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1. Refining the drift barrier hypothesis: a role of recessive gene count and an inhomogeneous Muller`s ratchet

Author

La Rocca, Luis A., Gerischer, Konrad, Bovier, Anton, and Krawitz, Peter M.

Subjects
Quantitative Biology - Populations and Evolution
Abstract

The drift-barrier hypothesis states that random genetic drift constrains the refinement of a phenotype under natural selection. The influence of effective population size and the genome-wide deleterious mutation rate were studied theoretically, and an inverse relationship between mutation rate and genome size has been observed for many species. However, the effect of the recessive gene count, an important feature of the genomic architecture, is unknown. In a Wright-Fisher model, we studied the mutation burden for a growing number of N completely recessive and lethal disease genes. Diploid individuals are represented with a binary $2 \times N$ matrix denoting wild-type and mutated alleles. Analytic results for specific cases were complemented by simulations across a broad parameter regime for gene count, mutation and recombination rates. Simulations revealed transitions to higher mutation burden and prevalence within a few generations that were linked to the extinction of the wild-type haplotype (least-loaded class). This metastability, that is, phases of quasi-equilibrium with intermittent transitions, persists over $100\,000$ generations. The drift-barrier hypothesis is confirmed by a high mutation burden resulting in population collapse. Simulations showed the emergence of mutually exclusive haplotypes for a mutation rate above 0.02 lethal equivalents per generation for a genomic architecture and population size representing complex multicellular organisms such as humans. In such systems, recombination proves pivotal, preventing population collapse and maintaining a mutation burden below 10. This study advances our understanding of gene pool stability, and particularly the role of the number of recessive disorders. Insights into Muller`s ratchet dynamics are provided, and the essential role of recombination in curbing mutation burden and stabilizing the gene pool is demonstrated., Comment: 21 pages, 4 figures

Published
2024

2. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, Danyel, Magdalena, Grundmann, Kathrin, Brunet, Theresa, Klinkhammer, Hannah, Hsieh, Tzung-Chien, Engels, Hartmut, Peters, Sophia, Knaus, Alexej, Moosa, Shahida, Averdunk, Luisa, Boschann, Felix, Sczakiel, Henrike Lisa, Schwartzmann, Sarina, Mensah, Martin Atta, Pantel, Jean Tori, Holtgrewe, Manuel, Bösch, Annemarie, Weiß, Claudia, Weinhold, Natalie, Suter, Aude-Annick, Stoltenburg, Corinna, Neugebauer, Julia, Kallinich, Tillmann, Kaindl, Angela M., Holzhauer, Susanne, Bührer, Christoph, Bufler, Philip, Kornak, Uwe, Ott, Claus-Eric, Schülke, Markus, Nguyen, Hoa Huu Phuc, Hoffjan, Sabine, Grasemann, Corinna, Rothoeft, Tobias, Brinkmann, Folke, Matar, Nora, Sivalingam, Sugirthan, Perne, Claudia, Mangold, Elisabeth, Kreiss, Martina, Cremer, Kirsten, Betz, Regina C., Mücke, Martin, Grigull, Lorenz, Klockgether, Thomas, Spier, Isabel, Heimbach, André, Bender, Tim, Brand, Fabian, Stieber, Christiane, Morawiec, Alexandra Marzena, Karakostas, Pantelis, Schäfer, Valentin S., Bernsen, Sarah, Weydt, Patrick, Castro-Gomez, Sergio, Aziz, Ahmad, Grobe-Einsler, Marcus, Kimmich, Okka, Kobeleva, Xenia, Önder, Demet, Lesmann, Hellen, Kumar, Sheetal, Tacik, Pawel, Basin, Meghna Ahuja, Incardona, Pietro, Lee-Kirsch, Min Ae, Berner, Reinhard, Schuetz, Catharina, Körholz, Julia, Kretschmer, Tanita, Di Donato, Nataliya, Schröck, Evelin, Heinen, André, Reuner, Ulrike, Hanßke, Amalia-Mihaela, Kaiser, Frank J., Manka, Eva, Munteanu, Martin, Kuechler, Alma, Cordula, Kiewert, Hirtz, Raphael, Schlapakow, Elena, Schlein, Christian, Lisfeld, Jasmin, Kubisch, Christian, Herget, Theresia, Hempel, Maja, Weiler-Normann, Christina, Ullrich, Kurt, Schramm, Christoph, Rudolph, Cornelia, Rillig, Franziska, Groffmann, Maximilian, Muntau, Ania, Tibelius, Alexandra, Schwaibold, Eva M. C., Schaaf, Christian P., Zawada, Michal, Kaufmann, Lilian, Hinderhofer, Katrin, Okun, Pamela M., Kotzaeridou, Urania, Hoffmann, Georg F., Choukair, Daniela, Bettendorf, Markus, Spielmann, Malte, Ripke, Annekatrin, Pauly, Martje, Münchau, Alexander, Lohmann, Katja, Hüning, Irina, Hanker, Britta, Bäumer, Tobias, Herzog, Rebecca, Hellenbroich, Yorck, Westphal, Dominik S., Strom, Tim, Kovacs, Reka, Riedhammer, Korbinian M., Mayerhanser, Katharina, Graf, Elisabeth, Brugger, Melanie, Hoefele, Julia, Oexle, Konrad, Mirza-Schreiber, Nazanin, Berutti, Riccardo, Schatz, Ulrich, Krenn, Martin, Makowski, Christine, Weigand, Heike, Schröder, Sebastian, Rohlfs, Meino, Vill, Katharina, Hauck, Fabian, Borggraefe, Ingo, Müller-Felber, Wolfgang, Kurth, Ingo, Elbracht, Miriam, Knopp, Cordula, Begemann, Matthias, Kraft, Florian, Lemke, Johannes R., Hentschel, Julia, Platzer, Konrad, Strehlow, Vincent, Abou Jamra, Rami, Kehrer, Martin, Demidov, German, Beck-Wödl, Stefanie, Graessner, Holm, Sturm, Marc, Zeltner, Lena, Schöls, Ludger J., Magg, Janine, Bevot, Andrea, Kehrer, Christiane, Kaiser, Nadja, Turro, Ernest, Horn, Denise, Grüters-Kieslich, Annette, Klein, Christoph, Mundlos, Stefan, Nöthen, Markus, Riess, Olaf, Meitinger, Thomas, Krude, Heiko, Krawitz, Peter M., Haack, Tobias, Ehmke, Nadja, and Wagner, Matias

Published
2024
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3. Delineation of the adult phenotype of Coffin–Siris syndrome in 35 individuals

Author

Schmetz, Ariane, Lüdecke, Hermann-Josef, Surowy, Harald, Sivalingam, Sugirtahn, Bruel, Ange-Line, Caumes, Roseline, Charles, Perrine, Chatron, Nicolas, Chrzanowska, Krystyna, Codina-Solà, Marta, Colson, Cindy, Cuscó, Ivon, Denommé-Pichon, Anne-Sophie, Edery, Patrick, Faivre, Laurence, Green, Andrew, Heide, Solveig, Hsieh, Tzung-Chien, Hustinx, Alexander, Kleinendorst, Lotte, Knopp, Cordula, Kraft, Florian, Krawitz, Peter M., Lasa-Aranzasti, Amaia, Lesca, Gaetan, López-González, Vanesa, Maraval, Julien, Mignot, Cyril, Neuhann, Teresa, Netzer, Christian, Oehl-Jaschkowitz, Barbara, Petit, Florence, Philippe, Christophe, Posmyk, Renata, Putoux, Audrey, Reis, André, Sánchez-Soler, María José, Suh, Julia, Tkemaladze, Tinatin, Tran Mau Them, Frédéric, Travessa, André, Trujillano, Laura, Valenzuela, Irene, van Haelst, Mieke M., Vasileiou, Georgia, Vincent-Delorme, Catherine, Walther, Mona, Verde, Pablo, Bramswig, Nuria C., and Wieczorek, Dagmar

