, Nana, Weitzel, Jeffrey N., Wiesmuller, Lisa, Winham, Stacey, Yadav, Siddhartha, Yannoukakos, Drakoulis, Yao, Song, Zampiga, Valentina, Zethoven, Magnus, Zhang, Ze Wen, Zima, Tomas, Spurdle, Amanda B., Vega, Ana, Rossing, Maria, Valle, Jesús Del, De Nicolo, Arcangela, Hahnen, Eric, Claes, Kathleen B.M., Ngeow, Joanne, Momozawa, Yukihide, James, Paul A., Couch, Fergus J., Macurek, Libor, Kleibl, Zdenek, Stolarova, Lenka, Kleiblova, Petra, Zemankova, Petra, Stastna, Barbora, Janatova, Marketa, Soukupova, Jana, Achatz, Maria Isabel, Ambrosone, Christine, Apostolou, Paraskevi, Arun, Banu K., Auer, Paul, Barnard, Mollie, Bertelsen, Birgitte, Japan, Biobank, Blok, Marinus J., Boddicker, Nicholas, Brunet, Joan, Burnside, Elizabeth S., Calvello, Mariarosaria, Campbell, Ian, Chan, Sock Hoai, Chen, Fei, Chiang, Jian Bang, Coppa, Anna, Cortesi, Laura, Crujeiras-González, Ana, Czecanca, Consortium, De Leeneer, Kim, De Putter, Robin, DePersia, Allison, Devereux, Lisa, Domchek, Susan, Efremidis, Anna, Engel, Christoph, Ernst, Corinna, Evans, Gareth D.R., Feliubadaló, Lidia, Fostira, Florentia, Fuentes-Ríos, Olivia, Gómez-García, Encarna B., González, Sara, Haiman, Christopher, van Overeem Hansen, Thomas, Hauke, Jan, Hodge, James, Hu, Chunling, Huang, Hongyan, Binte Ishak, Nur Diana, Iwasaki, Yusuke, Konstantopoulou, Irene, Kraft, Peter, Lacey, James, Lázaro, Conxi, Li, Na, Lim, Weng Khong, Lindstrom, Sara, Lori, Adriana, Martinez, Elana, Martins, Alexandra, Matsuda, Koichi, Matullo, Giuseppe, McInerny, Simone, Michailidou, Kyriaki, Montagna, Marco, Monteiro, Alvaro N.A., Mori, Luigi, Nathanson, Katherine, Neuhausen, Susan L., Nevanlinna, Heli, Olson, Janet E., Palmer, Julie, Pasini, Barbara, Patel, Alpa, Piane, Maria, Poppe, Bruce, Radice, Paolo, Renieri, Alessandra, Resta, Nicoletta, Richardson, Marcy E., Rosseel, Toon, Ruddy, Kathryn J., Santamariña, Marta, Dos Santos, Elizabeth Santana, Teras, Lauren, Toland, Amanda E., Trentham-Dietz, Amy, Vachon, Celine M., Volk, Alexander E., Weber-Lassalle, Nana, Weitzel, Jeffrey N., Wiesmuller, Lisa, Winham, Stacey, Yadav, Siddhartha, Yannoukakos, Drakoulis, Yao, Song, Zampiga, Valentina, Zethoven, Magnus, Zhang, Ze Wen, Zima, Tomas, Spurdle, Amanda B., Vega, Ana, Rossing, Maria, Valle, Jesús Del, De Nicolo, Arcangela, Hahnen, Eric, Claes, Kathleen B.M., Ngeow, Joanne, Momozawa, Yukihide, James, Paul A., Couch, Fergus J., Macurek, Libor, and Kleibl, Zdenek

Abstract

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with n, Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ~ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N ¼ 102), functionally intermediate (N ¼ 12), or functionally wild-type (WT)–like (N ¼ 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk

Published
2023

107. Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Author

Yaldiz, Burcu, Kucuk, Erdi, Hampstead, Juliet, Hofste, Tom, Pfundt, Rolph, Corominas Galbany, Jordi, Rinne, Tuula, Yntema, Helger G., Hoischen, Alexander, Nelen, Marcel, Gilissen, Christian, consortium, Solve-R. D., Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoen, Peter A. C. T, Vissers, Lisenka E. L. M., Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Frederikse, Wilhemina Skerstjens, Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, de Sainte Agathe, Jean-Madeleine, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Osorio, Andrés Nascimento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Beeson, David, Cossins, Judith, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Başak, Ayşe Nazlı, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Claeys, Kristl, Santen, Gijs W. E., Bijlsma, Emilia K., Hoffer, Mariette J. V., Ruivenkamp, Claudia A. L., Boztug, Kaan, Haimel, Matthias, Maystadt, Isabelle, Cordts, Isabelle, Deschauer, Marcus, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Depienne, Christel, Roos, Andreas, May, Patrick, and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences]
Abstract

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques.

Published
2023

108. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Author

Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack A, Cirulli, Elizabeth T, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy D, Sloofman, Laura G, Jordan, Daniel M, Thompson, Ryan C, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric E, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph D, Beckmann, Noam D, Charney, Alexander W, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess D, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J Kenneth, Stuckey, Alex, Salas, Antonio, Bello, Xabier, Pardo-Seco, Jacobo, Gómez-Carballa, Alberto, Rivero-Calle, Irene, Martinón-Torres, Federico, Ganna, Andrea, Karczewski, Konrad J, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert Jm, Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklos, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly M, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicolas, Motameny, Susanne, Alaamery, Manal, Massadeh, Salam, Aljawini, Nora, Almutairi, Mansour S, Arabi, Yaseen M, Alqahtani, Saleh A, Al Harthi, Fawz S, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal A, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Mount Sinai Clinical Intelligence Center, GEN-COVID Consortium (Spain), GenOMICC Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Geschwind, Daniel H, Arteaga, Stephanie, Stephens, Alexis, Butte, Manish J, Boutros, Paul C, Yamaguchi, Takafumi N, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul J, Broudy, Michael E, Pan, Yu, Gonzalez, Alfredo, Chavan, Nikhil, Johnson, Ruth, Pasaniuc, Bogdan, Yaspan, Brian, Smieszek, Sandra, Rivolta, Carlo, Bibert, Stephanie, Bochud, Pierre-Yves, Dabrowski, Maciej, Zawadzki, Pawel, Sypniewski, Mateusz, Kaja, Elżbieta, Chariyavilaskul, Pajaree, Nilaratanakul, Voraphoj, Hirankarn, Nattiya, Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Tokunaga, Katsushi, Sugiyama, Masaya, Kawai, Yosuke, Hasegawa, Takanori, Naito, Tatsuhiko, Namkoong, Ho, Edahiro, Ryuya, Kimura, Akinori, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, Okada, Yukinori, Imoto, Seiya, Miyano, Satoru, Mangul, Serghei, Abedalthagafi, Malak S, Zeberg, Hugo, Grzymski, Joseph J, Washington, Nicole L, Ossowski, Stephan, Ludwig, Kerstin U, Schulte, Eva C, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said I, Verma, Anurag, Goldstein, David B, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel AR, Richards, J Brent, Butler-Laporte, Guillaume [0000-0001-5388-0396], Povysil, Gundula [0000-0003-4625-5909], Kosmicki, Jack A [0000-0003-1252-6192], Cirulli, Elizabeth T [0000-0001-7808-2809], Drivas, Theodore [0000-0002-8717-0111], Saad, Chadi [0000-0001-6963-9126], Olszewski, Pawel [0000-0003-1010-8843], Korotko, Urszula [0000-0002-1779-8368], Quinodoz, Mathieu [0000-0002-9841-4433], Çelik, Elifnaz [0000-0002-0324-5228], Kundu, Kousik [0000-0002-1019-8351], Walter, Klaudia [0000-0003-4448-0301], Sloofman, Laura G [0000-0001-7628-4378], Jordan, Daniel M [0000-0002-5318-8225], Thompson, Ryan C [0000-0002-0450-8181], Del Valle, Diane [0000-0001-6983-5362], Simons, Nicole [0000-0002-3952-1458], Chang, Timothy [0000-0002-9225-9874], Brand, Fabian [0000-0003-1885-7021], Chwialkowska, Karolina [0000-0001-8053-8959], Niemira, Magdalena [0000-0002-0701-4961], Pula, Szymon [0000-0002-5684-5358], Stuckey, Alex [0000-0001-8636-737X], Bello, Xabier [0000-0002-4990-8496], Karczewski, Konrad J [0000-0003-2878-4671], Bourgey, Mathieu [0000-0002-8432-834X], Bourque, Guillaume [0000-0002-3933-9656], Eveleigh, Robert Jm [0000-0002-4147-382X], Morrison, David [0000-0001-8380-3615], Langlais, David [0000-0003-4429-0110], Mooser, Vincent [0000-0002-8632-0448], Nakanishi, Tomoko [0000-0001-9510-5646], Frithiof, Robert [0000-0003-2278-7951], Hultström, Michael [0000-0003-4675-1099], Lipcsey, Miklos [0000-0002-1976-4129], Nordlund, Jessica [0000-0001-8699-9959], Schiabor Barrett, Kelly M [0000-0001-6194-787X], Bolze, Alexandre [0000-0001-7399-2766], White, Simon [0000-0001-6375-2363], Dabe, Shaun [0000-0002-2494-962X], Casadei, Nicolas [0000-0003-2209-0580], Motameny, Susanne [0000-0003-1186-1108], Massadeh, Salam [0000-0001-9193-0008], Almutairi, Mansour S [0000-0003-2736-8991], Arabi, Yaseen M [0000-0001-5735-6241], Fawzy, Mohammad [0000-0002-1318-9979], Arteaga, Stephanie [0000-0003-1441-8849], Stephens, Alexis [0000-0002-5979-6838], Yamaguchi, Takafumi N [0000-0003-1082-3871], Eng, Stefan [0000-0002-5245-6507], Gonzalez, Alfredo [0000-0001-8963-3135], Johnson, Ruth [0000-0002-1929-0998], Yaspan, Brian [0000-0002-3787-2510], Smieszek, Sandra [0000-0002-8006-0454], Rivolta, Carlo [0000-0002-0733-9950], Bochud, Pierre-Yves [0000-0002-2208-4757], Dabrowski, Maciej [0000-0003-4150-3985], Zawadzki, Pawel [0000-0002-9032-2315], Kaja, Elżbieta [0000-0003-1277-6140], Chariyavilaskul, Pajaree [0000-0003-1096-6020], Nilaratanakul, Voraphoj [0000-0002-3964-5477], Hirankarn, Nattiya [0000-0003-2224-6856], Shotelersuk, Vorasuk [0000-0002-1856-0589], Pongpanich, Monnat [0000-0003-3228-3351], Phokaew, Chureerat [0000-0002-4246-2604], Chetruengchai, Wanna [0000-0003-2495-6595], Sugiyama, Masaya [0000-0002-9084-7197], Kawai, Yosuke [0000-0003-0666-1224], Hasegawa, Takanori [0000-0001-7251-9950], Namkoong, Ho [0000-0001-6181-4284], Miyano, Satoru [0000-0002-1753-6616], Mangul, Serghei [0000-0003-4770-3443], Zeberg, Hugo [0000-0001-7118-1249], Grzymski, Joseph J [0000-0003-2646-8958], Ossowski, Stephan [0000-0002-7416-9568], Ludwig, Kerstin U [0000-0002-8541-2519], Schulte, Eva C [0000-0003-3105-5672], Verma, Anurag [0000-0002-5063-9107], Goldstein, David B [0000-0001-7627-0259], Kiryluk, Krzysztof [0000-0002-5047-6715], Renieri, Alessandra [0000-0002-0846-9220], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Medicine and health sciences, Research and analysis methods, Physical sciences, Toll-Like Receptor 7, Biology and life sciences, SARS-CoV-2, FOS: Physical sciences, Humans, COVID-19, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Research Article
Abstract

Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables., Funder: Lady Davis Institute of the Jewish General Hospital, Funder: Canadian Foundation for Innovation, Funder: NIH Foundation, Funder: Fonds de Recherche Québec Santé (FRQS), Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4), Funder: Jewish General Hospital Foundation, Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062, Funder: Public Health Agency of Canada, Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582, Funder: Calcul Québec and Compute Canada, Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020, Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380, Funder: State of Saarland, Funder: Dr. Rolf M. Schwiete Foundation, Funder: Munich Clinician Scientist Programm, Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021, Funder: Federal Ministry of Education and Research, Funder: Leenaards Foundation, Funder: Santos-Suarez Foundation, Funder: Carigest, Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”, Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency), Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Published
2022

109. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

Author

Butler-Laporte, Guillaume, Nakanishi, Tomoko, Mooser, Vincent, Morrison, David R., Abdullah, Tala, Adeleye, Olumide, Mamlouk, Noor, Kimchi, Nofar, Afrasiabi, Zaman, Rezk, Nardin, Giliberti, Annarita, Renieri, Alessandra, Chen, Yiheng, Zhou, Sirui, Forgetta, Vincenzo, and Richards, J. Brent

Subjects
Alfacalcidol -- Health aspects -- Usage, Calcifediol -- Health aspects -- Usage, Vitamin D -- Health aspects -- Usage, Dietary supplements -- Health aspects -- Usage, Biological sciences
Abstract

Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. Conclusions In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials., Author(s): Guillaume Butler-Laporte 1,2, Tomoko Nakanishi 1,3,4,5, Vincent Mooser 3,6, David R. Morrison 1, Tala Abdullah 1, Olumide Adeleye 1, Noor Mamlouk 1, Nofar Kimchi 1,7, Zaman Afrasiabi 1, Nardin [...]

