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528 results on '"Pérez-Jurado, Luis A."'

3. ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

Author

Schlüter, Agatha, Vélez-Santamaría, Valentina, Verdura, Edgard, Rodríguez-Palmero, Agustí, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Launay, Nathalie, Guilera, Cristina, Martínez, Juan José, Homedes-Pedret, Christian, Albertí-Aguiló, M. Antonia, Zulaika, Miren, Martí, Itxaso, Troncoso, Mónica, Tomás-Vila, Miguel, Bullich, Gemma, García-Pérez, M. Asunción, Sobrido-Gómez, María-Jesús, López-Laso, Eduardo, Fons, Carme, Del Toro, Mireia, Macaya, Alfons, Beltran, Sergi, Gutiérrez-Solana, Luis G., Pérez-Jurado, Luis A., Aguilera-Albesa, Sergio, de Munain, Adolfo López, Casasnovas, Carlos, and Pujol, Aurora

Published
2023
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4. Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

Author

Dias, Kerith-Rae, Shrestha, Rupendra, Schofield, Deborah, Evans, Carey-Anne, O’Heir, Emily, Zhu, Ying, Zhang, Futao, Standen, Krystle, Weisburd, Ben, Stenton, Sarah L., Sanchis-Juan, Alba, Brand, Harrison, Talkowski, Michael E., Ma, Alan, Ghedia, Sondy, Wilson, Meredith, Sandaradura, Sarah A., Smith, Janine, Kamien, Benjamin, Turner, Anne, Bakshi, Madhura, Adès, Lesley C., Mowat, David, Regan, Matthew, McGillivray, George, Savarirayan, Ravi, White, Susan M., Tan, Tiong Yang, Stark, Zornitza, Brown, Natasha J., Pérez-Jurado, Luis A., Krzesinski, Emma, Hunter, Matthew F., Akesson, Lauren, Fennell, Andrew Paul, Yeung, Alison, Boughtwood, Tiffany, Ewans, Lisa J., Kerkhof, Jennifer, Lucas, Christopher, Carey, Louise, French, Hugh, Rapadas, Melissa, Stevanovski, Igor, Deveson, Ira W., Cliffe, Corrina, Elakis, George, Kirk, Edwin P., Dudding-Byth, Tracy, Fletcher, Janice, Walsh, Rebecca, Corbett, Mark A., Kroes, Thessa, Gecz, Jozef, Meldrum, Cliff, Cliffe, Simon, Wall, Meg, Lunke, Sebastian, North, Kathryn, Amor, David J., Field, Michael, Sadikovic, Bekim, Buckley, Michael F., O’Donnell-Luria, Anne, and Roscioli, Tony

Published
2024
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5. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Author

Johnson, Brett V, Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A, VanHasselt, Peter M, Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pena, Loren, Shashi, Vandana, Undiagnosed Diseases Network, Schoch, Kelly, Sullivan, Jennifer A, Pinto E Vairo, Filippo, Pichurin, Pavel N, Ewing, Sarah A, Barnett, Sarah S, Klee, Eric W, Perry, M Scott, Koenig, Mary Kay, Keegan, Catherine E, Schuette, Jane L, Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D, Rosenfeld, Jill A, Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E, Steeves, Marcie A, Hollander, Nicolette den, Hoffer, Mariëtte JV, Reijnders, Margot RF, Demirdas, Serwet, Koboldt, Daniel C, Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E, Shieh, Christine, Sanchez-Lara, Pedro A, Graham, John M, Tezcan, Kamer, Schaefer, GB, Danylchuk, Noelle R, Asamoah, Alexander, Jackson, Kelly E, Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A, and Kleefstra, Tjitske

Subjects
Undiagnosed Diseases Network, Animals, Humans, Mice, Ubiquitin Thiolesterase, Transforming Growth Factor beta, Developmental Disabilities, Signal Transduction, Phenotype, Female, Male, Haploinsufficiency, Intellectual Disability, Brain malformation, Deubiquitylating enzyme, Hippocampus, Neurodevelopmental disorder, TGFβ, USP9X, Congenital Structural Anomalies, Genetics, Neurosciences, Pediatric, Mental Health, Behavioral and Social Science, Brain Disorders, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, TGF beta, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

Published
2020

7. The early-life exposome modulates the effect of polymorphic inversions on DNA methylation

Author

Carreras-Gallo, Natàlia, Cáceres, Alejandro, Balagué-Dobón, Laura, Ruiz-Arenas, Carlos, Andrusaityte, Sandra, Carracedo, Ángel, Casas, Maribel, Chatzi, Leda, Grazuleviciene, Regina, Gutzkow, Kristine Bjerve, Lepeule, Johanna, Maitre, Léa, Nieuwenhuijsen, Mark, Slama, Remy, Stratakis, Nikos, Thomsen, Cathrine, Urquiza, Jose, Wright, John, Yang, Tiffany, Escaramís, Geòrgia, Bustamante, Mariona, Vrijheid, Martine, Pérez-Jurado, Luis A., and González, Juan R.