Published
2024
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5. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Published
2023
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6. The GA4GH Phenopacket schema defines a computable representation of clinical data

Author

Jacobsen, Julius OB, Baudis, Michael, Baynam, Gareth S, Beckmann, Jacques S, Beltran, Sergi, Buske, Orion J, Callahan, Tiffany J, Chute, Christopher G, Courtot, Mélanie, Danis, Daniel, Elemento, Olivier, Essenwanger, Andrea, Freimuth, Robert R, Gargano, Michael A, Groza, Tudor, Hamosh, Ada, Harris, Nomi L, Kaliyaperumal, Rajaram, Lloyd, Kevin C Kent, Khalifa, Aly, Krawitz, Peter M, Köhler, Sebastian, Laraway, Brian J, Lehväslaiho, Heikki, Matalonga, Leslie, McMurry, Julie A, Metke-Jimenez, Alejandro, Mungall, Christopher J, Munoz-Torres, Monica C, Ogishima, Soichi, Papakonstantinou, Anastasios, Piscia, Davide, Pontikos, Nikolas, Queralt-Rosinach, Núria, Roos, Marco, Sass, Julian, Schofield, Paul N, Seelow, Dominik, Siapos, Anastasios, Smedley, Damian, Smith, Lindsay D, Steinhaus, Robin, Sundaramurthi, Jagadish Chandrabose, Swietlik, Emilia M, Thun, Sylvia, Vasilevsky, Nicole A, Wagner, Alex H, Warner, Jeremy L, Weiland, Claus, Haendel, Melissa A, and Robinson, Peter N

Subjects
GAGH Phenopacket Modeling Consortium
Published
2022

7. A lower prevalence for recessive disorders in a random mating population is a transient phenomenon during and after a growth phase

Author

La Rocca, Luis A., Frank, Julia, Bentzen, Heidi Beate, Pantel, Jean-Tori, Gerischer, Konrad, Bovier, Anton, and Krawitz, Peter M.

Subjects
Quantitative Biology - Populations and Evolution
Abstract

Despite increasing data from population-wide sequencing studies, the risk for recessive disorders in consanguineous partnerships is still heavily debated. An important aspect that has not sufficiently been investigated theoretically, is the influence of inbreeding on mutation load and incidence rates when the population sizes change. We therefore developed a model to study these dynamics for a wide range of growth and mating conditions. In the phase of population expansion and shortly afterwards, our simulations show that there is a drop of diseased individuals at the expense of an increasing mutation load for random mating, while both parameters remain almost constant in highly consanguineous partnerships. This explains the empirical observation in present times that a high degree of consanguinity is associated with an increased risk of autosomal recessive disorders. However, it also states that the higher frequency of severe recessive disorders with developmental delay in inbred populations is a transient phenomenon before a mutation-selection balance is reached again., Comment: A video clip of our simulations can be found at https://youtu.be/5hOgLyRqWPg

Published
2020

8. Role of CAMK2D in neurodevelopment and associated conditions

Author

Rigter, Pomme M.F., de Konink, Charlotte, Dunn, Matthew J., Proietti Onori, Martina, Humberson, Jennifer B., Thomas, Matthew, Barnes, Caitlin, Prada, Carlos E., Weaver, K. Nicole, Ryan, Thomas D., Caluseriu, Oana, Conway, Jennifer, Calamaro, Emily, Fong, Chin-To, Wuyts, Wim, Meuwissen, Marije, Hordijk, Eva, Jonkers, Carsten N., Anderson, Lucas, Yuseinova, Berfin, Polonia, Sarah, Beysen, Diane, Stark, Zornitza, Savva, Elena, Poulton, Cathryn, McKenzie, Fiona, Bhoj, Elizabeth, Bupp, Caleb P., Bézieau, Stéphane, Mercier, Sandra, Blevins, Amy, Wentzensen, Ingrid M., Xia, Fan, Rosenfeld, Jill A., Hsieh, Tzung-Chien, Krawitz, Peter M., Elbracht, Miriam, Veenma, Danielle C.M., Schulman, Howard, Stratton, Margaret M., Küry, Sébastien, and van Woerden, Geeske M.

Published
2024
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12. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors

Author

Hsieh, Tzung-Chien, Bar-Haim, Aviram, Moosa, Shahida, Ehmke, Nadja, Gripp, Karen W., Pantel, Jean Tori, Danyel, Magdalena, Mensah, Martin Atta, Horn, Denise, Rosnev, Stanislav, Fleischer, Nicole, Bonini, Guilherme, Hustinx, Alexander, Schmid, Alexander, Knaus, Alexej, Javanmardi, Behnam, Klinkhammer, Hannah, Lesmann, Hellen, Sivalingam, Sugirthan, Kamphans, Tom, Meiswinkel, Wolfgang, Ebstein, Frédéric, Krüger, Elke, Küry, Sébastien, Bézieau, Stéphane, Schmidt, Axel, Peters, Sophia, Engels, Hartmut, Mangold, Elisabeth, Kreiß, Martina, Cremer, Kirsten, Perne, Claudia, Betz, Regina C., Bender, Tim, Grundmann-Hauser, Kathrin, Haack, Tobias B., Wagner, Matias, Brunet, Theresa, Bentzen, Heidi Beate, Averdunk, Luisa, Coetzer, Kimberly Christine, Lyon, Gholson J., Spielmann, Malte, Schaaf, Christian P., Mundlos, Stefan, Nöthen, Markus M., and Krawitz, Peter M.

Published
2022
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13. Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding.

Author

Abdelrazek, Ibrahim M., Knaus, Alexej, Javanmardi, Behnam, Krawitz, Peter M., Horn, Denise, Abdalla, Ebtesam M., and Kumar, Sheetal

Abstract

Background: Acromesomelic chondrodysplasias are a rare subgroup of the clinically and genetically heterogeneous osteochondrodysplasias that are characterised by abnormalities in the limb development and short stature. Here, we report a 2‐year‐old boy, offspring of consanguineous parents, with acromesomelic dysplasia and postaxial polydactyly in which exome sequencing identified a novel homozygous missense variant in BMPR1B. The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula. Methods: Whole trio exome sequencing was conducted to identify potential genetic variants in the patient. Results: The analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B. Conclusion: The skeletal phenotype can be brought in line with the phenotypes of previously reported cases of BMPR1B‐associated chondrodysplasias. However, the postaxial polydactyly described here is a novel clinical finding in a BMPR1B‐related case; notably, it has previously been reported in other acromesomelic dysplasia cases caused by homozygous pathogenic variants in GDF5—a gene which encodes for growth differentiation factor 5, a high‐affinity ligand to BMPR1B. [ABSTRACT FROM AUTHOR]

Published
2024
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14. A CRISPR-Cas9–engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions

Author

de los Santos, Miguel Rodríguez, Rivalan, Marion, David, Friederike S., Stumpf, Alexander, Pitsch, Julika, Tsortouktzidis, Despina, Velasquez, Laura Moreno, Voigt, Anne, Schilling, Karl, Mattei, Daniele, Long, Melissa, Vogt, Guido, Knaus, Alexej, Fischer-Zirnsak, Björn, Wittler, Lars, Timmermann, Bernd, Robinson, Peter N., Horn, Denise, Mundlos, Stefan, Kornak, Uwe, Becker, Albert J., Schmitz, Dietmar, Winter, York, and Krawitz, Peter M.