Published
2021
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110. Phenotype and genotype of 87 patients with Mowat–Wilson syndrome and recommendations for care

Author

Ivanovski, Ivan, Djuric, Olivera, Caraffi, Stefano Giuseppe, Santodirocco, Daniela, Pollazzon, Marzia, Rosato, Simonetta, Cordelli, Duccio Maria, Abdalla, Ebtesam, Accorsi, Patrizia, Adam, Margaret P, Ajmone, Paola Francesca, Badura-Stronka, Magdalena, Baldo, Chiara, Baldi, Maddalena, Bayat, Allan, Bigoni, Stefania, Bonvicini, Federico, Breckpot, Jeroen, Callewaert, Bert, Cocchi, Guido, Cuturilo, Goran, De Brasi, Daniele, Devriendt, Koenraad, Dinulos, Mary Beth, Hjortshøj, Tina Duelund, Epifanio, Roberta, Faravelli, Francesca, Fiumara, Agata, Formisano, Debora, Giordano, Lucio, Grasso, Marina, Grønborg, Sabine, Iodice, Alessandro, Iughetti, Lorenzo, Kuburovic, Vladimir, Kutkowska-Kazmierczak, Anna, Lacombe, Didier, Lo Rizzo, Caterina, Luchetti, Anna, Malbora, Baris, Mammi, Isabella, Mari, Francesca, Montorsi, Giulia, Moutton, Sebastien, Møller, Rikke S, Muschke, Petra, Nielsen, Jens Erik Klint, Obersztyn, Ewa, Pantaleoni, Chiara, Pellicciari, Alessandro, Pisanti, Maria Antonietta, Prpic, Igor, Poch-Olive, Maria Luisa, Raviglione, Federico, Renieri, Alessandra, Ricci, Emilia, Rivieri, Francesca, Santen, Gijs W, Savasta, Salvatore, Scarano, Gioacchino, Schanze, Ina, Selicorni, Angelo, Silengo, Margherita, Smigiel, Robert, Spaccini, Luigina, Sorge, Giovanni, Szczaluba, Krzysztof, Tarani, Luigi, Tone, Luis Gonzaga, Toutain, Annick, Trimouille, Aurelien, Valera, Elvis Terci, Vergano, Samantha Schrier, Zanotta, Nicoletta, Zenker, Martin, Conidi, Andrea, Zollino, Marcella, Rauch, Anita, Zweier, Christiane, and Garavelli, Livia

Published
2018
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112. An Example of Neuro-Glial Commitment and Differentiation of Muse Stem Cells Obtained from Patients with IQSEC2-Related Neural Disorder: A Possible New Cell-Based Disease Model

Author

Al Sammarraie, Sura Hilal Ahmed, primary, Aprile, Domenico, additional, Meloni, Ilaria, additional, Alessio, Nicola, additional, Mari, Francesca, additional, Manata, Marianna, additional, Lo Rizzo, Caterina, additional, Di Bernardo, Giovanni, additional, Peluso, Gianfranco, additional, Renieri, Alessandra, additional, and Galderisi, Umberto, additional

Published
2023
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114. Correction to: High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

Author

Croci, Susanna, primary, Carriero, Miriam Lucia, additional, Capitani, Katia, additional, Daga, Sergio, additional, Donati, Francesco, additional, Frullanti, Elisa, additional, Lamacchia, Vittoria, additional, Tita, Rossella, additional, Giliberti, Annarita, additional, Valentino, Floriana, additional, Benetti, Elisa, additional, Ciabattini, Annalisa, additional, Furini, Simone, additional, Lo Rizzo, Caterina, additional, Pinto, Anna Maria, additional, Conticello, Silvestro Giovanni, additional, Renieri, Alessandra, additional, and Meloni, Ilaria, additional

Published
2023
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115. Correction: Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

Author

Savige, Judy, primary, Storey, Helen, additional, Watson, Elizabeth, additional, Hertz, Jens Michael, additional, Deltas, Constantinos, additional, Renieri, Alessandra, additional, Mari, Francesca, additional, Hilbert, Pascale, additional, Plevova, Pavlina, additional, Byers, Peter, additional, Cerkauskaite, Agne, additional, Gregory, Martin, additional, Cerkauskiene, Rimante, additional, Ljubanovic, Danica Galesic, additional, Becherucci, Francesca, additional, Errichiello, Carmela, additional, Massella, Laura, additional, Aiello, Valeria, additional, Lennon, Rachel, additional, Hopkinson, Louise, additional, Koziell, Ania, additional, Lungu, Adrian, additional, Rothe, Hansjorg Martin, additional, Hoefele, Julia, additional, Zacchia, Miriam, additional, Martic, Tamara Nikuseva, additional, Gupta, Asheeta, additional, van Eerde, Albertien, additional, Gear, Susie, additional, Landini, Samuela, additional, Palazzo, Viviana, additional, al-Rabadi, Laith, additional, Claes, Kathleen, additional, Corveleyn, Anniek, additional, Van Hoof, Evelien, additional, van Geel, Micheel, additional, Williams, Maggie, additional, Ashton, Emma, additional, Belge, Hendica, additional, Ars, Elisabeth, additional, Bierzynska, Agnieszka, additional, Gangemi, Concetta, additional, and Lipska-Ziętkiewicz, Beata S., additional

Published
2023
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116. Corrigendum: Spondyloocular syndrome: A novel XYLT2 variant with description of the neonatal phenotype

Author

Doddato, Gabriella, primary, Fabbiani, Alessandra, additional, Fallerini, Chiara, additional, Bruttini, Mirella, additional, Hadjistilianou, Theodora, additional, Landi, Martino, additional, Coradeschi, Caterina, additional, Grosso, Salvatore, additional, Tomasini, Barbara, additional, Mencarelli, Maria Antonietta, additional, Renieri, Alessandra, additional, and Ariani, Francesca, additional

Published
2023
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117. Correction: The 2019 and 2021 International workshops on Alport syndrome

Author

Daga, Sergio, primary, Ding, Jie, additional, Deltas, Constantinos, additional, Savige, Judy, additional, Lipska-Ziętkiewicz, Beata S., additional, Hoefele, Julia, additional, Flinter, Frances, additional, Gale, Daniel P., additional, Aksenova, Marina, additional, Kai, Hirofumi, additional, Perin, Laura, additional, Barua, Moumita, additional, Torra, Roser, additional, Miner, Jeff H., additional, Massella, Laura, additional, Ljubanović, Danica Galešić, additional, Lennon, Rachel, additional, Weinstock, Andrè B., additional, Knebelmann, Bertrand, additional, Cerkauskaite, Agne, additional, Gear, Susie, additional, Gross, Oliver, additional, Turner, A. Neil, additional, Baldassarri, Margherita, additional, Pinto, Anna Maria, additional, and Renieri, Alessandra, additional

Published
2023
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118. Correction: New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

Author

Daga, Sergio, primary, Donati, Francesco, additional, Capitani, Katia, additional, Croci, Susanna, additional, Tita, Rossella, additional, Giliberti, Annarita, additional, Valentino, Floriana, additional, Benetti, Elisa, additional, Fallerini, Chiara, additional, Niccheri, Francesca, additional, Baldassarri, Margherita, additional, Mencarelli, Maria Antonietta, additional, Frullanti, Elisa, additional, Furini, Simone, additional, Conticello, Silvestro Giovanni, additional, Renieri, Alessandra, additional, and Pinto, Anna Maria, additional

Published
2023
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119. A Solve-RD ClinVar-based reanalysis of 1,522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Denommé-Pichon, Anne-Sophie, primary, Matalonga, Leslie, additional, de Boer, Elke, additional, Jackson, Adam, additional, Benetti, Elisa, additional, Banka, Siddharth, additional, Bruel, Ange-Line, additional, Ciolfi, Andrea, additional, Clayton-Smith, Jill, additional, Dallapiccola, Bruno, additional, Duffourd, Yannis, additional, Ellwanger, Kornelia, additional, Fallerini, Chiara, additional, Gilissen, Christian, additional, Graessner, Holm, additional, Haack, Tobias B., additional, Havlovicova, Marketa, additional, Hoischen, Alexander, additional, Jean-Marçais, Nolwenn, additional, Kleefstra, Tjitske, additional, López-Martín, Estrella, additional, Macek, Milan, additional, Mencarelli, Maria Antonietta, additional, Moutton, Sébastien, additional, Pfundt, Rolph, additional, Pizzi, Simone, additional, Posada, Manuel, additional, Radio, Francesca Clementina, additional, Renieri, Alessandra, additional, Rooryck, Caroline, additional, Ryba, Lukas, additional, Safraou, Hana, additional, Schwarz, Martin, additional, Tartaglia, Marco, additional, Thauvin-Robinet, Christel, additional, Thevenon, Julien, additional, Mau-Them, Frédéric Tran, additional, Trimouille, Aurélien, additional, Votypka, Pavel, additional, de Vries, Bert B.A., additional, Willemsen, Marjolein H., additional, Zurek, Birte, additional, Verloes, Alain, additional, Philippe, Christophe, additional, Vitobello, Antonio, additional, Vissers, Lisenka E.L.M., additional, and Faivre, Laurence, additional

Published
2023
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120. Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor

Author

Breckpot, Jeroen, Vercruyssen, Marieke, Weyts, Eddy, Vandevoort, Sean, D'Haenens, Greet, Van Buggenhout, Griet, Leempoels, Lore, Brischoux-Boucher, Elise, Van Maldergem, Lionel, Renieri, Alessandra, Mencarelli, Maria Antonietta, D'Angelo, Carla, Mericq, Veronica, Hoffer, Mariette J., Tauber, Maithé, Molinas, Catherine, Castiglioni, Claudia, Brison, Nathalie, Vermeesch, Joris R., Danckaerts, Marina, Sienaert, Pascal, Devriendt, Koenraad, and Vogels, Annick

Published
2016
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121. Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Author

Zguro, Kristina, Baldassarri, Margherita, Fava, Francesca, Beligni, Giada, Daga, Sergio, Leoncini, Roberto, Galasso, Lucrezia, Cirianni, Michele, Rusconi, Stefano, Siano, Matteo, Francisci, Daniela, Schiaroli, Elisabetta, Luchi, Sauro, Morelli, Giovanna, Martinelli, Enrico, Girardis, Massimo, Busani, Stefano, Parisi, Saverio Giuseppe, Panese, Sandro, Piscopo, Carmelo, Capasso, Mario, Tacconi, Danilo, Spertilli Raffaelli, Chiara, Giliberti, Annarita, Gori, Giulia, Katsikis, Peter D, Lorubbio, Maria, Calzoni, Paola, Ognibene, Agostino, Bocchia, Monica, Tozzi, Monica, Bucalossi, Alessandro, Marotta, Giuseppe, Furini, Simone, Gen-Covid Multicenter Study, Null, Renieri, Alessandra, Fallerini, Chiara, GEN-COVID Multicenter Study, Mari, Francesca, Bruttini, Mirella, Meloni, Ilaria, Croci, Susanna, Gabriella, Doddato, Serio, VIOLA BIANCA, Mirjam, Lista, Maffeo, Debora, Pasquinelli, Elena, Ludovica, Mercuri, Brunelli, Giulia, Rossella, Tita, Maria Antonietta Mencarelli, LO RIZZO, Caterina, Pinto, ANNA MARIA, Ariani, Francesca, Montagnani, Francesca, Tumbarello, Mario, Ilaria, Rancan, Massimiliano, Fabbiani, Bargagli, Elena, Bergantini, Laura, D'Alessandro, Miriana, Cameli, Paolo, Bennett, David, Federico, Anedda, Simona, Marcantonio, Scolletta, Sabino, Franchi, Federico, Mazzei, MARIA ANTONIETTA, Susanna, Guerrini, Edoardo, Conticini, Cantarini, Luca, Frediani, Bruno, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Alessandro, Pancrazzi, Massimo, Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Mondelli, Mario U., Stefania, Mantovani, Raffaele, Bruno, Marco, Vecchia, Marcello, Maffezzoni, Sophie, Venturelli, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Arianna, Gabrieli, Agostino, Riva, Andrea, Tommasi, Pier Giorgio Scotton, Francesca, Andretta, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo della Monica, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Giuseppe, Merla, Gabriella Maria Squeo, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Valente, Serafina, Alex Di Florio, Mandala', Marco, Giorli, Alessia, Salerni, Lorenzo, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Cristina, Mussini, Luisa, Tavecchia, Lia, Crotti, Gianfranco, Parati, Roberto, Menè, Maurizio, Sanarico, Gori, Marco, Nicola, Picchiotti, Francesco, Raimondi, Alessandra, Stella, Filippo, Biscarini, Tiziana, Bachetti, Maria Teresa La Rovere, Maurizio, Bussotti, Serena, Ludovisi, Katia, Capitani, Chiara, Gabbi, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Giulia, Micheli, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Davide, Grassi, Claudio, Ferri, Franco, Marinangeli, Francesco, Brancati, Antonella, Vincenti, Valentina, Borgo, Stefania, Lombardi, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Alessio, Bellucci, Marta, Colaneri, Patrizia, Casprini, Cristoforo, Pomara, Massimiliano, Esposito, Marco Antonio Bellini, Zguro, Kristina, Baldassarri, Margherita, Fava, Francesca, Beligni, Giada, Daga, Sergio, Leoncini, Roberto, Galasso, Lucrezia, Cirianni, Michele, Rusconi, Stefano, Siano, Matteo, Francisci, Daniela, Schiaroli, Elisabetta, Luchi, Sauro, Morelli, Giovanna, Martinelli, Enrico, Girardis, Massimo, Busani, Stefano, Parisi, Saverio Giuseppe, Panese, Sandro, Piscopo, Carmelo, Capasso, Mario, Tacconi, Danilo, Spertilli Raffaelli, Chiara, Giliberti, Annarita, Gori, Giulia, Katsikis, Peter D, Lorubbio, Maria, Calzoni, Paola, Ognibene, Agostino, Bocchia, Monica, Tozzi, Monica, Bucalossi, Alessandro, Marotta, Giuseppe, Furini, Simone, Gen-Covid Multicenter Study, Null, Renieri, Alessandra, Fallerini, Chiara, Gen-Covid Multicenter Study, null, and Immunology

Subjects
Thrombotic Thrombocytopenic, Purpura, Thrombotic Thrombocytopenic, SARS-CoV-2, COVID-19, ADAMTS13, thromboembolism, add-on therapy, ADAMTS13 Protein, ADAM Proteins, Infectious Diseases, SDG 3 - Good Health and Well-being, Virology, von Willebrand Factor, Humans, Purpura
Abstract

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF–platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.