Published
2022
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8. A Humanized Yeast Model for Studying TRAPP Complex Mutations; Proof-of-Concept Using Variants from an Individual with a TRAPPC1 -Associated Neurodevelopmental Syndrome.

Author

Zykaj, Erta, Abboud, Chelsea, Asadi, Paria, Warsame, Simane, Almousa, Hashem, Milev, Miroslav P., Greco, Brittany M., López-Sánchez, Marcos, Bratkovic, Drago, Kachroo, Aashiq H., Pérez-Jurado, Luis Alberto, and Sacher, Michael

Subjects
MUSCULAR dystrophy, CARRIER proteins, GENETIC variation, MEMBRANE proteins, SACCHAROMYCES cerevisiae, DYSPLASIA
Abstract

Variants in membrane trafficking proteins are known to cause rare disorders with severe symptoms. The highly conserved transport protein particle (TRAPP) complexes are key membrane trafficking regulators that are also involved in autophagy. Pathogenic genetic variants in specific TRAPP subunits are linked to neurological disorders, muscular dystrophies, and skeletal dysplasias. Characterizing these variants and their phenotypes is important for understanding the general and specialized roles of TRAPP subunits as well as for patient diagnosis. Patient-derived cells are not always available, which poses a limitation for the study of these diseases. Therefore, other systems, like the yeast Saccharomyces cerevisiae, can be used to dissect the mechanisms at the intracellular level underlying these disorders. The development of CRISPR/Cas9 technology in yeast has enabled a scar-less editing method that creates an efficient humanized yeast model. In this study, core yeast subunits were humanized by replacing them with their human orthologs, and TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC6A, and TRAPPC6B were found to successfully replace their yeast counterparts. This system was used for studying the first reported individual with an autosomal recessive disorder caused by biallelic TRAPPC1 variants, a girl with a severe neurodevelopmental disorder and myopathy. We show that the maternal variant (TRAPPC1 p.(Val121Alafs*3)) is non-functional while the paternal variant (TRAPPC1 p.(His22_Lys24del)) is conditional-lethal and affects secretion and non-selective autophagy in yeast. This parallels defects seen in fibroblasts derived from this individual which also showed membrane trafficking defects and altered Golgi morphology, all of which were rescued in the human system by wild-type TRAPPC1. This study suggests that humanized yeast can be an efficient means to study TRAPP subunit variants in the absence of human cells and can assign significance to variants of unknown significance (VUS). This study lays the foundation for characterizing further TRAPP variants through this system, rapidly contributing to disease diagnosis. [ABSTRACT FROM AUTHOR]

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

Author

Genetica, Genetica Sectie Research, Cancer, Child Health, 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, Genetica, Genetica Sectie Research, Cancer, Child Health, 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

Published
2024

11. 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

12. Variability in Phelan-McDermid syndrome in a cohort of 210 Individuals

Author

Nevado Blanco, Julián, García Miñaúr, Sixto, Palomares Bralo, María, Vallespín, Elena, Guillén Navarro, Encarna, Rosell, Jordi, Bel Fenellos, María Cristina, Mori, María Ángeles, Milá, Montserrat, del Campo, Miguel, Barrúz, Pilar, Santos Simarro, Fernando, Obregón, Gabriela, Orellana, Carmen, Pachajoa, Harry, Tenorio, Jair Antonio, Galán, Enrique, Cigudosa, Juan C., Moresco, Angélica, Saleme, César, Castillo, Silvia, Gabau, Elisabeth, Pérez Jurado, Luis, Barcia, Ana, Martín, María Soledad, Mansilla, Elena, Vallcorba, Isabel, García Murillo, Pedro, Cammarata Scalisi, Franco, Gonçalves Pereira, Natálya, Blanco Lago, Raquel, Serrano, Mercedes, Ortigoza Escobar, Juan Dario, Gener, Blanca, Seidel, Verónica Adriana, Tirado, Pilar, Lapuniza, Pablo, Nevado Blanco, Julián, García Miñaúr, Sixto, Palomares Bralo, María, Vallespín, Elena, Guillén Navarro, Encarna, Rosell, Jordi, Bel Fenellos, María Cristina, Mori, María Ángeles, Milá, Montserrat, del Campo, Miguel, Barrúz, Pilar, Santos Simarro, Fernando, Obregón, Gabriela, Orellana, Carmen, Pachajoa, Harry, Tenorio, Jair Antonio, Galán, Enrique, Cigudosa, Juan C., Moresco, Angélica, Saleme, César, Castillo, Silvia, Gabau, Elisabeth, Pérez Jurado, Luis, Barcia, Ana, Martín, María Soledad, Mansilla, Elena, Vallcorba, Isabel, García Murillo, Pedro, Cammarata Scalisi, Franco, Gonçalves Pereira, Natálya, Blanco Lago, Raquel, Serrano, Mercedes, Ortigoza Escobar, Juan Dario, Gener, Blanca, Seidel, Verónica Adriana, Tirado, Pilar, and Lapuniza, Pablo