Published
2021

17. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author

Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, Hakonarson, Hakon, Li, Dong, Wang, Qin, Bayat, Allan, Battig, Mark R., Zhou, Yijing, Bosch, Daniëlle G.M., van Haaften, Gijs, Granger, Leslie, Petersen, Andrea K., Pérez-Jurado, Luis A., Aznar-Laín, Gemma, Aneja, Anushree, Hancarova, Miroslava, Bendova, Sarka, Schwarz, Martin, Pourova, Radka Kremlikova, Sedlacek, Zdenek, Keena, Beth A., March, Michael E., Hou, Cuiping, O’Connor, Nora, Bhoj, Elizabeth J., Harr, Margaret H., Lemire, Gabrielle, Boycott, Kym M., Towne, Meghan, Li, Megan, Tarnopolsky, Mark, Brady, Lauren, Parker, Michael J., Faghfoury, Hanna, Parsley, Lea Kristin, Agolini, Emanuele, Dentici, Maria Lisa, Novelli, Antonio, Wright, Meredith, Palmquist, Rachel, Lai, Khanh, Scala, Marcello, Striano, Pasquale, Iacomino, Michele, Zara, Federico, Cooper, Annina, Maarup, Timothy J., Byler, Melissa, Lebel, Robert Roger, Balci, Tugce B., Louie, Raymond, Lyons, Michael, Douglas, Jessica, Nowak, Catherine, Afenjar, Alexandra, Hoyer, Juliane, Keren, Boris, Maas, Saskia M., Motazacker, Mahdi M., Martinez-Agosto, Julian A., Rabani, Ahna M., McCormick, Elizabeth M., Falk, Marni J., Ruggiero, Sarah M., Helbig, Ingo, Møller, Rikke S., Tessarollo, Lino, Ardori, Francesco Tomassoni, Palko, Mary Ellen, Hsieh, Tzung Chien, Krawitz, Peter M., Ganapathi, Mythily, Gelb, Bruce D., Jobanputra, Vaidehi, Wilson, Ashley, Greally, John, Jacquemont, Sébastien, Jizi, Khadijé, Bruel, Ange Line, Quelin, Chloé, Misra, Vinod K., Chick, Erika, Romano, Corrado, Greco, Donatella, Arena, Alessia, Morleo, Manuela, Nigro, Vincenzo, Seyama, Rie, Uchiyama, Yuri, Matsumoto, Naomichi, Taira, Ryoji, Tashiro, Katsuya, Sakai, Yasunari, Yigit, Gökhan, Wollnik, Bernd, Wagner, Michael, Kutsche, Barbara, Hurst, Anna C.E., Thompson, Michelle L., Schmidt, Ryan, Randolph, Linda, Spillmann, Rebecca C., Shashi, Vandana, Higginbotham, Edward J., Cordeiro, Dawn, Carnevale, Amanda, Costain, Gregory, Khan, Tayyaba, Funalot, Benoît, Mau-Them, Frederic Tran, Garcia Moya, Luis Fernandez, García-Miñaúr, Sixto, Osmond, Matthew, Chad, Lauren, Quercia, Nada, Carrasco, Diana, Li, Chumei, Sanchez-Valle, Amarilis, Kelley, Meghan, Nizon, Mathilde, Jensson, Brynjar O., Sulem, Patrick, Stefansson, Kari, Gorokhova, Svetlana, Busa, Tiffany, Rio, Marlène, Habdallah, Hamza Hadj, Lesieur-Sebellin, Marion, Amiel, Jeanne, Pingault, Véronique, Mercier, Sandra, Vincent, Marie, Philippe, Christophe, Fatus-Fauconnier, Clemence, Friend, Kathryn, Halligan, Rebecca K., Biswas, Sunita, Rosser, Jane, Shoubridge, Cheryl, Corbett, Mark, Barnett, Christopher, Gecz, Jozef, Leppig, Kathleen, Slavotinek, Anne, Marcelis, Carlo, Pfundt, Rolph, de Vries, Bert B.A., van Slegtenhorst, Marjon A., Brooks, Alice S., Cogne, Benjamin, Rambaud, Thomas, Tümer, Zeynep, Zackai, Elaine H., Akizu, Naiara, Song, Yuanquan, and Hakonarson, Hakon

Abstract

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Published
2024

18. A post glycosylphosphatidylinositol (GPI) attachment to proteins, type 2 (PGAP2) variant identified in Mabry syndrome index cases: Molecular genetics of the prototypical inherited GPI disorder

Author

Thompson, Miles D., Knaus, Alexej A., Barshop, Bruce A., Caliebe, Almuth, Muhle, Hiltrud, Nguyen, Thi Tuyet Mai, Baratang, Nissan V., Kinoshita, Taroh, Percy, Maire E., Campeau, Philippe M., Murakami, Yoshiko, Cole, David E., Krawitz, Peter M., and Mabry, C. Charlton

Published
2020
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19. Unveiling the crucial neuronal role of the proteasomal ATPase subunit genePSMC5in neurodevelopmental proteasomopathies