Published
2022

122. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Author

Guillaume, Butler-Laporte, Gundula, Povysil, Kosmicki, Jack A., Cirulli, Elizabeth T., Theodore, Drivas, Furini, Simone, Chadi, Saad, Axel, Schmidt, Pawel, Olszewski, Urszula, Korotko, Mathieu, Quinodoz, Elifnaz, Çelik, Kousik, Kundu, Klaudia, Walter, Junghyun, Jung, Stockwell, Amy D., Sloofman, Laura G., Jordan, Daniel M., Thompson, Ryan C., Diane Del Valle, Nicole, Simons, Esther, Cheng, Robert, Sebra, Schadt, Eric E., Seunghee, Kim-Schulze, Sacha, Gnjatic, Miriam, Merad, Buxbaum, Joseph D., Beckmann, Noam D., Charney, Alexander W., Bartlomiej, Przychodzen, Timothy, Chang, Pottinger, Tess D., Ning, Shang, Fabian, Brand, Fava, Francesca, Mari, Francesca, Karolina, Chwialkowska, Magdalena, Niemira, Szymon, Pula, J Kenneth Baillie, Alex, Stuckey, Antonio, Salas, Xabier, Bello, Jacobo, Pardo-Seco, Alberto, Gómez-Carballa, Irene, Rivero-Calle, Federico, Martinón-Torres, Andrea, Ganna, Karczewski, Konrad J., Kumar, Veerapen, Mathieu, Bourgey, Guillaume, Bourque, Robert JM Eveleigh, Vincenzo, Forgetta, David, Morrison, David, Langlais, Mark, Lathrop, Vincent, Mooser, Tomoko, Nakanishi, Robert, Frithiof, Michael, Hultström, Miklos, Lipcsey, Yanara, Marincevic-Zuniga, Jessica, Nordlund, Schiabor Barrett, Kelly M., William, Lee, Alexandre, Bolze, Simon, White, Stephen, Riffle, Francisco, Tanudjaja, Efren, Sandoval, Iva, Neveux, Shaun, Dabe, Nicolas, Casadei, Susanne, Motameny, Manal, Alaamery, Salam, Massadeh, Nora, Aljawini, Almutairi, Mansour S., Arabi, Yaseen M., Alqahtani, Saleh A., Al Harthi, Fawz S., Amal, Almutairi, Fatima, Alqubaishi, Sarah, Alotaibi, Albandari, Binowayn, Alsolm, Ebtehal A., Hadeel El Bardisy, Mohammad, Fawzy, Fang, Cai, Nicole, Soranzo, Adam, Butterworth, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Daga, Sergio, Meloni, Ilaria, Mount Sinai Clinical Intelligence Center, GEN-COVID consortium (Spain), Genomicc, Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Geschwind, Daniel H., Stephanie, Arteaga, Alexis, Stephens, Butte, Manish J., Boutros, Paul C., Yamaguchi, Takafumi N., Shu, Tao, Stefan, Eng, Timothy, Sanders, Tung, Paul J., Broudy, Michael E., Pan, Yu, Alfredo, Gonzalez, Nikhil, Chavan, Ruth, Johnson, Bogdan, Pasaniuc, Brian, Yaspan, Sandra, Smieszek, Carlo, Rivolta, Stephanie, Bibert, Pierre-Yves, Bochud, Maciej, Dabrowski, Pawel, Zawadzki, Mateusz, Sypniewski, Elżbieta, Kaja, Pajaree, Chariyavilaskul, Voraphoj, Nilaratanakul, Nattiya, Hirankarn, Vorasuk, Shotelersuk, Monnat, Pongpanich, Chureerat, Phokaew, Wanna, Chetruengchai, Katsushi, Tokunaga, Masaya, Sugiyama, Yosuke, Kawai, Takanori, Hasegawa, Tatsuhiko, Naito, Namkoong, Ho, Ryuya, Edahiro, Akinori, Kimura, Seishi, Ogawa, Takanori, Kanai, Koichi, Fukunaga, Yukinori, Okada, Seiya, Imoto, Satoru, Miyano, Serghei, Mangul, Abedalthagafi, Malak S., Hugo, Zeberg, Grzymski, Joseph J., Washington, Nicole L., Stephan, Ossowski, Ludwig, Kerstin U., Schulte, Eva C., Olaf, Riess, Marcin, Moniuszko, Miroslaw, Kwasniewski, Hamdi, Mbarek, Ismail, Said I., Anurag, Verma, Goldstein, David B., Krzysztof, Kiryluk, Renieri, Alessandra, Ferreira, Manuel A. R., J Brent Richards, Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack A, Cirulli, Elizabeth T, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy D, Sloofman, Laura G, Jordan, Daniel M, Thompson, Ryan C, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric E, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph D, Beckmann, Noam D, Charney, Alexander W, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess D, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J Kenneth, Stuckey, Alex, Salas, Antonio, Bello, Xabier, Pardo-Seco, Jacobo, Gómez-Carballa, Alberto, Rivero-Calle, Irene, Martinón-Torres, Federico, Ganna, Andrea, Karczewski, Konrad J, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert Jm, Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklo, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly M, Lee, William, Bolze, Alexandre, White, Simon, Riffle, Stephen, Tanudjaja, Francisco, Sandoval, Efren, Neveux, Iva, Dabe, Shaun, Casadei, Nicola, Motameny, Susanne, Alaamery, Manal, Massadeh, Salam, Aljawini, Nora, Almutairi, Mansour S, Arabi, Yaseen M, Alqahtani, Saleh A, Al Harthi, Fawz S, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal A, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, Geschwind, Daniel H, Arteaga, Stephanie, Stephens, Alexi, Butte, Manish J, Boutros, Paul C, Yamaguchi, Takafumi N, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul J, Broudy, Michael E, Pan, Yu, Gonzalez, Alfredo, Chavan, Nikhil, Johnson, Ruth, Pasaniuc, Bogdan, Yaspan, Brian, Smieszek, Sandra, Rivolta, Carlo, Bibert, Stephanie, Bochud, Pierre-Yve, Dabrowski, Maciej, Zawadzki, Pawel, Sypniewski, Mateusz, Kaja, Elżbieta, Chariyavilaskul, Pajaree, Nilaratanakul, Voraphoj, Hirankarn, Nattiya, Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Tokunaga, Katsushi, Sugiyama, Masaya, Kawai, Yosuke, Hasegawa, Takanori, Naito, Tatsuhiko, Namkoong, Ho, Edahiro, Ryuya, Kimura, Akinori, Ogawa, Seishi, Kanai, Takanori, Fukunaga, Koichi, Okada, Yukinori, Imoto, Seiya, Miyano, Satoru, Mangul, Serghei, Abedalthagafi, Malak S, Zeberg, Hugo, Grzymski, Joseph J, Washington, Nicole L, Ossowski, Stephan, Ludwig, Kerstin U, Schulte, Eva C, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said I, Verma, Anurag, Goldstein, David B, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel A R, Richards, J Brent, Data Science Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, University of Helsinki, and Helsinki Institute of Life Science HiLIFE

Subjects
Infectious Medicine, Cancer Research, Host genetics is a key determinant of COVID-19 outcomes. Previously, Infektionsmedicin, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights, Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, Genetics, Humans, Exome, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, SARS-CoV-2, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, 1184 Genetics, developmental biology, physiology, COVID-19, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5, 737 controls, Toll-Like Receptor 7, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, 085 severe disease cases and 571, thereby informing therapeutics development. Here, Medical Genetics, Genome-Wide Association Study
Abstract

Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Published
2022

123. Coffin–Siris and Nicolaides–Baraitser syndromes are a common well recognizable cause of intellectual disability

Author

Mari, Francesca, Marozza, Annabella, Mencarelli, Maria Antonietta, Lo Rizzo, Caterina, Fallerini, Chiara, Dosa, Laura, Di Marco, Chiara, Carignani, Giulia, Baldassarri, Margherita, Cianci, Paola, Vivarelli, Rossella, Vascotto, Marina, Grosso, Salvatore, Rubegni, Pietro, Caffarelli, Carla, Pretegiani, Elena, Fimiani, Michele, Garavelli, Livia, Cristofoli, Francesca, Vermeesch, Joris R., Nuti, Ranuccio, Dotti, Maria Teresa, Balestri, Paolo, Hayek, Joussef, Selicorni, Angelo, and Renieri, Alessandra

Published
2015
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124. Positive predictive values and outcomes for uninformative cell‐free DNA tests: An Italian multicentric Cytogenetic and cytogenomic Audit of diagnOstic testing (ICARO study)

Author

Grati, Francesca Romana, primary, Bestetti, Ilaria, additional, De Siero, Daria, additional, Malvestiti, Francesca, additional, Villa, Nicoletta, additional, Sala, Elena, additional, Crosti, Francesca, additional, Parisi, Valentina, additional, Nardone, Anna Maria, additional, Di Giacomo, Gianluca, additional, Pettinari, Antonella, additional, Tortora, Giada, additional, Montaldi, Annamaria, additional, Calò, Annapaola, additional, Saccilotto, Donatella, additional, Zanchetti, Sara, additional, Celli, Paola, additional, Guerneri, Silvana, additional, Silipigni, Rosamaria, additional, Cardarelli, Laura, additional, Lippi, Elisabetta, additional, Cavani, Simona, additional, Malacarne, Michela, additional, Genesio, Rita, additional, Beltrami, Nicola, additional, Pittalis, Maria Carla, additional, Desiderio, Laura, additional, Gentile, Mattia, additional, Ficarella, Romina, additional, Recalcati, Maria Paola, additional, Catusi, Ilaria, additional, Garzo, Maria, additional, Miele, Lorena, additional, Corti, Cecilia, additional, Ghezzo, Sara, additional, Bertini, Veronica, additional, Cambi, Francesca, additional, Valetto, Angelo, additional, Facchinetti, Barbara, additional, Bernardini, Laura, additional, Capalbo, Anna, additional, Balducci, Federica, additional, Pelo, Elisabetta, additional, Minuti, Barbara, additional, Pescucci, Chiara, additional, Giuliani, Costanza, additional, Renieri, Alessandra, additional, Longo, Ilaria, additional, Tita, Rossella, additional, Castello, Giuseppe, additional, Casalone, Rosario, additional, Righi, Rossana, additional, Raso, Barbara, additional, Civolani, Alessandro, additional, Muzi, Maria Cristina, additional, di Natale, Manuela, additional, Varriale, Luigia, additional, Gasperini, Daniela, additional, Nuzzi, Maria Cristina, additional, Cellamare, Angelo, additional, Casieri, Paola, additional, Busuito, Rosa, additional, Ceccarini, Caterina, additional, Cesarano, Carla, additional, Privitera, Orsola, additional, Melani, Daniela, additional, Menozzi, Cristina, additional, Falcinelli, Cristina, additional, Calabrese, Olga, additional, Battaglia, Paola, additional, Tanzariello, Antonella, additional, Stampalija, Tamara, additional, Ardisia, Carmela, additional, Gasparini, Paolo, additional, Benn, Peter, additional, and Novelli, Antonio, additional

Published
2022
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125. Digenic Alport Syndrome

Author

Savige, Judy, primary, Renieri, Alessandra, additional, Ars, Elisabet, additional, Daga, Sergio, additional, Pinto, Anna Maria, additional, Rothe, Hansjorg, additional, Gale, Daniel P., additional, Aksenova, Marina, additional, Cerkauskaite, Agne, additional, Bielska, Olga, additional, Lipska-Zietkiewicz, Beata, additional, and Gibson, Joel T., additional

Published
2022
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126. Expanding the clinical spectrum associated with the PACS1 p.Arg203Trp mutational hot‐spot: Two additional Italian patients

Author

Bruno, Lucia Pia, primary, Doddato, Gabriella, additional, Baldassarri, Margherita, additional, Rizzo, Caterina Lo, additional, Resciniti, Sara, additional, Bruttini, Mirella, additional, Mirjam, Lista, additional, Zguro, Kristina, additional, Furini, Simone, additional, Mencarelli, Maria Antonietta, additional, Renieri, Alessandra, additional, and Ariani, Francesca, additional

Published
2022
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127. Solving unsolved rare neurological diseases-a Solve-RD viewpoint