Abstract

REDES/FIBHULP08. FIBHULP PI: 2735. FIBHULP Auchan Reserch Project. FIBHULP. Raregenomics (B2017/BMD-3721). Referencias bibliográficas: • Anderlid B.-M. Schoumans J. Annerén G. Sahlén S. Kyllerman M. Vujic M. et al. (2002a). Subtelomeric Rearrangements Detected in Patients with Idiopathic Mental Retardation. Am. J. Med. Genet. 107 (4), 275–284. 10.1002/ajmg.10029 • Anderlid B.-M. Schoumans J. Annerén G. Tapia-Paez I. Dumanski J. Blennow E. et al. (2002b). FISH-mapping of a 100-kb Terminal 22q13 Deletion. Hum. Genet. 110 (5), 439–443. 10.1007/s00439-002-0713-7 • Betancur C. Buxbaum J. D. (2013). SHANK3 Haploinsufficiency: a "common" but Underdiagnosed Highly Penetrant Monogenic Cause of Autism Spectrum Disorders. Mol. Autism 4 (1), 17. 10.1186/2040-2392-4-17 • Boccuto L. Lauri M. Sarasua S. M. Skinner C. D. Buccella D. Dwivedi A. et al. (2013). Prevalence of SHANK3 Variants in Patients with Different Subtypes of Autism Spectrum Disorders. Eur. J. Hum. Genet. 21, 310–316. 10.1038/ejhg.2012.175 • Boeckers T. M. (2006). The Postsynaptic Density. Cell Tissue Res 326 (2), 409–422. 10.1007/s00441-006-0274-5 • Bonaglia M. C. Giorda R. Beri S. De Agostini C. Novara F. Fichera M. et al. (2011). Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome. Plos Genet. 7, e1002173. 10.1371/journal.pgen.1002173 • Bonaglia M. C. Giorda R. Borgatti R. Felisari G. Gagliardi C. Selicorni A. et al. (2001b). Disruption of the ProSAP2 Gene in a t(12;22)(q24.1;q13.3) Is Associated with the 22q13.3 Deletion Syndrome. Am. J. Hum. Genet. 69 (2), 261–268. 10.1086/321293 • Bonaglia M. C. Giorda R. Mani E. Aceti G. Anderld B. M. Baroncini A. et al. (2001a). Identification of a Recurrent Breakpoint within the SHANK3 Gene in the 22q13.3 Deletion Syndrome. Am. J. Hum. Genet. 69 (2), 261–268. • Bowling K. M. Thompson M. L. Amaral M. D. Finnila C. R. Hiatt S. M. Engel K. L. et al. (2017). Genomic Diagnosis for Children with Intellectual Disab, Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed., Depto. de Investigación y Psicología en Educación, Fac. de Educación, TRUE, pub

Published
2024

13. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

Author

Pena, Loren, Shashi, Vandana, Schoch, Kelly, Sullivan, Jennifer A., Acosta, Maria T., Adams, David R., Aday, Aaron, Alejandro, Mercedes E., Allard, Patrick, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Barbouth, Deborah, Batzli, Gabriel F., Beggs, Alan H., Bellen, Hugo J., Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bick, David P., Birch, Camille L., Bivona, Stephanie, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brokamp, Elly, Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Carrasquillo, Olveen, Peter Chang, Ta Chen, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D'Souza, Precilla, Dasari, Surendra, Davids, Mariska, Davidson, Jean M., Dayal, Jyoti G., Dell'Angelica, Esteban C., Dhar, Shweta U., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Dries, Annika M., Duncan, Laura, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Enns, Gregory M., Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Friedman, Noah D., Gahl, William A., Godfrey, Rena A., Goldman, Alica M., Goldstein, David B., Gourdine, Jean-Philippe F., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., High, Frances, Holm, Ingrid A., Hom, Jason, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Karaviti, Lefkothea, Kelley, Emily G., Koeller, David M., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Korrick, Susan, Koziura, Mary, Krier, Joel B., Kyle, Jennifer E., Lalani, Seema R., Lam, Byron, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Merker, Jason D., Metz, Thomas O., Might, Matthew, Morava-Kozicz, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nath, Avi, Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Renteri, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rowley, Robb K., Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Shakachite, Lisa, Sharma, Prashant, Shields, Kathleen, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Solnica-Krezel, Lilianna, Spillmann, Rebecca C., Stoler, Joan M., Stong, Nicholas, Sweetser, David A., Tamburro, Cecelia P., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Vogel, Tiphanie P., Waggott, Daryl M., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Wegner, Daniel, Westerfield, Monte, Wheeler, Matthew T., Wise, Anastasia L., Wolfe, Lynne A., Woods, Jeremy D., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, John, Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Gahl, William, Johnson, Brett V., Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A., VanHasselt, Peter M., Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pinto e Vairo, Filippo, Pichurin, Pavel N., Ewing, Sarah A., Barnett, Sarah S., Klee, Eric W., Perry, M. Scott, Koenig, Mary Kay, Keegan, Catherine E., Schuette, Jane L., Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D., Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E., Steeves, Marcie A., Hollander, Nicolette den, Hoffer, Mariëtte J.V., Reijnders, Margot R.F., Demirdas, Serwet, Koboldt, Daniel C., Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E., Shieh, Christine, Sanchez-Lara, Pedro A., Graham, John M., Jr., Tezcan, Kamer, Schaefer, G.B., Danylchuk, Noelle R., Asamoah, Alexander, Jackson, Kelly E., Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A., Kleefstra, Tjitske, Penzes, Peter, Wood, Stephen A., Burne, Thomas, Pierson, Tyler Mark, Piper, Michael, Gécz, Jozef, and Jolly, Lachlan A.