Author

Küry, Sébastien, primary, Stanton, Janelle E., additional, van Woerden, Geeske, additional, Hsieh, Tzung-Chien, additional, Rosenfelt, Cory, additional, Pier Scott-Boyer, Marie, additional, Most, Victoria, additional, Wang, Tianyun, additional, Papendorf, Jonas Johannes, additional, de Konink, Charlotte, additional, Deb, Wallid, additional, Vignard, Virginie, additional, Studencka-Turski, Maja, additional, Besnard, Thomas, additional, Hajdukowicz, Anna Marta, additional, Thiel, Franziska, additional, Moller, Sophie, additional, Florenceau, Laetitia, additional, Cuinat, Silvestre, additional, Marsac, Sylvain, additional, Wentzensen, Ingrid, additional, Tuttle, Annabelle, additional, Forster, Cara, additional, Striesow, Johanna, additional, Golnik, Richard, additional, Ortiz, Damara, additional, Jenkins, Laura, additional, Rosenfeld, Jill A., additional, Ziegler, Alban, additional, Houdayer, Clara, additional, Bonneau, Dominique, additional, Torti, Erin, additional, Begtrup, Amber, additional, Monaghan, Kristin G., additional, Mullegama, Sureni V., additional, Volker-Touw, C.M.L. (Nienke), additional, van Gassen, Koen L.I., additional, Oegema, Renske, additional, de Pagter, Mirjam, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Ivanovski, Ivan, additional, McDonald, Kimberly, additional, Boothe, Emily, additional, Dauber, Andrew, additional, Baker, Janice, additional, Fabie, Noelle Andrea V., additional, Bernier, Raphael A., additional, Turner, Tychele N., additional, Srivastava, Siddharth, additional, Dies, Kira A., additional, Swanson, Lindsay, additional, Costin, Carrie, additional, Jobling, Rebekah K., additional, Pappas, John, additional, Rabin, Rachel, additional, Niyazov, Dmitriy, additional, Tsai, Anne Chun-Hui, additional, Kovak, Karen, additional, Beck, David B., additional, Malicdan, May Christine V, additional, Adams, David R, additional, Wolfe, Lynne, additional, Ganetzky, Rebecca D., additional, Muraresku, Colleen, additional, Babikyan, Davit, additional, Sedlacek, Zdenek, additional, Hancarova, Miroslava, additional, Timberlake, Andrew T., additional, Al Saif, Hind, additional, Schmidt, Berkley, additional, King, Kayla, additional, Hajianpour, MJ, additional, Costain, Gregory, additional, Prendergast, D'Arcy, additional, Li, Chumei, additional, Genevieve, David, additional, Vitobello, Antonio, additional, Sorlin, Arthur, additional, Philippe, Christophe, additional, Harel, Tamar, additional, Toker, Ori, additional, Sabir, Ataf, additional, Lim, Derek, additional, Hamilton, Mark, additional, Bryson, Lisa, additional, Cleary, Elaine, additional, Weber, Sacha, additional, Hoffman, Trevor L., additional, Cueto-Gonzalez, Anna Maria, additional, Tizzano, Eduardo Fidel, additional, Gomez-Andres, David, additional, Codina-Sola, Marta, additional, Ververi, Athina, additional, Pavlidou, Efterpi, additional, Lambropoulos, Alexandros, additional, Garganis, Kyriakos, additional, Rio, Marlene, additional, Levy, Jonathan, additional, Jurgensmeyer, Sarah, additional, McRae, Anne M., additional, Lessard, Mathieu K., additional, DAgostino, Maria Daniela, additional, De Bie, Isabelle, additional, Wegler, Meret, additional, Abou Jamra, Rami, additional, Kamphausen, Susanne B., additional, Bothe, Viktoria, additional, Busch, Larissa M., additional, Volker, Uwe, additional, Hammer, Elke, additional, Wende, Kristian, additional, Cogne, Benjamin, additional, Isidor, Bertrand, additional, Meiler, Jens, additional, Bosc-Rosati, Amelie, additional, Marcoux, Julien, additional, Bousquet, Marie-Pierre, additional, Poschmann, Jeremie, additional, Laumonnier, Frederic, additional, Hildebrand, Peter W., additional, Eichler, Evan E., additional, McWalter, Kirsty, additional, Krawitz, Peter M., additional, Droit, Arnaud, additional, Elgersma, Ype, additional, Grabrucker, Andreas M., additional, Bolduc, Francois, additional, Bézieau, Stéphane, additional, Ebstein, Frédéric, additional, and Krüger, Elke, additional

Published
2024
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20. Delineation of the adult phenotype of Coffin–Siris syndrome in 35 individuals

Author

Schmetz, Ariane, primary, Lüdecke, Hermann-Josef, additional, Surowy, Harald, additional, Sivalingam, Sugirtahn, additional, Bruel, Ange-Line, additional, Caumes, Roseline, additional, Charles, Perrine, additional, Chatron, Nicolas, additional, Chrzanowska, Krystyna, additional, Codina-Solà, Marta, additional, Colson, Cindy, additional, Cuscó, Ivon, additional, Denommé-Pichon, Anne-Sophie, additional, Edery, Patrick, additional, Faivre, Laurence, additional, Green, Andrew, additional, Heide, Solveig, additional, Hsieh, Tzung-Chien, additional, Hustinx, Alexander, additional, Kleinendorst, Lotte, additional, Knopp, Cordula, additional, Kraft, Florian, additional, Krawitz, Peter M., additional, Lasa-Aranzasti, Amaia, additional, Lesca, Gaetan, additional, López-González, Vanesa, additional, Maraval, Julien, additional, Mignot, Cyril, additional, Neuhann, Teresa, additional, Netzer, Christian, additional, Oehl-Jaschkowitz, Barbara, additional, Petit, Florence, additional, Philippe, Christophe, additional, Posmyk, Renata, additional, Putoux, Audrey, additional, Reis, André, additional, Sánchez-Soler, María José, additional, Suh, Julia, additional, Tkemaladze, Tinatin, additional, Tran Mau Them, Frédéric, additional, Travessa, André, additional, Trujillano, Laura, additional, Valenzuela, Irene, additional, van Haelst, Mieke M., additional, Vasileiou, Georgia, additional, Vincent-Delorme, Catherine, additional, Walther, Mona, additional, Verde, Pablo, additional, Bramswig, Nuria C., additional, and Wieczorek, Dagmar, additional

Published
2023
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21. Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation

Author

Hochsmann, Britta, Murakami, Yoshiko, Osato, Makiko, Knaus, Alexej, Kawamoto, Michi, Inoue, Norimitsu, Hirata, Tetsuya, Murata, Shogo, Anliker, Markus, Eggermann, Thomas, Jager, Marten, Floettmann, Ricarda, Hollein, Alexander, Murase, Sho, Ueda, Yasutaka, Nishimura, Jun-ichi, Kanakura, Yuzuru, Kohara, Nobuo, Schrezenmeier, Hubert, Krawitz, Peter M., and Kinoshita, Taroh

Subjects
Eculizumab, Lectins -- Genetic aspects, Canakinumab, B cells -- Genetic aspects, Gene mutation -- Genetic aspects, Medical research, Anakinra, Genes, Proteins, Book publishing, Meningitis, Hemolysis, Health care industry, Osaka University
Abstract

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PICA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PICT on chromosome 20. These PIGTPNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PICT allele, whereas the other PICT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients' leukocytes and of PICT-KO THP-1 cells we show that, through increased IL-1[beta] secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations., Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell (HSC) disorder characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure (1, 2). Affected cells harbor a somatic mutation [...]

Published
2019
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22. PEDIA: prioritization of exome data by image analysis

Author

Hsieh, Tzung-Chien, Mensah, Martin A., Pantel, Jean T., Aguilar, Dione, Bar, Omri, Bayat, Allan, Becerra-Solano, Luis, Bentzen, Heidi B., Biskup, Saskia, Borisov, Oleg, Braaten, Oivind, Ciaccio, Claudia, Coutelier, Marie, Cremer, Kirsten, Danyel, Magdalena, Daschkey, Svenja, Eden, Hilda David, Devriendt, Koenraad, Wilson, Sandra, Douzgou, Sofia, Đukić, Dejan, Ehmke, Nadja, Fauth, Christine, Fischer-Zirnsak, Björn, Fleischer, Nicole, Gabriel, Heinz, Graul-Neumann, Luitgard, Gripp, Karen W., Gurovich, Yaron, Gusina, Asya, Haddad, Nechama, Hajjir, Nurulhuda, Hanani, Yair, Hertzberg, Jakob, Hoertnagel, Konstanze, Howell, Janelle, Ivanovski, Ivan, Kaindl, Angela, Kamphans, Tom, Kamphausen, Susanne, Karimov, Catherine, Kathom, Hadil, Keryan, Anna, Knaus, Alexej, Köhler, Sebastian, Kornak, Uwe, Lavrov, Alexander, Leitheiser, Maximilian, Lyon, Gholson J., Mangold, Elisabeth, Reina, Purificación Marín, Carrascal, Antonio Martinez, Mitter, Diana, Herrador, Laura Morlan, Nadav, Guy, Nöthen, Markus, Orrico, Alfredo, Ott, Claus-Eric, Park, Kristen, Peterlin, Borut, Pölsler, Laura, Raas-Rothschild, Annick, Randolph, Linda, Revencu, Nicole, Fagerberg, Christina Ringmann, Robinson, Peter Nick, Rosnev, Stanislav, Rudnik, Sabine, Rudolf, Gorazd, Schatz, Ulrich, Schossig, Anna, Schubach, Max, Shanoon, Or, Sheridan, Eamonn, Smirin-Yosef, Pola, Spielmann, Malte, Suk, Eun-Kyung, Sznajer, Yves, Thiel, Christian T., Thiel, Gundula, Verloes, Alain, Vrecar, Irena, Wahl, Dagmar, Weber, Ingrid, Winter, Korina, Wiśniewska, Marzena, Wollnik, Bernd, Yeung, Ming W., Zhao, Max, Zhu, Na, Zschocke, Johannes, Mundlos, Stefan, Horn, Denise, and Krawitz, Peter M.