Author

Schüle, Rebecca, Timmann, Dagmar, Erasmus, Corrie E., Reichbauer, Jennifer, Wayand, Melanie, Solve-RD-DITF-RND Baets Jonathan Balicza Peter Chinnery Patrick Dürr Alexandra Haack Tobias Hengel Holger Horvath Rita Houlden Henry Kamsteeg Erik-Jan Kamsteeg Christoph Lohmann Katja Macaya Alfons Marcé-Grau Anna Maver Ales Molnar Judit Münchau Alexander Peterlin Borut Riess Olaf Schöls Ludger European Reference Network for Rare Neurological Diseases, Tübingen, Germany Schüle Rebecca European Reference Network for Rare Neurological Diseases, Tübingen, Germany Stevanin Giovanni Synofzik Matthis European Reference Network for Rare Neurological Diseases, Tübingen, Germany Timmerman Vincent van de Warrenburg Bart Department of Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands van Os Nienke Vandrovcova Jana Wayand Melanie German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany Wilke Carlo German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany, Baets, Jonathan, Balicza, Peter, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Horvath, Rita, Houlden, Henry, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, van de Warrenburg, Bart, van Os, Nienke, Vandrovcova, Jana, Wilke, Carlo, Bevot, Andrea, Zuchner, Stephan, Beltran, Sergi, Laurie, Steven, Matalonga, Leslie, Graessner, Holm, The Solve-RD Consortium Graessner Holm Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany Zurek Birte Ellwanger Kornelia Ossowski Stephan Demidov German Sturm Marc Schulze-Hentrich Julia M. Heutink Peter Brunner Han Scheffer Hans Hoogerbrugge Nicoline Hoischen Alexander ’t Hoen Peter A. C. Vissers Lisenka E. L. M. Gilissen Christian Steyaert Wouter Sablauskas Karolis de Voer Richarda M. Janssen Erik de Boer Elke Steehouwer Marloes Yaldiz Burcu Kleefstra Tjitske Brookes Anthony J. Veal Colin Gibson Spencer Wadsley Marc Mehtarizadeh Mehdi Riaz Umar Warren Greg Dizjikan Farid Yavari Shorter Thomas Töpf Ana Straub Volker Bettolo Chiara Marini Specht Sabine Clayton-Smith Jill Banka Siddharth Alexander Elizabeth Jackson Adam Faivre Laurence Thauvin Christel Vitobello Antonio Denommé-Pichon Anne-Sophie Duffourd Yannis Tisserant Emilie Bruel Ange-Line Peyron Christine Pélissier Aurore Beltran Sergi Facultat de Biologia, Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona (UB), Barcelona, Spain Gut Ivo Glynne Laurie Steven CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Piscia Davide Matalonga Leslie CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Papakonstantinou Anastasios Bullich Gemma Corvo Alberto Garcia Carles Fernandez-Callejo Marcos Hernández Carles Picó Daniel Paramonov Ida Lochmüller Hanns Gumus Gulcin Bros-Facer Virginie Rath Ana Hanauer Marc Olry Annie Lagorce David Havrylenko Svitlana Izem Katia Rigour Fanny Durr Alexandra Davoine Claire-Sophie Guillot-Noel Léna Heinzmann Anna Coarelli Giulia Bonne Gisèle Evangelista Teresinha Allamand Valérie Nelson Isabelle Yaou Rabah Ben Metay Corinne Eymard Bruno Cohen Enzo Atalaia Antonio Stojkovic Tanya Macek Milan Jr. Turnovec Marek Thomasová Dana Kremliková Radka Pourová Franková Vera Havlovicová Markéta Kremlik Vlastimil Parkinson Helen Keane Thomas Spalding Dylan Senf Alexander Robinson Peter Danis Daniel Robert Glenn Costa Alessia Patch Christine Hanna Mike Houlden Henry Reilly Mary Vandrovcova Jana Muntoni Francesco Zaharieva Irina Sarkozy Anna de Jonghe Peter Nigro Vincenzo Banfi Sandro Torella Annalaura Musacchia Francesco Piluso Giulio Ferlini Alessandra Selvatici Rita Rossi Rachele Neri Marcella Aretz Stefan Spier Isabel Sommer Anna Katharina Peters Sophia Oliveira Carla Pelaez Jose Garcia Matos Ana Rita José Celina São Ferreira Marta Gullo Irene Fernandes Susana Garrido Luzia Ferreira Pedro Carneiro Fátima Swertz Morris A. Johansson Lennart van der Velde Joeri K. van der Vries Gerben Neerincx Pieter B. Roelofs-Prins Dieuwke Köhler Sebastian Metcalfe Alison Verloes Alain Drunat Séverine Rooryck Caroline Trimouille Aurelien Castello Raffaele Morleo Manuela Pinelli Michele Varavallo Alessandra De la Paz Manuel Posada Sánchez Eva Bermejo Martín Estrella López Delgado Beatriz Martínez de la Rosa F. Javier Alonso García Ciolfi Andrea Dallapiccola Bruno Pizzi Simone Radio Francesca Clementina Tartaglia Marco Renieri Alessandra Benetti Elisa Balicza Peter Molnar Maria Judit Maver Ales Peterlin Borut Münchau Alexander Lohmann Katja Herzog Rebecca Pauly Martje Macaya Alfons Marcé-Grau Anna Osorio Andres Nascimiento de Benito Daniel Natera Lochmüller Hanns Thompson Rachel Polavarapu Kiran Beeson David Cossins Judith Cruz Pedro M. Rodriguez Hackman Peter Johari Mridul Savarese Marco Udd Bjarne Horvath Rita Capella Gabriel Valle Laura Holinski-Feder Elke Laner Andreas Steinke-Lange Verena Schröck Evelin Rump Andreas, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoischen, Alexander, ’t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Gilissen, Christian, Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Spalding, Dylan, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Solve-RD-DITF-RND, Solve-RD Consortium, Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., van de Warrenburg, B., Schols, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Synofzik, M., Nigro, V., Banfi, S., Torella, A., Piluso, G., Medicum, University of Helsinki, Department of Medical and Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Wilke, Carlo [0000-0002-7250-8597], Beltran, Sergi [0000-0002-2810-3445], Laurie, Steven [0000-0003-3913-5829], Graessner, Holm [0000-0001-9803-7183], Synofzik, Matthis [0000-0002-2280-7273], and Apollo - University of Cambridge Repository

Subjects
genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Datasets as Topic, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, Genetics (clinical), 0303 health sciences, methods [Genomics], Management science, Neurodevelopmental disorders, Neurodegenerative diseases, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetics [Nervous System Diseases], 3. Good health, Chemistry, Practice Guidelines as Topic, Malalties rares, pathology [Rare Diseases], methods [Genetic Testing], Movement disorders, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Socio-culturale, standards [Exome Sequencing], standards [Genetic Testing], pathology [Nervous System Diseases], 03 medical and health sciences, Rare Diseases, Viewpoint, Exome Sequencing, Genetics, Humans, Genetic Testing, ddc:610, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Sistema nerviós -- Malalties, methods [Exome Sequencing], standards [Genomics], 3111 Biomedicine, Human medicine, Nervous System Diseases, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

Rare genetic neurological disorders (RND; ORPHA:71859) are a heterogeneous group of disorders comprising >1700 distinct genetic disease entities. However, genetic discoveries have not yet translated into dramatic increases of diagnostic yield and indeed rates of molecular genetic diagnoses have been stuck at about 30–50% across NGS modalities and RND phenotypes [1, 2]. Existence of yet unknown disease genes as well as shortcomings of commonly employed NGS technologies and analysis pipelines in detecting certain variant types are typically cited to explain the low diagnosis rates. To increase the diagnostic yield in RNDs - one of the four focus disease groups in Solve-RD - we follow two major approaches, that we will here present and exemplify: (i) systematic state-of the art re-analysis of large cohorts of unsolved whole-exome/genome sequencing (WES/WGS) RND datasets; and (ii) novel-omics approaches. Based on the way Solve-RD systematically organizes researchers’ expertise to channel this approach [3], the European Reference Network for Rare Neurological Diseases (ERN-RND) has established its own Data Interpretation Task Force (DITF) within SOLVE-RD, which is currently composed of clinical and genetic experts from 29 sites in 15 European countries. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (Grant Numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (Grant Numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. The study was further funded by the Federal Ministry of Education and Research, Germany, through the TreatHSP network (01GM1905 to RS and LS), the National Institute of Neurological Diseases and Stroke (R01NS072248 to SZ and RS), the European Joint Program on Rare Diseases-EJP-RD COFUND-EJP N° 825575 through funding for the PROSPAX consortium (441409627 to MS, RS and BvW). CW was supported by the PATE program of the Medical Faculty, University of Tübingen. CEE received support from the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund. Authors on this paper are members of the European Reference Network for Rare Neurological Diseases (ERN-RND, Project ID 739510)

Published
2021

129. Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Author

NordForsk, Academy of Finland, Canadian Institutes of Health Research, Lady Davis Institute, Canada Foundation for Innovation, Cancer Research UK, National Institutes of Health (US), Genome Canada, Japan Society for the Promotion of Science, European Commission, Medical Research Council (UK), National Institute for Health Research (UK), Wellcome Trust, German Research Foundation, Federal Ministry of Education and Research (Germany), Instituto de Salud Carlos III, Junta de Andalucía, Columbia University, Università degli Studi di Siena, Ministero della Salute, Consejo Superior de Investigaciones Científicas (España), Swedish Research Council, Technical University of Munich, University of Helsinki, Nakanishi, Tomoko [0000-0001-9510-5646], Pigazzini, Sara [0000-0002-0641-9393], Cordioli, Mattia [0000-0002-4872-0520], Butler-Laporte, Guillaume [0000-0001-5388-0396], Maya-Miles, Douglas [0000-0002-0669-6526], Nafria Jimenez, Beatriz [0000-0002-4698-5680], Bouysran, Youssef [0000-0003-1368-6550], Niemi, Mari [0000-0003-0696-6175], Palom, Adriana [0000-0002-0130-1302], Ellinghaus, David [0000-0002-4332-6110], Khan, Atlas [0000-0002-6651-2725], Martínez-Bueno, Manuel [0000-0002-4333-4487], Roade, Luisa [0000-0002-8160-9613], Fava, Francesca [0000-0002-4363-2353], Spinner, Christoph D. [0000-0002-3875-5367], Prati, Daniele [0000-0002-2281-7498], Bernardo, David [0000-0002-2843-6696], Darcis, Gilles [0000-0001-8192-1351], Fernández-Cadenas, Israel [0000-0003-4821-2363], Holter, Jan Cato [0000-0003-1618-5022], Frithiof, Robert [0000-0003-2278-7951], Kiryluk, Krzysztof [0000-0002-5047-6715], Duga, Stefano [0000-0003-3457-1410], Asselta, Rosanna [0000-0001-5351-0619], Pereira, Alexandre [0000-0002-7782-5540], Romero-Gómez, Manuel [0000-0001-8494-8947], Hov, Johannes R. [0000-0002-5900-8096], Migeotte, Isabelle [0000-0002-8972-8211], Renieri, Alessandra [0000-0002-0846-9220], Planas, Anna M. [0000-0002-6147-1880], Ludwig, Kerstin [0000-0002-8541-2519], Buti, María [0000-0002-0732-3078], Rahmouni, Souad [0000-0003-0956-0242], Alarcón-Riquelme, M. E. [0000-0002-7632-4154], Schulte, Eva C. [0000-0003-3105-5672], Karlsen, Tom H. [0000-0002-8289-9931], Valenti, Luca [0000-0001-8909-0345], Zeberg, Hugo [0000-0001-7118-1249], Richards, Brent [0000-0002-3746-9086], Ganna, Andrea [0000-0002-8147-240X], Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Cordioli, Mattia, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Nafría-Jiménez, Beatriz, Bouysran, Youssef, Niemi, Mari, Palom, Adriana, Ellinghaus, David, Khan, Atlas, Martínez-Bueno, Manuel, Rolker, Selina, Amitano, Sara, Roade, Luisa, FinnGen, The COVID-19 Host Genetics Initiative, Fava, Francesca, Spinner, Christoph D., Prati, Daniele, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesús M., Frithiof, Robert, Kiryluk, Krzysztof, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre, Romero-Gómez, Manuel, Bujanda, Luis, Hov, Johannes R., Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M., Ludwig, Kerstin, Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Franke, Andre, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, NordForsk, Academy of Finland, Canadian Institutes of Health Research, Lady Davis Institute, Canada Foundation for Innovation, Cancer Research UK, National Institutes of Health (US), Genome Canada, Japan Society for the Promotion of Science, European Commission, Medical Research Council (UK), National Institute for Health Research (UK), Wellcome Trust, German Research Foundation, Federal Ministry of Education and Research (Germany), Instituto de Salud Carlos III, Junta de Andalucía, Columbia University, Università degli Studi di Siena, Ministero della Salute, Consejo Superior de Investigaciones Científicas (España), Swedish Research Council, Technical University of Munich, University of Helsinki, Nakanishi, Tomoko [0000-0001-9510-5646], Pigazzini, Sara [0000-0002-0641-9393], Cordioli, Mattia [0000-0002-4872-0520], Butler-Laporte, Guillaume [0000-0001-5388-0396], Maya-Miles, Douglas [0000-0002-0669-6526], Nafria Jimenez, Beatriz [0000-0002-4698-5680], Bouysran, Youssef [0000-0003-1368-6550], Niemi, Mari [0000-0003-0696-6175], Palom, Adriana [0000-0002-0130-1302], Ellinghaus, David [0000-0002-4332-6110], Khan, Atlas [0000-0002-6651-2725], Martínez-Bueno, Manuel [0000-0002-4333-4487], Roade, Luisa [0000-0002-8160-9613], Fava, Francesca [0000-0002-4363-2353], Spinner, Christoph D. [0000-0002-3875-5367], Prati, Daniele [0000-0002-2281-7498], Bernardo, David [0000-0002-2843-6696], Darcis, Gilles [0000-0001-8192-1351], Fernández-Cadenas, Israel [0000-0003-4821-2363], Holter, Jan Cato [0000-0003-1618-5022], Frithiof, Robert [0000-0003-2278-7951], Kiryluk, Krzysztof [0000-0002-5047-6715], Duga, Stefano [0000-0003-3457-1410], Asselta, Rosanna [0000-0001-5351-0619], Pereira, Alexandre [0000-0002-7782-5540], Romero-Gómez, Manuel [0000-0001-8494-8947], Hov, Johannes R. [0000-0002-5900-8096], Migeotte, Isabelle [0000-0002-8972-8211], Renieri, Alessandra [0000-0002-0846-9220], Planas, Anna M. [0000-0002-6147-1880], Ludwig, Kerstin [0000-0002-8541-2519], Buti, María [0000-0002-0732-3078], Rahmouni, Souad [0000-0003-0956-0242], Alarcón-Riquelme, M. E. [0000-0002-7632-4154], Schulte, Eva C. [0000-0003-3105-5672], Karlsen, Tom H. [0000-0002-8289-9931], Valenti, Luca [0000-0001-8909-0345], Zeberg, Hugo [0000-0001-7118-1249], Richards, Brent [0000-0002-3746-9086], Ganna, Andrea [0000-0002-8147-240X], Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Cordioli, Mattia, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Nafría-Jiménez, Beatriz, Bouysran, Youssef, Niemi, Mari, Palom, Adriana, Ellinghaus, David, Khan, Atlas, Martínez-Bueno, Manuel, Rolker, Selina, Amitano, Sara, Roade, Luisa, FinnGen, The COVID-19 Host Genetics Initiative, Fava, Francesca, Spinner, Christoph D., Prati, Daniele, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesús M., Frithiof, Robert, Kiryluk, Krzysztof, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre, Romero-Gómez, Manuel, Bujanda, Luis, Hov, Johannes R., Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M., Ludwig, Kerstin, Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Franke, Andre, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Richards, Brent, and Ganna, Andrea