Published
2020
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14. Correction: A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells

Author

Awamleh, Zain, primary, Choufani, Sanaa, additional, Wu, Wendy, additional, Rots, Dmitrijs, additional, Dingemans, Alexander J. M., additional, Nadif Kasri, Nael, additional, Boronat, Susana, additional, Ibañez-Mico, Salvador, additional, Cuesta Herraiz, Laura, additional, Ferrer, Irene, additional, Martínez Carrascal, Antonio, additional, Pérez-Jurado, Luis A., additional, Aznar Lain, Gemma, additional, Ortigoza-Escobar, Juan Dario, additional, de Vries, Bert B. A., additional, Koolen, David A., additional, and Weksberg, Rosanna, additional

Published
2024
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16. A six-attribute classification of genetic mosaicism

Author

Martínez-Glez, Víctor, Tenorio, Jair, Nevado, Julián, Gordo, Gema, Rodríguez-Laguna, Lara, Feito, Marta, de Lucas, Raúl, Pérez-Jurado, Luis A., Ruiz Pérez, Víctor L., Torrelo, Antonio, Spinner, Nancy B., Happle, Rudolf, Biesecker, Leslie G., and Lapunzina, Pablo

Published
2020
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18. 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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20. Provision of Genetic Services for Autism and Its Impact on Spanish Families

Author

Codina-Solà, Marta, Pérez-Jurado, Luis A., Cuscó, Ivon, and Serra-Juhé, Clara

Abstract

Although a genetic evaluation can identify the etiology in 15-30% of individuals with autism spectrum disorder, several studies show an underuse of genetic services by affected families. We have explored the access to genetic services and perception of genetics and recurrence risk in parents of autistic children in Spain. Despite the high interest in genetics, our results show a remarkable underutilization of genetic services, with only 30% of families having visited a genetic service and 13% of patients having undergone the recommended genetic test. This poor service provision influenced recurrence risk perception and had a great impact on family planning. The National Health System should ensure their access to genetic services allowing them to take informed decisions with precise information.

Published
2017
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21. Behavioral Profiles of Children with Williams Syndrome from Spain and the United States: Cross-Cultural Similarities and Differences

Author

Pérez-García, Débora, Brun-Gasca, Carme, Pérez-Jurado, Luis A., and Mervis, Carolyn B.

Abstract

To identify similarities and differences in the behavioral profile of children with Williams syndrome from Spain (n = 53) and the United States (n = 145), we asked parents of 6- to 14-year-olds with Williams syndrome to complete the Child Behavior Checklist 6-18. The distribution of raw scores was significantly higher for the Spanish sample than the American sample for all of the higher-order factors and half of both the empirically based and "Diagnostic and Statistical Manual of Mental Disorders" ("DSM")-oriented scales. In contrast, analyses based on country-specific T-scores indicated that the distribution for the Spanish sample was significantly higher than for the American sample only on the Social Problems scale. No gender differences were found. Genetic and cultural influences on children's behavior and cultural influences on parental ratings of behavior are discussed.

Published
2017
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22. Missense variant contribution to USP9X-female syndrome

Author

Jolly, Lachlan A., Parnell, Euan, Gardner, Alison E., Corbett, Mark A., Pérez-Jurado, Luis A., Shaw, Marie, Lesca, Gaetan, Keegan, Catherine, Schneider, Michael C., Griffin, Emily, Maier, Felicitas, Kiss, Courtney, Guerin, Andrea, Crosby, Kathleen, Rosenbaum, Kenneth, Tanpaiboon, Pranoot, Whalen, Sandra, Keren, Boris, McCarrier, Julie, Basel, Donald, Sadedin, Simon, White, Susan M., Delatycki, Martin B., Kleefstra, Tjitske, Küry, Sébastien, Brusco, Alfredo, Sukarova-Angelovska, Elena, Trajkova, Slavica, Yoon, Sehoun, Wood, Stephen A., Piper, Michael, Penzes, Peter, and Gecz, Jozef

Published
2020
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24. Epimutation detection in the clinical context: guidelines and a use case from a new Bioconductor package

Author

Ruiz-Arenas, Carlos, primary, Abarrategui, Leire, additional, Hernandez-Ferrer, Carles, additional, Escribà-Montagut, Xavier, additional, Pelegrí-Sisó, Dolors, additional, Ryser-Welch, Patricia, additional, Vrijheid, Martine, additional, Bustamante, Mariona, additional, Grazuleviciene, Regina, additional, Lepeule, Johanna, additional, Mathai, Mathew, additional, Vafeiadi, Marina, additional, Beltran, Sergi, additional, Pérez-Jurado, Luis A, additional, and González, Juan R, additional