Published
2019
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23. Understanding recessive disease risk in multi‐ethnic populations with different degrees of consanguinity.

Author

La Rocca, Luis A., Frank, Julia, Bentzen, Heidi Beate, Pantel, Jean Tori, Gerischer, Konrad, Bovier, Anton, and Krawitz, Peter M.

Abstract

Population medical genetics aims at translating clinically relevant findings from recent studies of large cohorts into healthcare for individuals. Genetic counseling concerning reproductive risks and options is still mainly based on family history, and consanguinity is viewed to increase the risk for recessive diseases regardless of the demographics. However, in an increasingly multi‐ethnic society with diverse approaches to partner selection, healthcare professionals should also sharpen their intuition for the influence of different mating schemes in non‐equilibrium dynamics. We, therefore, revisited the so‐called out‐of‐Africa model and studied in forward simulations with discrete and not overlapping generations the effect of inbreeding on the average number of recessive lethals in the genome. We were able to reproduce in both frameworks the drop in the incidence of recessive disorders, which is a transient phenomenon during and after the growth phase of a population, and therefore showed their equivalence. With the simulation frameworks, we also provide the means to study and visualize the effect of different kin sizes and mating schemes on these parameters for educational purposes. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author

Li, Dong, primary, Wang, Qin, additional, Bayat, Allan, additional, Battig, Mark R., additional, Zhou, Yijing, additional, Bosch, Daniëlle G.M., additional, van Haaften, Gijs, additional, Granger, Leslie, additional, Petersen, Andrea K., additional, Pérez-Jurado, Luis A., additional, Aznar-Laín, Gemma, additional, Aneja, Anushree, additional, Hancarova, Miroslava, additional, Bendova, Sarka, additional, Schwarz, Martin, additional, Kremlíková Pourová, Radka, additional, Sedlacek, Zdenek, additional, Keena, Beth A., additional, March, Michael E., additional, Hou, Cuiping, additional, O'Connor, Nora, additional, Bhoj, Elizabeth J., additional, Harr, Margaret H., additional, Lemire, Gabrielle, additional, Boycott, Kym M., additional, Towne, Meghan C., additional, Li, Megan, additional, Tarnopolsky, Mark, additional, Brady, Lauren, additional, Parker, Michael J., additional, Faghfoury, Hanna, additional, Parsley, Lea Kristin, additional, Agolini, Emanuele, additional, Dentici, Maria Lisa, additional, Novelli, Antonio, additional, Wright, Meredith S., additional, Palmquist, Rachel, additional, Lai, Khanh, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Iacomino, Michele, additional, Zara, Federico, additional, Cooper, Annina, additional, Maarup, Timothy J., additional, Byler, Melissa, additional, Lebel, Robert Roger, additional, Balci, Tugce B., additional, Louie, Raymond J., additional, Lyons, Michael J., additional, Douglas, Jessica, additional, Nowak, Catherine B., additional, Afenjar, Alexandra, additional, Hoyer, Juliane, additional, Keren, Boris, additional, Maas, Saskia M., additional, Motazacker, Mahdi M., additional, Martinez-Agosto, Julian A., additional, Rabani, Ahna M., additional, McCormick, Elizabeth M., additional, Falk, Marni, additional, Ruggiero, Sarah M., additional, Helbig, Ingo, additional, Møller, Rikke S., additional, Tessarollo, Lino, additional, Tomassoni-Ardori, Francesco, additional, Palko, Mary Ellen, additional, Hsieh, Tzung-Chien, additional, Krawitz, Peter M., additional, Ganapathi, Mythily, additional, Gelb, Bruce D., additional, Jobanputra, Vaidehi, additional, Wilson, Ashley, additional, Greally, John, additional, Jacquemont, Sébastien, additional, Jizi, Khadijé, additional, Ange-Line, Bruel, additional, Quelin, Chloé, additional, Misra, Vinod K., additional, Chick, Erika, additional, Romano, Corrado, additional, Greco, Donatella, additional, Arena, Alessia, additional, Morleo, Manuela, additional, Nigro, Vincenzo, additional, Seyama, Rie, additional, Uchiyama, Yuri, additional, Matsumoto, Naomichi, additional, Taira, Ryoji, additional, Tashiro, Katsuya, additional, Sakai, Yasunari, additional, Yigit, Gökhan, additional, Wollnik, Bernd, additional, Wagner, Michael, additional, Kutsche, Barbara, additional, Hurst, Anna C.E., additional, Thompson, Michelle L., additional, Schmidt, Ryan J., additional, Randolph, Linda M., additional, Spillmann, Rebecca C., additional, Shashi, Vandana, additional, Higginbotham, Edward J., additional, Cordeiro, Dawn, additional, Carnevale, Amanda, additional, Costain, Gregory, additional, Khan, Tayyaba, additional, Funalot, Benoît, additional, Tran Mau-Them, Frederic, additional, Fernandez Garcia Moya, Luis, additional, García-Miñaúr, Sixto, additional, Osmond, Matthew, additional, Chad, Lauren, additional, Quercia, Nada, additional, Carrasco, Diana, additional, Li, Chumei, additional, Sanchez-Valle, Amarilis, additional, Kelley, Meghan, additional, Nizon, Mathilde, additional, Jensson, Brynjar O., additional, Sulem, Patrick, additional, Stefansson, Kari, additional, Gorokhova, Svetlana, additional, Busa, Tiffany, additional, Rio, Marlène, additional, Hadj Abdallah, Hamza, additional, Lesieur-Sebellin, Marion, additional, Amiel, Jeanne, additional, Pingault, Véronique, additional, Mercier, Sandra, additional, Vincent, Marie, additional, Philippe, Christophe, additional, Fatus-Fauconnier, Clemence, additional, Friend, Kathryn, additional, Halligan, Rebecca K., additional, Biswas, Sunita, additional, Rosser, Jane M.R., additional, Shoubridge, Cheryl, additional, Corbett, Mark A., additional, Barnett, Christopher, additional, Gecz, Jozef, additional, Leppig, Kathleen A., additional, Slavotinek, Anne, additional, Marcelis, Carlo, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Slegtenhorst, Marjon A., additional, Brooks, Alice S., additional, Cogne, Benjamin, additional, Rambaud, Thomas, additional, Tümer, Zeynep, additional, Zackai, Elaine H., additional, Akizu, Naiara, additional, Song, Yuanquan, additional, and Hakonarson, Hakon, additional

Published
2023
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25. Deeplasia: deep learning for bone age assessment validated on skeletal dysplasias

Author

Rassmann, Sebastian, primary, Keller, Alexandra, additional, Skaf, Kyra, additional, Hustinx, Alexander, additional, Gausche, Ruth, additional, Ibarra-Arrelano, Miguel A., additional, Hsieh, Tzung-Chien, additional, Madajieu, Yolande E. D., additional, Nöthen, Markus M., additional, Pfäffle, Roland, additional, Attenberger, Ulrike I., additional, Born, Mark, additional, Mohnike, Klaus, additional, Krawitz, Peter M., additional, and Javanmardi, Behnam, additional