Abstract

Background There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk fact

Published
2021

130. The Autoinflammatory Diseases Alliance Registry of monogenic autoinflammatory diseases

Author

Gaggiano, Carla, primary, Vitale, Antonio, additional, Tufan, Abdurrahman, additional, Ragab, Gaafar, additional, Aragona, Emma, additional, Wiesik-Szewczyk, Ewa, additional, Ait-Idir, Djouher, additional, Conti, Giovanni, additional, Iezzi, Ludovica, additional, Maggio, Maria Cristina, additional, Cattalini, Marco, additional, Torre, Francesco La, additional, Lopalco, Giuseppe, additional, Verrecchia, Elena, additional, Paulis, Amato de, additional, Sahin, Ali, additional, Insalaco, Antonella, additional, Sfikakis, Petros P., additional, Marino, Achille, additional, Frassi, Micol, additional, Ogunjimi, Benson, additional, Opris-Belinski, Daniela, additional, Parronchi, Paola, additional, Emmi, Giacomo, additional, Shahram, Farhad, additional, Ciccia, Francesco, additional, Piga, Matteo, additional, Hernández-Rodríguez, José, additional, Pereira, Rosa Maria R., additional, Alessio, Maria, additional, Naddei, Roberta, additional, Olivieri, Alma Nunzia, additional, Giudice, Emanuela Del, additional, Sfriso, Paolo, additional, Ruscitti, Piero, additional, Gobbi, Francesca Li, additional, Kucuk, Hamit, additional, Sota, Jurgen, additional, Hussein, Mohamed A., additional, Malizia, Giuseppe, additional, Jahnz-Różyk, Karina, additional, Sari-Hamidou, Rawda, additional, Romeo, Mery, additional, Ricci, Francesca, additional, Cardinale, Fabio, additional, Iannone, Florenzo, additional, Casa, Francesca Della, additional, Natale, Marco Francesco, additional, Laskari, Katerina, additional, Giani, Teresa, additional, Franceschini, Franco, additional, Sabato, Vito, additional, Yildirim, Derya, additional, Caggiano, Valeria, additional, Hegazy, Mohamed Tharwat, additional, Marzo, Rosalba Di, additional, Kucharczyk, Aleksandra, additional, Khellaf, Ghalia, additional, Tarsia, Maria, additional, Almaghlouth, Ibrahim A., additional, Laymouna, Ahmed Hatem, additional, Mastrorilli, Violetta, additional, Dotta, Laura, additional, Benacquista, Luca, additional, Grosso, Salvatore, additional, Crisafulli, Francesca, additional, Parretti, Veronica, additional, Giordano, Heitor F., additional, Mahmoud, Ayman Abdel-Monem Ahmed, additional, Nuzzolese, Rossana, additional, Musso, Marta De, additional, Chighizola, Cecilia Beatrice, additional, Gentileschi, Stefano, additional, Morrone, Mirella, additional, Cola, Ilenia Di, additional, Spedicato, Veronica, additional, Giardini, Henrique A. Mayrink, additional, Vasi, Ibrahim, additional, Renieri, Alessandra, additional, Fabbiani, Alessandra, additional, Mencarelli, Maria Antonietta, additional, Frediani, Bruno, additional, Balistreri, Alberto, additional, Tosi, Gian Marco, additional, Fabiani, Claudia, additional, Lidar, Merav, additional, Rigante, Donato, additional, and Cantarini, Luca, additional

Published
2022
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132. Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity

Author

Zhang, Sai, primary, Cooper-Knock, Johnathan, additional, Weimer, Annika K., additional, Shi, Minyi, additional, Kozhaya, Lina, additional, Unutmaz, Derya, additional, Harvey, Calum, additional, Julian, Thomas H., additional, Furini, Simone, additional, Frullanti, Elisa, additional, Fava, Francesca, additional, Renieri, Alessandra, additional, Gao, Peng, additional, Shen, Xiaotao, additional, Timpanaro, Ilia Sarah, additional, Kenna, Kevin P., additional, Baillie, J. Kenneth, additional, Davis, Mark M., additional, Tsao, Philip S., additional, and Snyder, Michael P., additional

Published
2022
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133. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD

Author

Pavinato, Lisa, primary, Delle Vedove, Andrea, additional, Carli, Diana, additional, Ferrero, Marta, additional, Carestiato, Silvia, additional, Howe, Jennifer L, additional, Agolini, Emanuele, additional, Coviello, Domenico A, additional, van de Laar, Ingrid, additional, Au, Ping Yee Billie, additional, Di Gregorio, Eleonora, additional, Fabbiani, Alessandra, additional, Croci, Susanna, additional, Mencarelli, Maria Antonietta, additional, Bruno, Lucia P, additional, Renieri, Alessandra, additional, Veltra, Danai, additional, Sofocleous, Christalena, additional, Faivre, Laurence, additional, Mazel, Benoit, additional, Safraou, Hana, additional, Denommé-Pichon, Anne-Sophie, additional, van Slegtenhorst, Marjon A, additional, Giesbertz, Noor, additional, van Jaarsveld, Richard H, additional, Childers, Anna, additional, Rogers, R Curtis, additional, Novelli, Antonio, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph D, additional, Scherer, Stephen W, additional, Ferrero, Giovanni Battista, additional, Wirth, Brunhilde, additional, and Brusco, Alfredo, additional

Published
2022
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134. Natural history of KBG syndrome in a large European cohort

Author

Loberti, Lorenzo, primary, Bruno, Lucia Pia, additional, Granata, Stefania, additional, Doddato, Gabriella, additional, Resciniti, Sara, additional, Fava, Francesca, additional, Carullo, Michele, additional, Rahikkala, Elisa, additional, Jouret, Guillaume, additional, Menke, Leonie A, additional, Lederer, Damien, additional, Vrielynck, Pascal, additional, Ryba, Lukáš, additional, Brunetti-Pierri, Nicola, additional, Lasa-Aranzasti, Amaia, additional, Cueto-González, Anna Maria, additional, Trujillano, Laura, additional, Valenzuela, Irene, additional, Tizzano, Eduardo F, additional, Spinelli, Alessandro Mauro, additional, Bruno, Irene, additional, Currò, Aurora, additional, Stanzial, Franco, additional, Benedicenti, Francesco, additional, Lopergolo, Diego, additional, Santorelli, Filippo Maria, additional, Aristidou, Constantia, additional, Tanteles, George A, additional, Maystadt, Isabelle, additional, Tkemaladze, Tinatin, additional, Reimand, Tiia, additional, Lokke, Helen, additional, Õunap, Katrin, additional, Haanpää, Maria K, additional, Holubová, Andrea, additional, Zoubková, Veronika, additional, Schwarz, Martin, additional, Žordania, Riina, additional, Muru, Kai, additional, Roht, Laura, additional, Tihveräinen, Annika, additional, Teek, Rita, additional, Thomson, Ulvi, additional, Atallah, Isis, additional, Superti-Furga, Andrea, additional, Buoni, Sabrina, additional, Canitano, Roberto, additional, Scandurra, Valeria, additional, Rossetti, Annalisa, additional, Grosso, Salvatore, additional, Battini, Roberta, additional, Baldassarri, Margherita, additional, Mencarelli, Maria Antonietta, additional, Rizzo, Caterina Lo, additional, Bruttini, Mirella, additional, Mari, Francesca, additional, Ariani, Francesca, additional, Renieri, Alessandra, additional, and Pinto, Anna Maria, additional

Published
2022
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135. Development and Implementation of the AIDA International Registry for Patients With VEXAS Syndrome

Author

Vitale, Antonio, primary, Caggiano, Valeria, additional, Della Casa, Francesca, additional, Hernández-Rodríguez, José, additional, Frassi, Micol, additional, Monti, Sara, additional, Tufan, Abdurrahman, additional, Telesca, Salvatore, additional, Conticini, Edoardo, additional, Ragab, Gaafar, additional, Lopalco, Giuseppe, additional, Almaghlouth, Ibrahim, additional, Pereira, Rosa Maria R., additional, Yildirim, Derya, additional, Cattalini, Marco, additional, Marino, Achille, additional, Giani, Teresa, additional, La Torre, Francesco, additional, Ruscitti, Piero, additional, Aragona, Emma, additional, Wiesik-Szewczyk, Ewa, additional, Del Giudice, Emanuela, additional, Sfikakis, Petros P., additional, Govoni, Marcello, additional, Emmi, Giacomo, additional, Maggio, Maria Cristina, additional, Giacomelli, Roberto, additional, Ciccia, Francesco, additional, Conti, Giovanni, additional, Ait-Idir, Djouher, additional, Lomater, Claudia, additional, Sabato, Vito, additional, Piga, Matteo, additional, Sahin, Ali, additional, Opris-Belinski, Daniela, additional, Ionescu, Ruxandra, additional, Bartoloni, Elena, additional, Franceschini, Franco, additional, Parronchi, Paola, additional, de Paulis, Amato, additional, Espinosa, Gerard, additional, Maier, Armin, additional, Sebastiani, Gian Domenico, additional, Insalaco, Antonella, additional, Shahram, Farhad, additional, Sfriso, Paolo, additional, Minoia, Francesca, additional, Alessio, Maria, additional, Makowska, Joanna, additional, Hatemi, Gülen, additional, Akkoç, Nurullah, additional, Li Gobbi, Francesca, additional, Gidaro, Antonio, additional, Olivieri, Alma Nunzia, additional, Al-Mayouf, Sulaiman M., additional, Erten, Sükran, additional, Gentileschi, Stefano, additional, Vasi, Ibrahim, additional, Tarsia, Maria, additional, Mahmoud, Ayman Abdel-Monem Ahmed, additional, Frediani, Bruno, additional, Fares Alzahrani, Musa, additional, Laymouna, Ahmed Hatem, additional, Ricci, Francesca, additional, Cardinale, Fabio, additional, Jahnz-Rózyk, Karina, additional, Tosi, Gian Marco, additional, Crisafulli, Francesca, additional, Balistreri, Alberto, additional, Dagostin, Marília A., additional, Ghanema, Mahmoud, additional, Gaggiano, Carla, additional, Sota, Jurgen, additional, Di Cola, Ilenia, additional, Fabiani, Claudia, additional, Giardini, Henrique A. Mayrink, additional, Renieri, Alessandra, additional, Fabbiani, Alessandra, additional, Carrer, Anna, additional, Bocchia, Monica, additional, Caroni, Federico, additional, Rigante, Donato, additional, and Cantarini, Luca, additional

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2022
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138. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author

de Boer, Elke, Ockeloen, Charlotte W., Matalonga, Leslie, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Peters, Sophia, Paramonov, Ida, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vitobello, Antonio, Rodenburg, Richard J., Coenen, Marieke J. H., Janssen, Mirian, Henssen, Dylan, Banka, Siddharth, Benetti, Elisa, Casari, Giorgio, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Ellwanger, Kornelia, Faivre, Laurence, Graessner, Holm, Haack, Tobias B., Hammarsjö, Anna, Havlovicova, Marketa, Hoischen, Alexander, Hugon, Anne, Jackson, Adam, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Macek, Milan, Morleo, Manuela, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Verloes, Alain, Vissers, Lisenka, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Trimouille, Aurélien, Vissers, Lisenka E. L. M., Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Research Council, Evelyn Trust, Newton Fund, European Project: 825619,AI4EU, Dutch Research Council (Holanda), Medical Research Council (Reino Unido), Lily Foundation, Unión Europea. Comisión Europea. H2020, Ockeloen, Charlotte W [0000-0003-0329-1520], Horvath, Rita [0000-0002-9841-170X], Rodenburg, Richard J [0000-0001-5227-3527], Gilissen, Christian [0000-0003-1693-9699], Steyaert, Wouter [0000-0001-8393-0788], Trimouille, Aurélien [0000-0002-3457-5684], Verloes, Alain [0000-0003-4819-0264], Vissers, Lisenka ELM [0000-0001-6470-5497], Apollo - University of Cambridge Repository, de Boer, E., Ockeloen, C. W., Matalonga, L., Horvath, R., Rodenburg, R. J., Coenen, M. J. H., Janssen, M., Henssen, D., Gilissen, C., Steyaert, W., Paramonov, I., Trimouille, A., Kleefstra, T., Verloes, A., Vissers, L. E. L. M., Nigro, V., Torella, A., and Banfi, S.

Subjects
Male, Proband, Mitochondrial DNA, RNA, Transfer, Leu, Brief Communication, Quadriplegia, Whole Exome Sequencing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Genetics research, Intellectual disability, Genetics, medicine, Humans, Genetics (clinical), Exome sequencing, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Neurodevelopmental disorders, 030305 genetics & heredity, Correction, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Translational research, medicine.disease, Heteroplasmy, 3. Good health, MT-TL1, Mutation, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Spastic tetraparesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological disorders, 030217 neurology & neurosurgery
Abstract

Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí

Published
2021

139. Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Author

Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Cordioli, Mattia, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Nafria Jimenez, Beatriz, Bouysran, Youssef, Niemi, Mari, Palom, Adriana, Ellinghaus, David, Khan, Atlas, Martínez-Bueno, Manuel, Rolker, Selina, Amitano, Sara, Roade, Luisa, FinnGen, The COVID-19 Host Genetics Initiative, Fava, Francesca, Spinner, Christoph D., Prati, Daniele, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesús M., Frithiof, Robert, Kiryluk, Krzysztof, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre, Romero-Gómez, Manuel, Bujanda, Luis, Hov, Johannes R., Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M., Ludwig, Kerstin, Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Franke, Andre, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, NordForsk, Academy of Finland, Canadian Institutes of Health Research, Lady Davis Institute, Canada Foundation for Innovation, Cancer Research UK, National Institutes of Health (US), Genome Canada, Japan Society for the Promotion of Science, European Commission, Medical Research Council (UK), National Institute for Health Research (UK), Wellcome Trust, German Research Foundation, Federal Ministry of Education and Research (Germany), Instituto de Salud Carlos III, Junta de Andalucía, Columbia University, Università degli Studi di Siena, Ministero della Salute, Consejo Superior de Investigaciones Científicas (España), Swedish Research Council, Technical University of Munich, University of Helsinki, Nakanishi, Tomoko [0000-0001-9510-5646], Pigazzini, Sara [0000-0002-0641-9393], Cordioli, Mattia [0000-0002-4872-0520], Butler-Laporte, Guillaume [0000-0001-5388-0396], Maya-Miles, Douglas [0000-0002-0669-6526], Nafria Jimenez, Beatriz [0000-0002-4698-5680], Bouysran, Youssef [0000-0003-1368-6550], Niemi, Mari [0000-0003-0696-6175], Palom, Adriana [0000-0002-0130-1302], Ellinghaus, David [0000-0002-4332-6110], Khan, Atlas [0000-0002-6651-2725], Martínez-Bueno, Manuel [0000-0002-4333-4487], Roade, Luisa [0000-0002-8160-9613], Fava, Francesca [0000-0002-4363-2353], Spinner, Christoph D. [0000-0002-3875-5367], Prati, Daniele [0000-0002-2281-7498], Bernardo, David [0000-0002-2843-6696], Darcis, Gilles [0000-0001-8192-1351], Fernández-Cadenas, Israel [0000-0003-4821-2363], Holter, Jan Cato [0000-0003-1618-5022], Frithiof, Robert [0000-0003-2278-7951], Kiryluk, Krzysztof [0000-0002-5047-6715], Duga, Stefano [0000-0003-3457-1410], Asselta, Rosanna [0000-0001-5351-0619], Pereira, Alexandre [0000-0002-7782-5540], Romero-Gómez, Manuel [0000-0001-8494-8947], Hov, Johannes R. [0000-0002-5900-8096], Migeotte, Isabelle [0000-0002-8972-8211], Renieri, Alessandra [0000-0002-0846-9220], Planas, Anna M. [0000-0002-6147-1880], Ludwig, Kerstin [0000-0002-8541-2519], Buti, María [0000-0002-0732-3078], Rahmouni, Souad [0000-0003-0956-0242], Alarcón-Riquelme, M. E. [0000-0002-7632-4154], Schulte, Eva C. [0000-0003-3105-5672], Karlsen, Tom H. [0000-0002-8289-9931], Valenti, Luca [0000-0001-8909-0345], Zeberg, Hugo [0000-0001-7118-1249], Richards, Brent [0000-0002-3746-9086], Ganna, Andrea [0000-0002-8147-240X], Junta de Castilla y León, Fundació Glòria Soler, Swedish Kidney Foundation, Research Council of Norway, Nakanishi, Tomoko, Pigazzini, Sara, Cordioli, Mattia, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Nafria Jimenez, Beatriz, Bouysran, Youssef, Niemi, Mari, Palom, Adriana, Ellinghaus, David, Khan, Atlas, Martínez-Bueno, Manuel, Roade, Luisa, Fava, Francesca, Spinner, Christoph D., Prati, Daniele, Bernardo, David, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Frithiof, Robert, Kiryluk, Krzysztof, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre, Romero-Gómez, Manuel, Hov, Johannes R., Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M., Ludwig, Kerstin, Buti, María, Rahmouni, Souad, Alarcón-Riquelme, M. E., Schulte, Eva C., Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, Nakanishi, T., Pigazzini, S., Degenhardt, F., Cordioli, M., Butler-Laporte, G., Maya-Miles, D., Bujanda, L., Bouysran, Y., Niemi, M. E. K., Palom, A., Ellinghaus, D., Khan, A., Martinez-Bueno, M., Rolker, S., Amitrano, S., Tato, L. R., Fava, F., Gen, F., Spinner, C. D., Prati, D., Bernardo, D., Garcia, F., Darcis, G., Fernandez-Cadenas, I., Holter, J. C., Banales, J. M., Frithiof, R., Kiryluk, K., Duga, S., Asselta, R., Pereira, A. C., Romero-Gomez, M., Nafria-Jimenez, B., Hov, J. R., Migeotte, I., Renieri, A., Planas, A. M., Ludwig, K. U., Buti, M., Rahmouni, S., Alarcon-Riquelme, M. E., Schulte, E. C., Franke, A., Karlsen, T. H., Valenti, L., Zeberg, H., Richards, J. B., and Ganna, A.

Subjects
Male, Coronavirus disease 2019 (COVID-19), Age dependent, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Gene Frequency, Risk Factors, Genetics, Medicine, Humans, Age Factor, Genetic variation, 030212 general & internal medicine, Respiratory system, Alleles, 030304 developmental biology, Aged, Allele, Aged, 80 and over, 0303 health sciences, Polymorphism, Genetic, business.industry, SARS-CoV-2, Risk Factor, Hazard ratio, Age Factors, Patient Acuity, COVID-19, Odds ratio, Covid-19, Genetic Variation, Sciences bio-médicales et agricoles, Middle Aged, COVID-19 (Enfermedad), Confidence interval, 3. Good health, Genetic Loci, Commentary, Female, Chromosomes, Human, Pair 3, Genetic risk factor, business, Venous thromboembolism, Human, Demography
Abstract

AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N. 340541. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research-funded BioResource and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. The Biobanque Québec COVID19 is funded by FRQS, Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding agencies had no role in the design, implementation or interpretation of this study. The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”). The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a philantropic donation from Stein Erik Hagen. The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de Salud y Familias" of the Andalusian Government. DMM is currently funded by the the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018). The Columbia University Biobank was supported by Columbia University and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Columbia University. The SPGRX study was supported by the Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150. The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020” to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119; and philanthropic donations to the Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by Tuscany Region “Bando Ricerca COVID-19 Toscana” grant to the Azienda Ospedaliero Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA consortium for providing computational resources; the Network for Italian Genomes (NIG) (http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for managing specimens. Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the Dolce&Gabbana Fashion Firm is gratefully acknowledged. Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV). Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2) study was supported by grants from Fondation Léon Fredericq and from Fonds de la Recherche Scientifique (FNRS). The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones Científicas. KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus Bergvalls Stiftelse. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland. These funding agencies had no role in the design, implementation or interpretation of this study., Background: There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management., Academy of Finland Fellow grant N. 323116, Academy of Finland for PREDICT consortium N. 340541., Canadian Institutes of Health Research (CIHR) (365825 and 409511), Lady Davis Institute of the Jewish General Hospital, Canadian Foundation for Innovation (CFI), NIH Foundation, Cancer Research UK, Genome Québec, Public Health Agency of Canada, McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS), Japan Society for the Promotion of Science for Young Scientists, CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship, FRQS Clinical Research Scholarship, Calcul Québec, Compute Canada, Welcome Trust, Medical Research Counc, European Union, National Institute for Health Research-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust, King’s College London, McGill Interdisciplinary Initiative in Infection and Immunity, Fonds de Recherche Québec Santé, (DFG Grant: “EXC2167”), (CompLS grant 031L0165), Stein Erik Hagen, "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia", Instituto de Salud Carlos III (CIBERehd and CIBERER), COVID-19-GWAS, COVID-PREMED initiatives, "Consejeria de Salud y Familias" of the Andalusian Government, Andalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018), Columbia University, National Center for Advancing Translational Sciences, NIH Grant Number UL1TR001873, Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150, MIUR grant “Dipartimenti di Eccellenza 2018-2020”, “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119, Tuscany Region “Bando Ricerca COVID-19 Toscana”, CINECA consortium, Network for Italian Genomes (NIG), COVID-19 Host Genetics Initiative, Genetic Biobank of Siena, EuroBioBank, RD-Connect, Ricerca Corrente (Italian Ministry of Health), Fondazione Humanitas per la Ricerca, Banca Intesa San Paolo, Dolce&Gabbana Fashion Firm, COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano, MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377), “Photonics” “101016726”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV), "Fonds Erasme", Fondation Léon Fredericq, Fonds de la Recherche Scientifique (FNRS), Consejo Superior de Investigaciones Científicas, German Research Foundation (LU 1944/3-1), SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182), Swedish Research Council (2014-02569 and 2014-07606), Jeansson Stiftelser, Magnus Bergvalls Stiftelse, Technical University of Munich, Munich, Germany, Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland

Published
2021

141. Novel genes and sex differences in COVID-19 severity

Author

Cruz, Raquel, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C, Pita, Guillermo, Lorenzo-Salazar, José M, González-Montelongo, Rafaela, Gago-Domínguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Nevado, Julian, Aguado, Jose María, Aguilar, Carlos, Aguilera-Albesa, Sergio, Almadana, Virginia, Almoguera, Berta, Alvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, Arango, Celso, Arranz, María J, Artiga, Maria-Jesus, Baptista-Rosas, Raúl C, Barreda-Sánchez, María, Belhassen-Garcia, Moncef, Bezerra, Joao F, Bezerra, Marcos A C, Boix-Palop, Lucía, Brion, María, Brugada, Ramón, Bustos, Matilde, Calderón, Enrique J, Carbonell, Cristina, Castano, Luis, Castelao, Jose E, Conde-Vicente, Rosa, Cordero-Lorenzana, M Lourdes, Cortes-Sanchez, Jose L, Corton, Marta, Darnaude, M Teresa, De Martino-Rodríguez, Alba, Del Campo-Pérez, Victor, Diaz de Bustamante, Aranzazu, Domínguez-Garrido, Elena, Luchessi, Andre D, Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Carmen Fariñas, María, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gil-Fournier, Belén, Gómez-Arrue, Javier, González Álvarez, Beatriz, Gonzalez Bernaldo de Quirós, Fernan, González-Peñas, Javier, Gutiérrez-Bautista, Juan F, Herrero, María José, Herrero-Gonzalez, Antonio, Jimenez-Sousa, María A, Lattig, María Claudia, Liger Borja, Anabel, Lopez-Rodriguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martinez-Nieto, Oscar, Martinez-Lopez, Iciar, Martinez-Resendez, Michel F, Martinez-Perez, Angel, Mazzeu, Juliana F, Merayo Macías, Eleuterio, Minguez, Pablo, Moreno Cuerda, Victor, Silbiger, Vivian N, Oliveira, Silviene F, Ortega-Paino, Eva, Parellada, Mara, Paz-Artal, Estela, Santos, Ney P C, Pérez-Matute, Patricia, Perez, Patricia, Pérez-Tomás, M Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N, Porras-Hurtado, Gloria L, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R, Rodríguez-Ruiz, Emilio, Rodriguez-Artalejo, Fernando, Rodriguez-Garcia, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Tamayo, Eduardo, Tamayo-Velasco, Alvaro, Taracido-Fernandez, Juan Carlos, Teper, Alejandro, Torres-Tobar, Lilian, Urioste, Miguel, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Amitrano, Sara, Roade, Luisa, Fava, Francesca, Spinner, Christoph D, Prati, Daniele, Bernardo, David, Garcia, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesus M, Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C, Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, Hov, Johannes R, Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M, Ludwig, Kerstin U, Buti, Maria, Rahmouni, Souad, Alarcón-Riquelme, Marta E, Schulte, Eva C, Franke, Andre, Karlsen, Tom H, Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, Boada, Mercè, de Rojas, Itziar, Ruiz, Agustín, Sánchez-Juan, Pascual, Real, Luis Miguel, Guillen-Navarro, Encarna, Ayuso, Carmen, González-Neira, Anna, Riancho, José A, Rojas-Martinez, Augusto, Flores, Carlos, Lapunzina, Pablo, Carracedo, Angel, Cruz, Raquel, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C, Pita, Guillermo, Lorenzo-Salazar, José M, González-Montelongo, Rafaela, Gago-Domínguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Nevado, Julian, Aguado, Jose María, Aguilar, Carlos, Aguilera-Albesa, Sergio, Almadana, Virginia, Almoguera, Berta, Alvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, Arango, Celso, Arranz, María J, Artiga, Maria-Jesus, Baptista-Rosas, Raúl C, Barreda-Sánchez, María, Belhassen-Garcia, Moncef, Bezerra, Joao F, Bezerra, Marcos A C, Boix-Palop, Lucía, Brion, María, Brugada, Ramón, Bustos, Matilde, Calderón, Enrique J, Carbonell, Cristina, Castano, Luis, Castelao, Jose E, Conde-Vicente, Rosa, Cordero-Lorenzana, M Lourdes, Cortes-Sanchez, Jose L, Corton, Marta, Darnaude, M Teresa, De Martino-Rodríguez, Alba, Del Campo-Pérez, Victor, Diaz de Bustamante, Aranzazu, Domínguez-Garrido, Elena, Luchessi, Andre D, Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Carmen Fariñas, María, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gil-Fournier, Belén, Gómez-Arrue, Javier, González Álvarez, Beatriz, Gonzalez Bernaldo de Quirós, Fernan, González-Peñas, Javier, Gutiérrez-Bautista, Juan F, Herrero, María José, Herrero-Gonzalez, Antonio, Jimenez-Sousa, María A, Lattig, María Claudia, Liger Borja, Anabel, Lopez-Rodriguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martinez-Nieto, Oscar, Martinez-Lopez, Iciar, Martinez-Resendez, Michel F, Martinez-Perez, Angel, Mazzeu, Juliana F, Merayo Macías, Eleuterio, Minguez, Pablo, Moreno Cuerda, Victor, Silbiger, Vivian N, Oliveira, Silviene F, Ortega-Paino, Eva, Parellada, Mara, Paz-Artal, Estela, Santos, Ney P C, Pérez-Matute, Patricia, Perez, Patricia, Pérez-Tomás, M Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N, Porras-Hurtado, Gloria L, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R, Rodríguez-Ruiz, Emilio, Rodriguez-Artalejo, Fernando, Rodriguez-Garcia, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Tamayo, Eduardo, Tamayo-Velasco, Alvaro, Taracido-Fernandez, Juan Carlos, Teper, Alejandro, Torres-Tobar, Lilian, Urioste, Miguel, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Amitrano, Sara, Roade, Luisa, Fava, Francesca, Spinner, Christoph D, Prati, Daniele, Bernardo, David, Garcia, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesus M, Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C, Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, Hov, Johannes R, Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M, Ludwig, Kerstin U, Buti, Maria, Rahmouni, Souad, Alarcón-Riquelme, Marta E, Schulte, Eva C, Franke, Andre, Karlsen, Tom H, Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, Boada, Mercè, de Rojas, Itziar, Ruiz, Agustín, Sánchez-Juan, Pascual, Real, Luis Miguel, Guillen-Navarro, Encarna, Ayuso, Carmen, González-Neira, Anna, Riancho, José A, Rojas-Martinez, Augusto, Flores, Carlos, Lapunzina, Pablo, and Carracedo, Angel

Abstract

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Published
2022
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142. Natural history of KBG syndrome in a large European cohort