Published
2023
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25. A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1variants and comparison to fibroblast cells

Author

Awamleh, Zain, Choufani, Sanaa, Wu, Wendy, Rots, Dmitrijs, Dingemans, Alexander J. M., Nadif Kasri, Nael, Boronat, Susana, Ibañez-Mico, Salvador, Cuesta Herraiz, Laura, Ferrer, Irene, Martínez Carrascal, Antonio, Pérez-Jurado, Luis A., Aznar Lain, Gemma, Ortigoza-Escobar, Juan Dario, de Vries, Bert B. A., Koolen, David A., and Weksberg, Rosanna

Abstract

Pathogenic variants in KANSL1and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina’s Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Published
2024
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29. Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum

Author

Urreizti, Roser, Lopez-Martin, Estrella, Martinez-Monseny, Antonio, Pujadas, Montse, Castilla-Vallmanya, Laura, Pérez-Jurado, Luis Alberto, Serrano, Mercedes, Natera-de Benito, Daniel, Martínez-Delgado, Beatriz, Posada-de-la-Paz, Manuel, Alonso, Javier, Marin-Reina, Purificación, O’Callaghan, Mar, Grinberg, Daniel, Bermejo-Sánchez, Eva, and Balcells, Susanna

Published
2020
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32. Expanding the genetic and phenotypic spectrum of congenital myasthenic syndrome: new homozygous VAMP1splicing variants in 2 novel individuals

Author

Cotrina-Vinagre, Francisco Javier, Rodríguez-García, María Elena, del Pozo-Filíu, Lucía, Hernández-Laín, Aurelio, Arteche-López, Ana, Morte, Beatriz, Sevilla, Marta, Pérez-Jurado, Luis Alberto, Quijada-Fraile, Pilar, Camacho, Ana, and Martínez-Azorín, Francisco

Abstract

We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1(Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3′ of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1variants.

Published
2024
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36. FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects

Author

Cospain, Auriane, primary, Rivera-Barahona, Ana, additional, Dumontet, Erwan, additional, Gener, Blanca, additional, Bailleul-Forestier, Isabelle, additional, Meyts, Isabelle, additional, Jouret, Guillaume, additional, Isidor, Bertrand, additional, Brewer, Carole, additional, Wuyts, Wim, additional, Moens, Leen, additional, Delafontaine, Selket, additional, Keung Lam, Wayne Wing, additional, Van Den Bogaert, Kris, additional, Boogaerts, Anneleen, additional, Scalais, Emmanuel, additional, Besnard, Thomas, additional, Cogne, Benjamin, additional, Guissard, Christophe, additional, Rollier, Paul, additional, Carre, Wilfrid, additional, Bouvet, Regis, additional, Tarte, Karin, additional, Gómez-Carmona, Ricardo, additional, Lapunzina, Pablo, additional, Odent, Sylvie, additional, Faoucher, Marie, additional, Dubourg, Christele, additional, Ruiz-Pérez, Víctor L., additional, Devriendt, Koen, additional, Pasquier, Laurent, additional, and Pérez-Jurado, Luis A., additional

Published
2022
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38. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Kayumi, Sayaka, primary, Pérez-Jurado, Luis A., additional, Palomares, María, additional, Rangu, Sneha, additional, Sheppard, Sarah E., additional, Chung, Wendy K., additional, Kruer, Michael C., additional, Kharbanda, Mira, additional, Amor, David J., additional, McGillivray, George, additional, Cohen, Julie S., additional, García-Miñaúr, Sixto, additional, van Eyk, Clare L., additional, Harper, Kelly, additional, Jolly, Lachlan A., additional, Webber, Dani L., additional, Barnett, Christopher P., additional, Santos-Simarro, Fernando, additional, Pacio-Míguez, Marta, additional, Pozo, Angela del, additional, Bakhtiari, Somayeh, additional, Deardorff, Matthew, additional, Dubbs, Holly A., additional, Izumi, Kosuke, additional, Grand, Katheryn, additional, Gray, Christopher, additional, Mark, Paul R., additional, Bhoj, Elizabeth J., additional, Li, Dong, additional, Ortiz-Gonzalez, Xilma R., additional, Keena, Beth, additional, Zackai, Elaine H., additional, Goldberg, Ethan M., additional, Perez de Nanclares, Guiomar, additional, Pereda, Arrate, additional, Llano-Rivas, Isabel, additional, Arroyo, Ignacio, additional, Fernández-Cuesta, María Ángeles, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, Garde, Aurore, additional, Mazel, Benoit, additional, Bruel, Ange-Line, additional, Tress, Michael L., additional, Brilstra, Eva, additional, Fine, Amena Smith, additional, Crompton, Kylie E., additional, Stegmann, Alexander P.A., additional, Sinnema, Margje, additional, Stevens, Servi C.J., additional, Nicolai, Joost, additional, Lesca, Gaetan, additional, Lion-François, Laurence, additional, Haye, Damien, additional, Chatron, Nicolas, additional, Piton, Amelie, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, Srivastava, Siddharth, additional, Bassetti, Jennifer, additional, Muss, Candace, additional, Gripp, Karen W., additional, Procopio, Rebecca A., additional, Millan, Francisca, additional, Morrow, Michelle M., additional, Assaf, Melissa, additional, Moreno-De-Luca, Andres, additional, Joss, Shelagh, additional, Hamilton, Mark J., additional, Bertoli, Marta, additional, Foulds, Nicola, additional, McKee, Shane, additional, MacLennan, Alastair H., additional, Gecz, Jozef, additional, and Corbett, Mark A., additional