Published
2023
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29. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Author

Kumar, Sheetal, primary, Borisov, Oleg, additional, Maj, Carlo, additional, Ralser, Damian J., additional, Humbatova, Aytaj, additional, Hanneken, Sandra, additional, Schmieder, Astrid, additional, Groß, Janina, additional, Maintz, Laura, additional, Heineke, Andre, additional, Knuever, Jana, additional, Fagerberg, Christina, additional, Parmentier, Laurent, additional, Anemüller, Waltraud, additional, Oji, Vinzenz, additional, Tantcheva-Poór, Iliana, additional, Fölster-Holst, Regina, additional, Wenzel, Joerg, additional, Krawitz, Peter M., additional, Frank, Jorge, additional, and Betz, Regina C., additional

Published
2023
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31. GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases

Author

Lesmann, Hellen, primary, Hustinx, Alexander, additional, Moosa, Shahida, additional, Marchi, Elaine, additional, Caro, Pilar, additional, Abdelrazek, Ibrahim M., additional, Pantel, Jean Tori, additional, Klinkhammer, Hannah, additional, ten Hagen, Merle, additional, Kamphans, Tom, additional, Meiswinkel, Wolfgang, additional, Li, Jing-Mei, additional, Javanmardi, Behnam, additional, Knaus, Alexej, additional, Uwineza, Annette, additional, Knopp, Cordula, additional, Tkemaladze, Tinatin, additional, Elbracht, Miriam, additional, Mattern, Larissa, additional, Jamra, Rami Abou, additional, Velmans, Clara, additional, Strehlow, Vincent, additional, Goel, Himanshu, additional, Nunes, Beatriz Carvalho, additional, Vilella, Thainá, additional, Pinheiro, Isabel Furquim, additional, Kim, Chong Ae, additional, Melaragno, Maria Isabel, additional, Barakat, Tahsin Stefan, additional, Nabil, Amira, additional, Suh, Julia, additional, Averdunk, Luisa, additional, Ekure, Ekanem, additional, Graziano, Claudio, additional, Phowthongkum, Prasit, additional, Güzel, Nergis, additional, Haack, Tobias B., additional, Brunet, Theresa, additional, Rudnik-Schöneborn, Sabine, additional, Platzer, Konrad, additional, Borovikov, Artem, additional, Schnabel, Franziska, additional, Heuft, Lara, additional, Herrmann, Vera, additional, Martinez-Monseny, Antonio F., additional, Höller, Matthias, additional, Alaaeldin, Khoshoua, additional, Jezela-Stanek, Aleksandra, additional, Mohamed, Amal, additional, Lasa-Aranzasti, Amaia, additional, Sayer, John A., additional, Hu, Ping, additional, Hanchard, Suzanna E. Ledgister, additional, Elmakkawy, Gehad, additional, Safwat, Sylvia, additional, Ebstein, Frédéric, additional, Krüger, Elke, additional, Küry, Sébastien, additional, Arlt, Annabelle, additional, Marbach, Felix, additional, Netzer, Christian, additional, Kaptain, Sophia, additional, Weiland, Hannah, additional, Li, Dong, additional, Dupuis, Lucie, additional, Mendoza-Londono, Roberto, additional, Houge, Sofia Douzgou, additional, Weis, Denisa, additional, Chung, Brian Hon-Yin, additional, Mak, Christopher C.Y., additional, Devriendt, Koen, additional, Gripp, Karen W., additional, Mücke, Martin, additional, Verloes, Alain, additional, Schaaf, Christian P., additional, Nellåker, Christoffer, additional, Solomon, Benjamin D., additional, Waikel, Rebekah L., additional, Nöthen, Markus M., additional, Abdalla, Ebtesam, additional, Lyon, Gholson J., additional, Krawitz, Peter M., additional, and Hsieh, Tzung-Chien, additional

Published
2023
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32. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Author

Kumar, Sheetal, Borisov, Oleg, Maj, Carlo, Ralser, Damian J., Humbatova, Aytaj, Hanneken, Sandra, Schmieder, Astrid, Groß, Janina, Maintz, Laura, Heineke, Andre, Knuever, Jana, Fagerberg, Christina, Parmentier, Laurent, Anemüller, Waltraud, Oji, Vinzenz, Tantcheva-Poór, Iliana, Fölster-Holst, Regina, Wenzel, Joerg, Krawitz, Peter M., Frank, Jorge, and Betz, Regina C.