Author

Loberti, L, Bruno, L, Granata, S, Doddato, G, Resciniti, S, Fava, F, Carullo, M, Rahikkala, E, Jouret, G, Menke, L, Lederer, D, Vrielynck, P, Ryba, L, Brunetti-Pierri, N, Lasa-Aranzasti, A, Cueto-González, A, Trujillano, L, Valenzuela, I, Tizzano, E, Spinelli, A, Bruno, I, Currò, A, Stanzial, F, Benedicenti, F, Lopergolo, D, Santorelli, F, Aristidou, C, Tanteles, G, Maystadt, I, Tkemaladze, T, Reimand, T, Lokke, H, Õunap, K, Haanpää, M, Holubová, A, Zoubková, V, Schwarz, M, Žordania, R, Muru, K, Roht, L, Tihveräinen, A, Teek, R, Thomson, U, Isis, A, Superti-Furga, A, Buoni, S, Canitano, R, Scandurra, V, Rossetti, A, Grosso, S, Battini, R, Baldassarri, M, Mencarelli, M, Rizzo, C, Bruttini, M, Mari, F, Ariani, F, Renieri, A, Pinto, A, Loberti, Lorenzo, Bruno, Lucia Pia, Granata, Stefania, Doddato, Gabriella, Resciniti, Sara, Fava, Francesca, Carullo, Michele, Rahikkala, Elisa, Jouret, Guillaume, Menke, Leonie A, Lederer, Damien, Vrielynck, Pascal, Ryba, Lukáš, Brunetti-Pierri, Nicola, Lasa-Aranzasti, Amaia, Cueto-González, Anna Maria, Trujillano, Laura, Valenzuela, Irene, Tizzano, Eduardo F, Spinelli, Alessandro Mauro, Bruno, Irene, Currò, Aurora, Stanzial, Franco, Benedicenti, Francesco, Lopergolo, Diego, Santorelli, Filippo Maria, Aristidou, Constantia, Tanteles, George A, Maystadt, Isabelle, Tkemaladze, Tinatin, Reimand, Tiia, Lokke, Helen, Õunap, Katrin, Haanpää, Maria K, Holubová, Andrea, Zoubková, Veronika, Schwarz, Martin, Žordania, Riina, Muru, Kai, Roht, Laura, Tihveräinen, Annika, Teek, Rita, Thomson, Ulvi, Isis, Atallah, Superti-Furga, Andrea, Buoni, Sabrina, Canitano, Roberto, Scandurra, Valeria, Rossetti, Annalisa, Grosso, Salvatore, Battini, Roberta, Baldassarri, Margherita, Mencarelli, Maria Antonietta, Rizzo, Caterina Lo, Bruttini, Mirella, Mari, Francesca, Ariani, Francesca, Renieri, Alessandra, Pinto, Anna Maria, Loberti, L, Bruno, L, Granata, S, Doddato, G, Resciniti, S, Fava, F, Carullo, M, Rahikkala, E, Jouret, G, Menke, L, Lederer, D, Vrielynck, P, Ryba, L, Brunetti-Pierri, N, Lasa-Aranzasti, A, Cueto-González, A, Trujillano, L, Valenzuela, I, Tizzano, E, Spinelli, A, Bruno, I, Currò, A, Stanzial, F, Benedicenti, F, Lopergolo, D, Santorelli, F, Aristidou, C, Tanteles, G, Maystadt, I, Tkemaladze, T, Reimand, T, Lokke, H, Õunap, K, Haanpää, M, Holubová, A, Zoubková, V, Schwarz, M, Žordania, R, Muru, K, Roht, L, Tihveräinen, A, Teek, R, Thomson, U, Isis, A, Superti-Furga, A, Buoni, S, Canitano, R, Scandurra, V, Rossetti, A, Grosso, S, Battini, R, Baldassarri, M, Mencarelli, M, Rizzo, C, Bruttini, M, Mari, F, Ariani, F, Renieri, A, Pinto, A, Loberti, Lorenzo, Bruno, Lucia Pia, Granata, Stefania, Doddato, Gabriella, Resciniti, Sara, Fava, Francesca, Carullo, Michele, Rahikkala, Elisa, Jouret, Guillaume, Menke, Leonie A, Lederer, Damien, Vrielynck, Pascal, Ryba, Lukáš, Brunetti-Pierri, Nicola, Lasa-Aranzasti, Amaia, Cueto-González, Anna Maria, Trujillano, Laura, Valenzuela, Irene, Tizzano, Eduardo F, Spinelli, Alessandro Mauro, Bruno, Irene, Currò, Aurora, Stanzial, Franco, Benedicenti, Francesco, Lopergolo, Diego, Santorelli, Filippo Maria, Aristidou, Constantia, Tanteles, George A, Maystadt, Isabelle, Tkemaladze, Tinatin, Reimand, Tiia, Lokke, Helen, Õunap, Katrin, Haanpää, Maria K, Holubová, Andrea, Zoubková, Veronika, Schwarz, Martin, Žordania, Riina, Muru, Kai, Roht, Laura, Tihveräinen, Annika, Teek, Rita, Thomson, Ulvi, Isis, Atallah, Superti-Furga, Andrea, Buoni, Sabrina, Canitano, Roberto, Scandurra, Valeria, Rossetti, Annalisa, Grosso, Salvatore, Battini, Roberta, Baldassarri, Margherita, Mencarelli, Maria Antonietta, Rizzo, Caterina Lo, Bruttini, Mirella, Mari, Francesca, Ariani, Francesca, Renieri, Alessandra, and Pinto, Anna Maria

Abstract

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: −0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Published
2022

143. Supplementary files of the article 'Novel genes and sex differences in COVID-19 severity' [Dataset]

Author

Cruz Modino, Raquel de la, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C., Pita, Guillermo, Lorenzo-Salazar, José M., González-Montelongo, Rafaela, Gago-Dominguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Carbonell, Cristina, Migeotte, Isabelle, Renieri, Alessandra, Aguilera-Albesa, Sergio, Planas, Anna M., Ludwig, Kerstin U., Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Tamayo-Velasco, Álvaro, Franke, Andre, Castaño, Luis, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Almadana Pacheco, Virginia, Richards, Brent, Ganna, Andrea, Boada, Mercè, Rojas, Itziar de, Gil-Fournier, Belén, Ruiz, Agustín, Sánchez-Juan, Pascual, Castelao, Jose E., Real, Luis Miguel, SCOURGE Cohort Group, HOSTAGE Cohort Group, GRA@CE Cohort Group, Almoguera, Berta, Guillen-Navarro, Encarna, Ayuso, Carmen, Gómez-Arrue, Javier, González-Neira, Anna, Riancho, José A., Rojas-Martinez, Augusto, Conde-Vicente, Rosa, Flores, Carlos, Lapunzina, Pablo, Carracedo, Ángel, Álvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, González Álvarez, Beatriz, Arango, Celso, Arranz, Maria J., Artiga, María Jesús, Baptista-Rosas, Raúl C., Cordero-Lorenzana, M. Lourdes, Barreda-Sánchez, María, Belhassen-García, Moncef, Bezerra, Joao F., Bezerra, Marcos A. C., Boix-Palop, Lucía, Gonzalez Bernaldo de Quirós, Fernán, Briones, María, Brugada, Ramón, Bustos, Matilde, Cortés-Sánchez, José L., Cortón, Marta, Darnaude, M. Teresa, Martino-Rodríguez, Alba de, Tamayo, Eduardo, Campo-Pérez, Víctor de, Diaz de Bustamante, Aranzazu, González-Peñas, Javier, Domínguez-Garrido, Elena, Luchessi, Andre D., Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Fariñas, María del Carmen, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gutiérrez-Bautista, Juan F., Herrero, María José, Herrero-Gonzalez, Antonio, Jiménez-Sousa, María A., Aguado, José María, Lattig, María Claudia, Taracido-Fernandez, Juan Carlos, Liger Borja, Anabel, López-Rodríguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martínez-Nieto, Oscar, Martinez-López, Icíar, Martinez-Resendez, Michel F., Amitrano, Sara, Martínez-Pérez, Àngel, Mazzeu, Juliana F, Teper, Alejandro, Merayo Macías, Eleuterio, Mínguez, Pablo, Moreno Cuerda, Víctor, Silbiger, Vivian N., Oliveira, Silviene F., Ortega-Paino, Eva, Parellada, Mara, Roade, Luisa, Paz-Artal, Estela, Santos, Ney P. C., Pérez-Matute, Patricia, Torres-Tobar, Lilian, Pérez Ramírez, Patricia, Pérez-Tomás, M. Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N., Porras-Hurtado, Gloria L., Fava, Francesca, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R., Urioste, Miguel, Rodríguez-Ruiz, Emilio, Rodríguez-Artalejo, Fernando, Rodríguez-García, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Spinner, Christoph D., Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Nevado, Julian, Pigazzini, Sara, Degenhardt, Frauke, Prati, Daniele, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Calderón, Enrique J., Holter, Jan Cato, Aguilar, Carlos, Banales, Jesús M., Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C., Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, Hov, Johannes R., Cruz Modino, Raquel de la, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C., Pita, Guillermo, Lorenzo-Salazar, José M., González-Montelongo, Rafaela, Gago-Dominguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Carbonell, Cristina, Migeotte, Isabelle, Renieri, Alessandra, Aguilera-Albesa, Sergio, Planas, Anna M., Ludwig, Kerstin U., Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Tamayo-Velasco, Álvaro, Franke, Andre, Castaño, Luis, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Almadana Pacheco, Virginia, Richards, Brent, Ganna, Andrea, Boada, Mercè, Rojas, Itziar de, Gil-Fournier, Belén, Ruiz, Agustín, Sánchez-Juan, Pascual, Castelao, Jose E., Real, Luis Miguel, SCOURGE Cohort Group, HOSTAGE Cohort Group, GRA@CE Cohort Group, Almoguera, Berta, Guillen-Navarro, Encarna, Ayuso, Carmen, Gómez-Arrue, Javier, González-Neira, Anna, Riancho, José A., Rojas-Martinez, Augusto, Conde-Vicente, Rosa, Flores, Carlos, Lapunzina, Pablo, Carracedo, Ángel, Álvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, González Álvarez, Beatriz, Arango, Celso, Arranz, Maria J., Artiga, María Jesús, Baptista-Rosas, Raúl C., Cordero-Lorenzana, M. Lourdes, Barreda-Sánchez, María, Belhassen-García, Moncef, Bezerra, Joao F., Bezerra, Marcos A. C., Boix-Palop, Lucía, Gonzalez Bernaldo de Quirós, Fernán, Briones, María, Brugada, Ramón, Bustos, Matilde, Cortés-Sánchez, José L., Cortón, Marta, Darnaude, M. Teresa, Martino-Rodríguez, Alba de, Tamayo, Eduardo, Campo-Pérez, Víctor de, Diaz de Bustamante, Aranzazu, González-Peñas, Javier, Domínguez-Garrido, Elena, Luchessi, Andre D., Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Fariñas, María del Carmen, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gutiérrez-Bautista, Juan F., Herrero, María José, Herrero-Gonzalez, Antonio, Jiménez-Sousa, María A., Aguado, José María, Lattig, María Claudia, Taracido-Fernandez, Juan Carlos, Liger Borja, Anabel, López-Rodríguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martínez-Nieto, Oscar, Martinez-López, Icíar, Martinez-Resendez, Michel F., Amitrano, Sara, Martínez-Pérez, Àngel, Mazzeu, Juliana F, Teper, Alejandro, Merayo Macías, Eleuterio, Mínguez, Pablo, Moreno Cuerda, Víctor, Silbiger, Vivian N., Oliveira, Silviene F., Ortega-Paino, Eva, Parellada, Mara, Roade, Luisa, Paz-Artal, Estela, Santos, Ney P. C., Pérez-Matute, Patricia, Torres-Tobar, Lilian, Pérez Ramírez, Patricia, Pérez-Tomás, M. Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N., Porras-Hurtado, Gloria L., Fava, Francesca, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R., Urioste, Miguel, Rodríguez-Ruiz, Emilio, Rodríguez-Artalejo, Fernando, Rodríguez-García, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Spinner, Christoph D., Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Nevado, Julian, Pigazzini, Sara, Degenhardt, Frauke, Prati, Daniele, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Calderón, Enrique J., Holter, Jan Cato, Aguilar, Carlos, Banales, Jesús M., Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C., Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, and Hov, Johannes R.