Published
2022
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39. Familial isolated acanthosis nigricans as a result of a recurrent FGFR3 truncating mutation.

Author

Pesqué, David, March-Rodriguez, Álvaro, Abreu-Rodríguez, Irene, Pérez-Jurado, Luis A, and Pujol, Ramon M

Subjects
ACANTHOSIS nigricans, FIBROBLAST growth factor receptors, GENETIC mutation, NUCLEOTIDE sequencing
Abstract

Furthermore, considering that, in the absence of insulin resistance and/or other associated syndromic features, acanthosis nigricans can be caused by a few specific variants in a single gene (targeted) mutation screening of I FGFR3 i should be included in the diagnostic workup of any patient with isolated acanthosis nigricans. Familial acanthosis nigricans (FAN) caused by a I FGFR3 i gene mutation is characterized by flexural hyperpigmentation, and additionally nasolabial and perioral hyperpigmentation.[1],[2] FAN is associated with skeletal disorders (Crouzon and Muenke syndrome). [Extracted from the article]

Published
2023
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41. Mutations in pregnancy‐associated plasma protein A2 cause short stature due to low IGF‐I availability

Author

Dauber, Andrew, Muñoz‐Calvo, María T, Barrios, Vicente, Domené, Horacio M, Kloverpris, Soren, Serra‐Juhé, Clara, Desikan, Vardhini, Pozo, Jesús, Muzumdar, Radhika, Martos‐Moreno, Gabriel Á, Hawkins, Federico, Jasper, Héctor G, Conover, Cheryl A, Frystyk, Jan, Yakar, Shoshana, Hwa, Vivian, Chowen, Julie A, Oxvig, Claus, Rosenfeld, Ron G, Pérez‐Jurado, Luis A, and Argente, Jesús

Published
2016
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43. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

Author

Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis A., Montoliu, Lluís, Carracedo, Angel, Millán, José M., Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José Antonio, Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodríguez de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto, Sanz, Pascual, Rubio, Vicente, and Llácer, José L.

Subjects
Biomedical Research, Epidemiology, Novel genes, Research network, New therapeutic approaches, Rare diseases, Rare Diseases, Diagnòstic, Diagnosis, Genetics, Humans, Malalties rares, Epidemiologia, Genètica, Genetics (clinical)
Abstract

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation

Published
2022

44. Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

Author

Schlüter, Agatha, Rodríguez-Palmero, Agustí, Verdura, Edgard, Vélez-Santamaría, Valentina, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Martínez, Juan José, Guilera, Cristina, Girós, Marisa, Artuch, R, Yoldi, María Eugenia, O'Callaghan, Mar, García-Cazorla, Angels, Armstrong, Judith, Marti, Itxaso, Mondragón Rezola, Elisabet, Redin, Claire, Mandel, Jean Louis, Conejo, David, Sierra-Córcoles, Concepción, Beltrán, Sergi, Gut, Marta, Vázquez, Elida, del Toro, Mireia, Troncoso, Mónica, Pérez-Jurado, Luis Alberto, Gutiérrez-Solana, Luis G., López de Munain, Adolfo, Casasnovas, Carlos, Aguilera-Albesa, Sergio, Macaya Ruiz, Alfons, Pujol, Aurora, Universitat Autònoma de Barcelona, Schlüter, Agatha, Rodríguez-Palmero, Agustí, Verdura, Edgard, Vélez-Santamaría, Valentina, Ruiz, Montserrat, Fourcade, Stéphane, Planas-Serra, Laura, Martínez, Juan José, Guilera, Cristina, Girós, Marisa, Artuch, R, Yoldi, María Eugenia, O'Callaghan, Mar, García-Cazorla, Angels, Armstrong, Judith, Marti, Itxaso, Mondragón Rezola, Elisabet, Redin, Claire, Mandel, Jean Louis, Conejo, David, Sierra-Córcoles, Concepción, Beltrán, Sergi, Gut, Marta, Vázquez, Elida, del Toro, Mireia, Troncoso, Mónica, Pérez-Jurado, Luis Alberto, Gutiérrez-Solana, Luis G., López de Munain, Adolfo, Casasnovas, Carlos, Aguilera-Albesa, Sergio, Macaya Ruiz, Alfons, Pujol, Aurora, and Universitat Autònoma de Barcelona