Published
2024
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33. Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, primary, Danyel, Magdalena, additional, Grundmann, Kathrin, additional, Brunet, Theresa, additional, Klinkhammer, Hannah, additional, Hsieh, Tzung-Chien, additional, Engels, Hartmut, additional, Peters, Sophia, additional, Knaus, Alexej, additional, Moosa, Shahida, additional, Averdunk, Luisa, additional, Boschann, Felix, additional, Sczakiel, Henrike, additional, Schwartzmann, Sarina, additional, Mensah, Martin Atta, additional, Pantel, Jean Tori, additional, Holtgrewe, Manuel, additional, Boesch, Annemarie, additional, Weiss, Claudia, additional, Weinhold, Natalie, additional, Suter, Aude-Annick, additional, Stoltenburg, Corinna, additional, Neugebauer, Julia, additional, Kallinich, Tillmann, additional, Kaindl, Angela M., additional, Holzhauer, Susanne, additional, Buehrer, Christoph, additional, Bufler, Philip, additional, Kornak, Uwe, additional, Ott, Claus-Eric, additional, Schuelke, Markus, additional, Nguyen, Hoa Huu Phuc, additional, Hoffjan, Sabine, additional, Grasemann, Corinna, additional, Rothoeft, Tobias, additional, Brinkmann, Folke, additional, Matar, Nora, additional, Sivalingam, Sugirthan, additional, Perne, Claudia, additional, Mangold, Elisabeth, additional, Kreiss, Martina, additional, Cremer, Kirsten, additional, Betz, Regina C., additional, Bender, Tim, additional, Muecke, Martin, additional, Grigull, Lorenz, additional, Klockgether, Thomas, additional, Isabel, Spier, additional, Heimbach, Andre, additional, Tim, Bender, additional, Brand, Fabian, additional, Stieber, Christiane, additional, Morawiec, Alexandra Marzena, additional, Karakostas, Pantelis, additional, Schaefer, Valentin S., additional, Bernsen, Sarah, additional, Weydt, Patrick, additional, Castro-Gomez, Sergio, additional, Aziz, Ahmad, additional, Grobe-Einsler, Marcus, additional, Kimmich, Okka, additional, Kobeleva, Xenia, additional, oender, Demet, additional, Lesmann, Hellen, additional, Kumar, Sheetal, additional, Tacik, Pawel, additional, Lee-Kirsch, Min Ae, additional, Berner, Reinhard, additional, Schuetz, Catharina, additional, Koerholz, Julia, additional, Kretschmer, Tanita, additional, Di Donato, Nataliya, additional, Schroeck, Evelin, additional, Heinen, Andre, additional, Reuner, Ulrike, additional, Hansske, Amalia-Mihaela, additional, Kaiser, Frank J., additional, Manka, Eva, additional, Munteanu, Martin, additional, Kuechler, Alma, additional, Cordula, Kiewert, additional, Hirtz, Raphael, additional, Schlapakow, Elena, additional, Schlein, Christian, additional, Lisfeld, Jasmin, additional, Kubisch, Christian, additional, Herget, Theresia, additional, Hempel, Maja, additional, Weiler-Normann, Christina, additional, Ullrich, Kurt, additional, Schramm, Christoph, additional, Rudolph, Cornelia, additional, Rillig, Franziska, additional, Groffmann, Maximilian, additional, Muntau, Ania, additional, Tibelius, Alexandra, additional, Schwaibold, Eva M. C., additional, Schaaf, Christian P., additional, Zawada, Michal, additional, Kaufmann, Lilian, additional, Hinderhofer, Katrin, additional, Okun, Pamela M., additional, Kotzaeridou, Urania, additional, Hoffmann, Georg F., additional, Choukair, Daniela, additional, Bettendorf, Markus, additional, Spielmann, Malte, additional, Ripke, Annekatrin, additional, Pauly, Martje, additional, Muenchau, Alexander, additional, Lohmann, Katja, additional, Huening, Irina, additional, Hanker, Britta, additional, Baeumer, Tobias, additional, Herzog, Rebecca, additional, Hellenbroich, Yorck, additional, Westphal, Dominik S., additional, Strom, Tim, additional, Kovacs, Reka, additional, Riedhammer, Korbinian M., additional, Mayerhanser, Katharina, additional, Graf, Elisabeth, additional, Brugger, Melanie, additional, Hoefele, Julia, additional, Oexle, Konrad, additional, Mirza-Schreiber, Nazanin, additional, Berutti, Riccardo, additional, Schatz, Ulrich, additional, Krenn, Martin, additional, Makowski, Christine, additional, Weigand, Heike, additional, Schroeder, Sebastian, additional, Rohlfs, Meino, additional, Katharina, Vill, additional, Hauck, Fabian, additional, Borggraefe, Ingo, additional, Mueller-Felber, Wolfgang, additional, Kurth, Ingo, additional, Elbracht, Miriam, additional, Knopp, Cordula, additional, Begemann, Matthias, additional, Kraft, Florian, additional, Lemke, Johannes, additional, Hentschel, Julia, additional, Platzer, Konrad, additional, Strehlow, Vincent, additional, Abou Jamra, Rami, additional, Kehrer, Martin, additional, Demidov, German, additional, Beck-Woedl, Stefanie, additional, Graessner, Holm, additional, Sturm, Marc, additional, Zeltner, Lena, additional, Schoels, Ludger J., additional, Magg, Janine, additional, Bevot, Andrea, additional, Kehrer, Christiane, additional, Kaiser, Nadja, additional, Horn, Denise, additional, Grueters-Kieslich, Annette, additional, Klein, Christoph, additional, Mundlos, Stefan, additional, Noethen, Markus, additional, Riess, Olaf, additional, Meitinger, Thomas, additional, Krude, Heiko, additional, Krawitz, Peter M., additional, Haack, Tobias, additional, Ehmke, Nadja, additional, and Wagner, Matias, additional

Published
2023
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34. Deeplasia: prior-free deep learning for pediatric bone age assessment robust to skeletal dysplasias

Author

Rassmann, Sebastian, primary, Keller, Alexandra, additional, Skaf, Kyra, additional, Hustinx, Alexander, additional, Gausche, Ruth, additional, Ibarra-Arrelano, Miguel A., additional, Hsieh, Tzung-Chien, additional, Madajieu, Yolande E. D., additional, Nöthen, Markus M., additional, Pfäffle, Roland, additional, Mohnike, Klaus, additional, Krawitz, Peter M., additional, and Javanmardi, Behnam, additional

Published
2023
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35. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

36. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

37. Founder Variants in KRT5and POGLUT1Are Implicated in Dowling-Degos Disease

Author

Kumar, Sheetal, Borisov, Oleg, Maj, Carlo, Ralser, Damian J., Humbatova, Aytaj, Hanneken, Sandra, Schmieder, Astrid, Groß, Janina, Maintz, Laura, Heineke, Andre, Knuever, Jana, Fagerberg, Christina, Parmentier, Laurent, Anemüller, Waltraud, Oji, Vinzenz, Tantcheva-Poór, Iliana, Fölster-Holst, Regina, Wenzel, Joerg, Krawitz, Peter M., Frank, Jorge, and Betz, Regina C.

Published
2024
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38. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype–phenotype correlation study

Author

Loong, Lucy, primary, Tardivo, Agostina, additional, Knaus, Alexej, additional, Hashim, Mona, additional, Pagnamenta, Alistair T., additional, Alt, Kerstin, additional, Böhrer-Rabel, Helena, additional, Caro-Llopis, Alfonso, additional, Cole, Trevor, additional, Distelmaier, Felix, additional, Edery, Patrick, additional, Ferreira, Carlos R., additional, Jezela-Stanek, Aleksandra, additional, Kerr, Bronwyn, additional, Kluger, Gerhard, additional, Krawitz, Peter M., additional, Kuhn, Marius, additional, Lemke, Johannes R., additional, Lesca, Gaetan, additional, Lynch, Sally Ann, additional, Martinez, Francisco, additional, Maxton, Caroline, additional, Mierzewska, Hanna, additional, Monfort, Sandra, additional, Nicolai, Joost, additional, Orellana, Carmen, additional, Pal, Deb K., additional, Płoski, Rafał, additional, Quarrell, Oliver W., additional, Rosello, Monica, additional, Rydzanicz, Małgorzata, additional, Sabir, Ataf, additional, Śmigiel, Robert, additional, Stegmann, Alexander P.A., additional, Stewart, Helen, additional, Stumpel, Constance, additional, Szczepanik, Elżbieta, additional, Tzschach, Andreas, additional, Wolfe, Lynne, additional, Taylor, Jenny C., additional, Murakami, Yoshiko, additional, Kinoshita, Taroh, additional, Bayat, Allan, additional, and Kini, Usha, additional

Published
2023
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39. Perspectives on the future of dysmorphology

Author

Solomon, Benjamin D., primary, Adam, Margaret P., additional, Fong, Chin‐To, additional, Girisha, Katta M., additional, Hall, Judith G., additional, Hurst, Anna C. E., additional, Krawitz, Peter M., additional, Moosa, Shahida, additional, Phadke, Shubha R., additional, Tekendo‐Ngongang, Cedrik, additional, and Wenger, Tara L., additional

Published
2022
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40. Next‐generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen‐de Vries syndrome

Author

Brand, Fabian, primary, Vijayananth, Aswinkumar, additional, Hsieh, Tzung‐Chien, additional, Schmidt, Axel, additional, Peters, Sophia, additional, Mangold, Elisabeth, additional, Cremer, Kirsten, additional, Bender, Tim, additional, Sivalingam, Sugirthan, additional, Hundertmark, Hela, additional, Knaus, Alexej, additional, Engels, Hartmut, additional, Krawitz, Peter M., additional, and Perne, Claudia, additional

Published
2022
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41. Clinical, Brain, and Multilevel Clustering in Early Psychosis and Affective Stages