Published
2022

144. Novel genes and sex differences in COVID-19 severity

Author

Instituto de Salud Carlos III, European Commission, Fundación Amancio Ortega, Banco Santander, Estrella de Levante, Colabora Mujer, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Cruz Modino, Raquel de la, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C., Pita, Guillermo, Lorenzo-Salazar, José M., González-Montelongo, Rafaela, Gago-Dominguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Carbonell, Cristina, Migeotte, Isabelle, Renieri, Alessandra, Aguilera-Albesa, Sergio, Planas, Anna M., Ludwig, Kerstin U., Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Tamayo-Velasco, Álvaro, Franke, Andre, Castaño, Luis, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Almadana Pacheco, Virginia, Richards, Brent, Ganna, Andrea, Boada, Mercè, Rojas, Itziar de, Gil-Fournier, Belén, Ruiz, Agustín, Sánchez-Juan, Pascual, Castelao, Jose E., Real, Luis Miguel, SCOURGE Cohort Group, HOSTAGE Cohort Group, GRA@CE Cohort Group, Almoguera, Berta, Guillen-Navarro, Encarna, Ayuso, Carmen, Gómez-Arrue, Javier, González-Neira, Anna, Riancho, José A., Rojas-Martinez, Augusto, Conde-Vicente, Rosa, Flores, Carlos, Lapunzina, Pablo, Carracedo, Ángel, Álvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, González Álvarez, Beatriz, Arango, Celso, Arranz, Maria J., Artiga, María Jesús, Baptista-Rosas, Raúl C., Cordero-Lorenzana, M. Lourdes, Barreda-Sánchez, María, Belhassen-García, Moncef, Bezerra, Joao F., Bezerra, Marcos A. C., Boix-Palop, Lucía, Gonzalez Bernaldo de Quirós, Fernán, Briones, María, Brugada, Ramón, Bustos, Matilde, Cortés-Sánchez, José L., Cortón, Marta, Darnaude, M. Teresa, Martino-Rodríguez, Alba de, Tamayo, Eduardo, Campo-Pérez, Víctor de, Diaz de Bustamante, Aranzazu, González-Peñas, Javier, Domínguez-Garrido, Elena, Luchessi, Andre D., Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Fariñas, María del Carmen, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gutiérrez-Bautista, Juan F., Herrero, María José, Herrero-Gonzalez, Antonio, Jiménez-Sousa, María A., Aguado, José María, Lattig, María Claudia, Taracido-Fernandez, Juan Carlos, Liger Borja, Anabel, López-Rodríguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martínez-Nieto, Oscar, Martinez-López, Icíar, Martinez-Resendez, Michel F., Amitrano, Sara, Martínez-Pérez, Àngel, Mazzeu, Juliana F, Teper, Alejandro, Merayo Macías, Eleuterio, Mínguez, Pablo, Moreno Cuerda, Víctor, Silbiger, Vivian N., Oliveira, Silviene F., Ortega-Paino, Eva, Parellada, Mara, Roade, Luisa, Paz-Artal, Estela, Santos, Ney P. C., Pérez-Matute, Patricia, Torres-Tobar, Lilian, Pérez Ramírez, Patricia, Pérez-Tomás, M. Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N., Porras-Hurtado, Gloria L., Fava, Francesca, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R., Urioste, Miguel, Rodríguez-Ruiz, Emilio, Rodríguez-Artalejo, Fernando, Rodríguez-García, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Spinner, Christoph D., Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Nevado, Julian, Pigazzini, Sara, Degenhardt, Frauke, Prati, Daniele, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Calderón, Enrique J., Holter, Jan Cato, Aguilar, Carlos, Banales, Jesús M., Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C., Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, Hov, Johannes R., Instituto de Salud Carlos III, European Commission, Fundación Amancio Ortega, Banco Santander, Estrella de Levante, Colabora Mujer, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Cruz Modino, Raquel de la, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C., Pita, Guillermo, Lorenzo-Salazar, José M., González-Montelongo, Rafaela, Gago-Dominguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Carbonell, Cristina, Migeotte, Isabelle, Renieri, Alessandra, Aguilera-Albesa, Sergio, Planas, Anna M., Ludwig, Kerstin U., Buti, María, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Tamayo-Velasco, Álvaro, Franke, Andre, Castaño, Luis, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Almadana Pacheco, Virginia, Richards, Brent, Ganna, Andrea, Boada, Mercè, Rojas, Itziar de, Gil-Fournier, Belén, Ruiz, Agustín, Sánchez-Juan, Pascual, Castelao, Jose E., Real, Luis Miguel, SCOURGE Cohort Group, HOSTAGE Cohort Group, GRA@CE Cohort Group, Almoguera, Berta, Guillen-Navarro, Encarna, Ayuso, Carmen, Gómez-Arrue, Javier, González-Neira, Anna, Riancho, José A., Rojas-Martinez, Augusto, Conde-Vicente, Rosa, Flores, Carlos, Lapunzina, Pablo, Carracedo, Ángel, Álvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, González Álvarez, Beatriz, Arango, Celso, Arranz, Maria J., Artiga, María Jesús, Baptista-Rosas, Raúl C., Cordero-Lorenzana, M. Lourdes, Barreda-Sánchez, María, Belhassen-García, Moncef, Bezerra, Joao F., Bezerra, Marcos A. C., Boix-Palop, Lucía, Gonzalez Bernaldo de Quirós, Fernán, Briones, María, Brugada, Ramón, Bustos, Matilde, Cortés-Sánchez, José L., Cortón, Marta, Darnaude, M. Teresa, Martino-Rodríguez, Alba de, Tamayo, Eduardo, Campo-Pérez, Víctor de, Diaz de Bustamante, Aranzazu, González-Peñas, Javier, Domínguez-Garrido, Elena, Luchessi, Andre D., Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Fariñas, María del Carmen, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gutiérrez-Bautista, Juan F., Herrero, María José, Herrero-Gonzalez, Antonio, Jiménez-Sousa, María A., Aguado, José María, Lattig, María Claudia, Taracido-Fernandez, Juan Carlos, Liger Borja, Anabel, López-Rodríguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martínez-Nieto, Oscar, Martinez-López, Icíar, Martinez-Resendez, Michel F., Amitrano, Sara, Martínez-Pérez, Àngel, Mazzeu, Juliana F, Teper, Alejandro, Merayo Macías, Eleuterio, Mínguez, Pablo, Moreno Cuerda, Víctor, Silbiger, Vivian N., Oliveira, Silviene F., Ortega-Paino, Eva, Parellada, Mara, Roade, Luisa, Paz-Artal, Estela, Santos, Ney P. C., Pérez-Matute, Patricia, Torres-Tobar, Lilian, Pérez Ramírez, Patricia, Pérez-Tomás, M. Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N., Porras-Hurtado, Gloria L., Fava, Francesca, Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R., Urioste, Miguel, Rodríguez-Ruiz, Emilio, Rodríguez-Artalejo, Fernando, Rodríguez-García, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Spinner, Christoph D., Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Nevado, Julian, Pigazzini, Sara, Degenhardt, Frauke, Prati, Daniele, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Bernardo, David, García, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Calderón, Enrique J., Holter, Jan Cato, Aguilar, Carlos, Banales, Jesús M., Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C., Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, and Hov, Johannes R.

Abstract

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Published
2022

145. Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Author

Fallerini, C, Picchiotti, N, Baldassarri, M, Zguro, K, Daga, S, Fava, F, Benetti, E, Amitrano, S, Bruttini, M, Palmieri, M, Croci, S, Lista, M, Beligni, G, Valentino, F, Meloni, I, Tanfoni, M, Minnai, F, Colombo, F, Cabri, E, Fratelli, M, Gabbi, C, Mantovani, S, Frullanti, E, Gori, M, Crawley, F, Butler-Laporte, G, Richards, B, Zeberg, H, Lipcsey, M, Hultström, M, Ludwig, K, Schulte, E, Pairo-Castineira, E, Baillie, J, Schmidt, A, Frithiof, R, Mari, F, Renieri, A, Furini, S, Crotti, L, Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklos, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone, Crotti, Lia, Fallerini, C, Picchiotti, N, Baldassarri, M, Zguro, K, Daga, S, Fava, F, Benetti, E, Amitrano, S, Bruttini, M, Palmieri, M, Croci, S, Lista, M, Beligni, G, Valentino, F, Meloni, I, Tanfoni, M, Minnai, F, Colombo, F, Cabri, E, Fratelli, M, Gabbi, C, Mantovani, S, Frullanti, E, Gori, M, Crawley, F, Butler-Laporte, G, Richards, B, Zeberg, H, Lipcsey, M, Hultström, M, Ludwig, K, Schulte, E, Pairo-Castineira, E, Baillie, J, Schmidt, A, Frithiof, R, Mari, F, Renieri, A, Furini, S, Crotti, L, Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklos, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone, and Crotti, Lia

Abstract

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

Published
2022

146. An explainable model of host genetic interactions linked to COVID-19 severity

Author

Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, Serena Ludovisi, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, and Serena Ludovisi

Abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

Published
2022

147. Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Author

Baldassarri, M, Zguro, K, Tomati, V, Pastorino, C, Fava, F, Croci, S, Bruttini, M, Picchiotti, N, Furini, S, Pedemonte, N, Gabbi, C, Renieri, A, Fallerini, C, Crotti, L, Baldassarri, Margherita, Zguro, Kristina, Tomati, Valeria, Pastorino, Cristina, Fava, Francesca, Croci, Susanna, Bruttini, Mirella, Picchiotti, Nicola, Furini, Simone, Pedemonte, Nicoletta, Gabbi, Chiara, Renieri, Alessandra, Fallerini, Chiara, Crotti,Lia, Baldassarri, M, Zguro, K, Tomati, V, Pastorino, C, Fava, F, Croci, S, Bruttini, M, Picchiotti, N, Furini, S, Pedemonte, N, Gabbi, C, Renieri, A, Fallerini, C, Crotti, L, Baldassarri, Margherita, Zguro, Kristina, Tomati, Valeria, Pastorino, Cristina, Fava, Francesca, Croci, Susanna, Bruttini, Mirella, Picchiotti, Nicola, Furini, Simone, Pedemonte, Nicoletta, Gabbi, Chiara, Renieri, Alessandra, Fallerini, Chiara, and Crotti,Lia

Abstract

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19.

Published
2022

148. Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Author

Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklós, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklós, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, and Furini, Simone

Abstract

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

Published
2022
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149. Guidelines for Genetic Testing and Management of Alport Syndrome

Author

Genetica Klinische Genetica, Child Health, Cancer, Savige, Judy, Lipska-Zietkiewicz, Beata S, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, Al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabet, Bierzynska, Agnieszka, Gangemi, Concetta, Renieri, Alessandra, Storey, Helen, Flinter, Frances, Genetica Klinische Genetica, Child Health, Cancer, Savige, Judy, Lipska-Zietkiewicz, Beata S, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, Al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabet, Bierzynska, Agnieszka, Gangemi, Concetta, Renieri, Alessandra, Storey, Helen, and Flinter, Frances

Published
2022

150. Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Author

Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklos, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone Simone Furini, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Maurizio, Spagnesi, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella, D 'Arminio Monforte, Federica Gaia Miraglia, Mario, U Mondelli, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Gabriella, Doddato, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Valentina, Perticaroli, Francesca, Ariani, Miriam Lucia Carriero, Laura Di Sarno, Diana, Alaverdian, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Leonardo Gianluca Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Francesco, Raimondi, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Menè, Roberto, Umberto, Zuccon, Lucia, Vietri, Stefano, Ceri, Pietro, Pinoli, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Raffaele, Bruno, Marco, Vecchia, Marta, Colaneri, Serena, Ludovisi, Yanara, Marincevic-Zuniga, Jessica, Nordlund, Tomas, Luther, Anders, Larsson, Katja Hanslin Anna Gradin, Sarah, Galien, Sara Bulow Anderberg, Jacob, Rosén, Sten, Rubertsson, Hugo, Zeberg, Robert, Frithiof, Miklós, Lipcsey, Michael, Hultström, Sara Clohisey Peter Horby, Johnny, Millar, Julian, Knight, Hugh, Montgomery, David, Maslove, Lowell, Ling, Alistair, Nichol, Charlotte, Summers, Tim, Walsh, Charles, Hinds, Malcolm, G Semple, Peter J, M Openshaw, Manu, Shankar-Hari, Antonia, Ho, Danny, Mcauley, Chris, Ponting, Kathy, Rowan, J Kenneth Baillie, Fiona, Griffiths, Wilna, Oosthuyzen, Jen, Meikle, Paul, Finernan, James, Furniss, Ellie, Mcmaster, Andy, Law, Sara, Clohisey, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Lee, Murphy, Angie, Fawkes, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Max Head Fourman, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Marie, Zechner, Nicholas, Parkinson, Erola, Pairo-Castineira, Lucija, Klaric, Andrew, D Bretherick, Konrad, Rawlik, Dorota, Pasko, Susan, Walker, Nick, Parkinson, Clark, D Russell, Anne, Richmond, Elvina, Gountouna, David, Harrison, Wang, Bo, Yang, Wu, Alison, Meynert, Athanasios, Kousathanas, Loukas, Moutsianas, Zhijian, Yang, Ranran, Zhai, Chenqing, Zheng, Graeme, Grimes, Jonathan, Millar, Barbara, Shih, Jian, Yang, Xia, Shen, Chris, P Ponting, Albert, Tenesa, Andrew, Law, Veronique, Vitart, James, F Wilson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthorpe, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnson, B, Hamilton, O, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, Jones, J, J Moreno Cuesta, Haldeos, A, Bakthavatsalam, D, Vincent, R, Elhassan, M, Xavier, K, Ganesan, A, Purohit, D, Abdelrazik, M, Morgan, J, Akeroyd, L, Bano, S, Warren, D, Bromley, M, Sellick, K, Gurr, L, Wilkinson, B, Nagarajan, V, Szedlak, P, Cupitt, J, Stoddard, E, Benham, L, Preston, S, Slawson, N, Bradshaw, Z, Brown, J, Caswell, M, Smelling, Bamford, P, Faulkner, M, Cawley, K, Jeffrey, H, London, E, Sainsbury, H, Nagra, I, Nasir, F, Dunmore, Ce, Jones, R, Abraheem, A, Al-Moasseb, M, Girach, R, Brantwood, C, Alexander, P, Bradley-Potts, J, Allen, S, Felton, T, Manna, S, Farnell-Ward, S, Leaver, S, Queiroz, J, Maccacari, E, Dawson, D, C Castro Delgado, R Pepermans Saluzzio, Ezeobu, O, Ding, L, Sicat, C, Kanu, R, Durrant, G, Texeira, J, Harrison, A, Samakomva, T, Willis, H, Hopkins, B, Thrasyvoulou, L, Jackson, M, Zaki, A, Tibke, C, Bennett, S, Woodyatt, W, Kent, A, Goodwin, E, Brandwood, C, Clark, R, Smith, L, Rooney, K, Thomson, N, Rodden, N, Hughes, E, Mcglynn, D, Clark, C, Clark, P, Abel, L, Sundaram, R, Gemmell, L, Brett, M, Hornsby, J, Macgoey, P, Price, R, Digby, B, O'Neil, P, Mcconnell, P, Henderson, P, Henderson, S, Sim, M, Kennedy-Hay, S, Mcparland, C, Rooney, L, Baxter, N, Pogson, D, Rose, S, Daly, Z, Brimfield, L, K Phull, M, Hussain, M, Pogreban, T, Rosaroso, L, E Salciute, L Grauslyte, Brealey, D, Wraith, E, Maccallum, N, Bercades, G, Hass, I, Smyth, D, Reyes, A, Martir, G, D Clement, I, Webster, K, Hays, C, Gulati, A, Hodgson, L, Margarson, M, Gomez, R, Baird, Y, Thirlwall, Y, Folkes, L, Butler, A, Meadows, E, Moore, S, Raynard, D, Fox, 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Subjects
Male, Medicin och hälsovetenskap, Linkage disequilibrium, Medizin, severity, Genome-wide association study, Disease, WES/WGS Working Group Within the HGI, Logistic regression, Severity of Illness Index, Medical and Health Sciences, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Lasso (statistics), GEN-COVID Multicenter Study, Germany, 80 and over, Genetics (clinical), Exome sequencing, Original Investigation, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Adult, Aged, COVID-19, Female, Humans, Italy, Middle Aged, Polymorphism, Single Nucleotide, Quebec, SARS-CoV-2, Sweden, United Kingdom, Genetic Predisposition to Disease, Phenotype, Single Nucleotide, covid-19, 1104 Complementary and Alternative Medicine, GenOMICC Consortium, Human, coding variants, Computational biology, Biology, 03 medical and health sciences, Exome Sequencing, Genetics, Polymorphism, Gene, 030304 developmental biology, 0604 Genetics, 1114 Paediatrics and Reproductive Medicine, Cohort Studie, 030217 neurology & neurosurgery, Coding (social sciences)
Abstract

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02397-7.

Published
2021

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