Abstract

Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel diseas

Published
2022

45. FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects

Author

Generalitat de Catalunya, Cospain, Auriane, Rivera-Barahona, Ana, Dumontet, Erwan, Gener, Blanca, Bailleul-Forestier, Isabelle, Meyts, Isabelle, Jouret, Guillaume, Isidor, Bertrand, Brewer, Carole, Wuyts, Wim, Moens, Leen, Delafontaine, Selket, Wing Keung Lam, Wayne, Van Den Bogaert, Kris, Boogaerts, Anneleen, Scalais, Emmanuel, Besnard, Thomas, Cogne, Benjamin, Guissard, Christophe, Rollier, Paul, Carre, Wilfrid, Bouvet, Regis, Tarte, Karin, Gómez Carmona, Ricardo, Lapunzina, Pablo, Odent, Sylvie, Faoucher, Marie, Dubourg, Christele, Ruiz-Pérez, Victor L., Devriendt, Koen, Pasquier, Laurent, Pérez-Jurado, Luis Alberto, Generalitat de Catalunya, Cospain, Auriane, Rivera-Barahona, Ana, Dumontet, Erwan, Gener, Blanca, Bailleul-Forestier, Isabelle, Meyts, Isabelle, Jouret, Guillaume, Isidor, Bertrand, Brewer, Carole, Wuyts, Wim, Moens, Leen, Delafontaine, Selket, Wing Keung Lam, Wayne, Van Den Bogaert, Kris, Boogaerts, Anneleen, Scalais, Emmanuel, Besnard, Thomas, Cogne, Benjamin, Guissard, Christophe, Rollier, Paul, Carre, Wilfrid, Bouvet, Regis, Tarte, Karin, Gómez Carmona, Ricardo, Lapunzina, Pablo, Odent, Sylvie, Faoucher, Marie, Dubourg, Christele, Ruiz-Pérez, Victor L., Devriendt, Koen, Pasquier, Laurent, and Pérez-Jurado, Luis Alberto

Abstract

[Purpose]: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex., [Methods]: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability., [Results]: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed., [Conclusion]: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.

Published
2022

46. CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

Author

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., Nieto, M. Ángela, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Marina, Alberto [0000-0002-1334-5273], Sanz, Pascual [0000-0002-2399-4103], Rubio, Vicente [0000-0001-8124-1196], Llácer, José L. [0000-0001-5304-1795], Luque, Juan M., Mendes, Ingrid, Gómez, Beatriz, Morte, Beatriz, Heredia, Miguel, Lopez Herreras, Enrique, Corrochano, Virginia, Bueren, Juan, Gallano, Pia, Artuch, Rafael, Fillat, Cristina, Pérez-Jurado, Luis Alberto, Montoliu, Lluís, Carracedo, Ángel, Millán, José María, Webb, Susan M., Palau, Francesc, CIBERER Network, Lapunzina, Pablo, Albiñana, Virginia, Arjona, Emilia, Bernabéu, Carmelo, Botella, Luisa María, Pinto, Sheila, Rodríguez de Córdoba, Santiago, Ruiz, Ángela, Antiñolo, Guillermo, Borrego, Salud, Bravo-Gil, Nereida, González-del Pozo, María, Méndez-Vidal, Cristina, Arbones, Maria L., Caparrós-Martín, José A., Cediel, Rafael, Contreras, Julio, Estañ, María Cristina, Guerrero-López, Rosa, Jiménez-Estrada, Juan Andrés, Manguan-García, Cristina, Murillo-Cuesta, Silvia, Palencia-Campos, Adrián, Perona Abellón, Rosario, Rivera-Barahona, Ana, Rodriguez-de la Rosa, Lourdes, Ruiz-Pérez, Victor L., Sastre, Leandro, Valencia, María, Varela-Nieto, Isabel, Cervera, Javier, Cima, Sergio de, Gougeard, Nadine, Llácer, José Luis, Marco-Marín, Clara, Marina, Alberto, Mollá, Belén, Moreno-Estellés, Mireia, Pérez-Jiménez, Eva, Rubio, Vicente, Sanz, Pascual, Cortés-Rodríguez, Ana Belén, Navas, Plácido, Sánchez Cuesta, Ana María, Santos-Ocaña, Carlos, Fraga, Mario F., and Nieto, M. Ángela

Abstract

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.