Author

Dwyer, Dominic B., Buciuman, Madalina-Octavia, Ruef, Anne, Kambeitz, Joseph, Sen Dong, Mark, Stinson, Caedyn, Kambeitz-Ilankovic, Lana, Degenhardt, Franziska, Sanfelici, Rachele, Antonucci, Linda A., Lalousis, Paris Alexandros, Wenzel, Julian, Urquijo-Castro, Maria Fernanda, Popovic, David, Oeztuerk, Oemer Faruk, Haas, Shalaila S., Weiske, Johanna, Hauke, Daniel, Neufang, Susanne, Schmidt-Kraepelin, Christian, Ruhrmann, Stephan, Penzel, Nora, Lichtenstein, Theresa, Rosen, Marlene, Chisholm, Katharine, Riecher-Roessler, Anita, Egloff, Laura, Schmidt, Andre, Andreou, Christina, Hietala, Jarmo, Schirmer, Timo, Romer, Georg, Michel, Chantal, Rossler, Wulf, Maj, Carlo, Borisov, Oleg, Krawitz, Peter M., Falkai, Peter, Pantelis, Christos, Lencer, Rebekka, Bertolino, Alessandro, Borgwardt, Stefan, Noethen, Markus, Brambilla, Paolo, Schultze-Lutter, Frauke, Meisenzahl, Eva, Wood, Stephen J., Davatzikos, Christos, Upthegrove, Rachel, Salokangas, Raimo K. R., Koutsouleris, Nikolaos, Dwyer, Dominic B., Buciuman, Madalina-Octavia, Ruef, Anne, Kambeitz, Joseph, Sen Dong, Mark, Stinson, Caedyn, Kambeitz-Ilankovic, Lana, Degenhardt, Franziska, Sanfelici, Rachele, Antonucci, Linda A., Lalousis, Paris Alexandros, Wenzel, Julian, Urquijo-Castro, Maria Fernanda, Popovic, David, Oeztuerk, Oemer Faruk, Haas, Shalaila S., Weiske, Johanna, Hauke, Daniel, Neufang, Susanne, Schmidt-Kraepelin, Christian, Ruhrmann, Stephan, Penzel, Nora, Lichtenstein, Theresa, Rosen, Marlene, Chisholm, Katharine, Riecher-Roessler, Anita, Egloff, Laura, Schmidt, Andre, Andreou, Christina, Hietala, Jarmo, Schirmer, Timo, Romer, Georg, Michel, Chantal, Rossler, Wulf, Maj, Carlo, Borisov, Oleg, Krawitz, Peter M., Falkai, Peter, Pantelis, Christos, Lencer, Rebekka, Bertolino, Alessandro, Borgwardt, Stefan, Noethen, Markus, Brambilla, Paolo, Schultze-Lutter, Frauke, Meisenzahl, Eva, Wood, Stephen J., Davatzikos, Christos, Upthegrove, Rachel, Salokangas, Raimo K. R., and Koutsouleris, Nikolaos

Abstract

IMPORTANCE Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. OBJECTIVE To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. DESIGN, SETTING, AND PARTICIPANTS A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. MAIN OUTCOMES AND MEASURES A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. RESULTS There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering re

Published
2022

43. Perspectives on the future of dysmorphology.

Author

Solomon, Benjamin D., Adam, Margaret P., Fong, Chin‐To, Girisha, Katta M., Hall, Judith G., Hurst, Anna C. E., Krawitz, Peter M., Moosa, Shahida, Phadke, Shubha R., Tekendo‐Ngongang, Cedrik, and Wenger, Tara L.

Abstract

The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable. Within genetics, the practice of dysmorphology, as defined by pioneering geneticist David W. Smith in the 1960s as "the study of, or general subject of abnormal development of tissue form" has also been affected by technological advances as well as more general trends in biomedicine. To address possibilities, potential, and perils regarding the future of dysmorphology, a group of clinical geneticists, representing different career stages, areas of focus, and geographic regions, have contributed to this piece by providing insights about how the practice of dysmorphology will develop over the next several decades. [ABSTRACT FROM AUTHOR]

Published
2023
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45. The GA4GH Phenopacket schema: A computable representation of clinical data for precision medicine

Author

Jacobsen, Julius O. B., primary, Baudis, Michael, additional, Baynam, Gareth S., additional, Beckmann, Jacques S., additional, Beltran, Sergi, additional, Callahan, Tiffany J., additional, Chute, Christopher G., additional, Courtot, Mélanie, additional, Danis, Daniel, additional, Elemento, Olivier, additional, Freimuth, Robert R., additional, Gargano, Michael A., additional, Groza, Tudor, additional, Hamosh, Ada, additional, Harris, Nomi L., additional, Kaliyaperumal, Rajaram, additional, Khalifa, Aly, additional, Krawitz, Peter M., additional, Köhler, Sebastian, additional, Laraway, Brian J., additional, Lehväslaiho, Heikki, additional, Lloyd, Kent C., additional, Matalonga, Leslie, additional, McMurry, Julie A., additional, Metke-Jimenez, Alejandro, additional, Mungall, Christopher J., additional, Munoz-Torres, Monica C., additional, Ogishima, Soichi, additional, Papakonstantinou, Anastasios, additional, Piscia, Davide, additional, Pontikos, Nikolas, additional, Queralt-Rosinach, Núria, additional, Roos, Marco, additional, Schofield, Paul N., additional, Siapos, Anastasios, additional, Smedley, Damian, additional, Smith, Lindsay D., additional, Steinhaus, Robin, additional, Sundaramurthi, Jagadish Chandrabose, additional, Swietlik, Emilia M., additional, Thun, Sylvia, additional, Vasilevsky, Nicole A., additional, Wagner, Alex H., additional, Warner, Jeremy L., additional, Weiland, Claus, additional, Haendel, Melissa A., additional, and Robinson, Peter N., additional

Published
2021
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46. KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Author

Guo, Lily, primary, Park, Jiyeon, additional, Yi, Edward, additional, Marchi, Elaine, additional, Hsieh, Tzung-Chien, additional, Kibalnyk, Yana, additional, Moreno-Sáez, Yolanda, additional, Biskup, Saskia, additional, Puk, Oliver, additional, Beger, Carmela, additional, Voronova, Anastassia, additional, Krawitz, Peter M., additional, and Lyon, Gholson J., additional

Published
2021
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49. TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19

Author

Schmidt, Axel, primary, Peters, Sophia, additional, Knaus, Alexej, additional, Sabir, Hemmen, additional, Hamsen, Frauke, additional, Maj, Carlo, additional, Fazaal, Julia, additional, Sivalingam, Sugirthan, additional, Savchenko, Oleksandr, additional, Mantri, Aakash, additional, Holzinger, Dirk, additional, Neudorf, Ulrich, additional, Müller, Andreas, additional, Ludwig, Kerstin U., additional, Krawitz, Peter M., additional, Engels, Hartmut, additional, Nöthen, Markus M., additional, and Bagci, Soyhan, additional

Published
2021
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50. Extending the allelic spectrum at noncoding risk loci of orofacial clefting

Author

Thieme, Frederic, primary, Henschel, Leonie, additional, Hammond, Nigel L., additional, Ishorst, Nina, additional, Hausen, Jonas, additional, Adamson, Antony D., additional, Biedermann, Angelika, additional, Bowes, John, additional, Zieger, Hanna K., additional, Maj, Carlo, additional, Kruse, Teresa, additional, Buness, Andreas, additional, Hoischen, Alexander, additional, Gilissen, Christian, additional, Kreusch, Thomas, additional, Jäger, Andreas, additional, Gölz, Lina, additional, Braumann, Bert, additional, Aldhorae, Khalid, additional, Rojas‐Martinez, Augusto, additional, Krawitz, Peter M., additional, Mangold, Elisabeth, additional, Dixon, Michael J., additional, and Ludwig, Kerstin U., additional

Published
2021
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