Published
2022

47. Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly

Author

Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Estonian Research Council, González, Juan R. [0000-0003-3267-2146], Pérez-Jurado, Luis Alberto, Cáceres, Alejandro, Esko, Tõnu, López de Heredia, Miguel, Quintela, Inés, Cruz, Raquel, Lapunzina, Pablo, Carracedo, Ángel, SCOURGE Cohort Group, González, Juan R., Almeida, Julia, Orfao, Alberto, Bustos, Matilde, Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Estonian Research Council, González, Juan R. [0000-0003-3267-2146], Pérez-Jurado, Luis Alberto, Cáceres, Alejandro, Esko, Tõnu, López de Heredia, Miguel, Quintela, Inés, Cruz, Raquel, Lapunzina, Pablo, Carracedo, Ángel, SCOURGE Cohort Group, González, Juan R., Almeida, Julia, Orfao, Alberto, and Bustos, Matilde

Abstract

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

Published
2022

48. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, Corbett, Mark A, Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, and Corbett, Mark A

Published
2022

49. Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Author

Bullich, Gemma, primary, Matalonga, Leslie, additional, Pujadas, Montserrat, additional, Papakonstantinou, Anastasios, additional, Piscia, Davide, additional, Tonda, Raúl, additional, Artuch, Rafael, additional, Gallano, Pia, additional, Garrabou, Glòria, additional, González, Juan R., additional, Grinberg, Daniel, additional, Guitart, Míriam, additional, Laurie, Steven, additional, Lázaro, Conxi, additional, Luengo, Cristina, additional, Martí, Ramon, additional, Milà, Montserrat, additional, Ovelleiro, David, additional, Parra, Genís, additional, Pujol, Aurora, additional, Tizzano, Eduardo, additional, Macaya, Alfons, additional, Palau, Francesc, additional, Ribes, Antònia, additional, Pérez-Jurado, Luis A., additional, Beltran, Sergi, additional, Schlüter, Agatha, additional, Rodriguez-Palmero, Agustí, additional, Cáceres, Alejandro, additional, Nascimento, Andrés, additional, García-Cazorla, Àngels, additional, Cueto-González, Anna, additional, Marcé-Grau, Anna, additional, Nel.lo, Anna Ruiz, additional, Martínez-Monseny, Antonio, additional, Sànchez, Aurora, additional, García, Belén, additional, Pérez-Dueñas, Belén, additional, Gel, Bernat, additional, Fusté, Berta, additional, Hernández-Ferrer, Carles, additional, Casasnovas, Carlos, additional, Ortez, Carlos, additional, Arjona, César, additional, Hernando-Davalillo, Cristina, additional, de Benito, Daniel Natera, additional, Amador, Daniel Picó, additional, Gómez-Andrés, David, additional, Yubero, Dèlia, additional, Pelegrí-Sisó, Dolors, additional, Verdura, Edgard, additional, García-Arumí, Elena, additional, Castellanos, Elisabeth, additional, Gabau, Elisabeth, additional, Tobías, Ester, additional, López-Grondona, Fermina, additional, Cardellach, Francesc, additional, Garcia-Garcia, Francesc Josep, additional, Munell, Francina, additional, Tort, Frederic, additional, Aznar, Gemma, additional, Olivé-Cirera, Gemma, additional, Tell, Gemma, additional, Muñoz-Pujol, Gerard, additional, Paramonov, Ida, additional, Blanco, Ignacio, additional, Madrigal, Irene, additional, Valenzuela, Irene, additional, Gut, Ivo, additional, Cusco, Ivon, additional, Trotta, Jean-Rémi, additional, Cruz, Jordi, additional, Díaz-Manera, Jordi, additional, Milisenda, José César, additional, Ma Grau, Josep, additional, Garcia-Villoria, Judit, additional, Armstrong, Judith, additional, Cantó, Judith, additional, Sala-Coromina, Júlia, additional, Rodríguez-Revenga, Laia, additional, Alias, Laura, additional, Gort, Laura, additional, González-Quereda, Lídia, additional, Costa, Mar, additional, Fernández-Callejo, Marcos, additional, López-Sánchez, Marcos, additional, Álvarez-Mora, Maria Isabel, additional, Gut, Marta, additional, Serrano, Mercedes, additional, Raspall-Chaure, Miquel, additional, Toro, Mireia del, additional, Bayés, Mònica, additional, Díez, Neus Baena, additional, Spataro, Nino, additional, Capdevila, Núria, additional, Ugarteburu, Olatz, additional, Muñoz-Cabello, Patricia, additional, Duque, Penélope Romero, additional, Rabionet, Raquel, additional, Rojas-García, Ricard, additional, Calvo, Rosa, additional, Urreizti, Roser, additional, Bernal, Sara, additional, Boronat, Susana, additional, Balcells, Susanna, additional, and Vendrell, Teresa, additional

Published
2022
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50. Biallelic alterations in PLXND1 cause common arterial trunk and other cardiac malformations in humans

Author

Guimier, Anne, primary, de Pontual, Loïc, additional, Braddock, Stephen R, additional, Torti, Erin, additional, Pérez-Jurado, Luis A, additional, Muñoz-Cabello, Patricia, additional, Arumí, Montserrat, additional, Monaghan, Kristin G, additional, Lee, Hane, additional, Wang, Lee-kai, additional, Pluym, Ilina D, additional, Lynch, Sally Ann, additional, Stals, Karen, additional, Ellard, Sian, additional, Muller, Cécile, additional, Houyel, Lucile, additional, Cohen, Laurence, additional, Lyonnet, Stanislas, additional, Bajolle, Fanny, additional, Amiel, Jeanne, additional, and Gordon, Christopher T, additional

Published
2022
Full Text
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