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1. Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

Author

Sheppard, Sarah E, March, Michael E, Seiler, Christoph, Matsuoka, Leticia S, Kim, Sophia E, Kao, Charlly, Rubin, Adam I, Battig, Mark R, Khalek, Nahla, Schindewolf, Erica, O’Connor, Nora, Pinto, Erin, Priestley, Jessica RC, Sanders, Victoria R, Niazi, Rojeen, Ganguly, Arupa, Hou, Cuiping, Slater, Diana, Frieden, Ilona J, Huynh, Thy, Shieh, Joseph T, Krantz, Ian D, Guerrero, Jessenia C, Surrey, Lea F, Biko, David M, Laje, Pablo, Castelo-Soccio, Leslie, Nakano, Taizo A, Snyder, Kristen, Smith, Christopher L, Li, Dong, Dori, Yoav, and Hakonarson, Hakon

Subjects
Rare Diseases, Pediatric, Animals, Humans, Zebrafish, Proto-Oncogene Proteins p21(ras), Endothelial Cells, Phosphorylation, Mitogen-Activated Protein Kinase Kinases, Zebrafish Proteins, Cardiology, Cardiovascular disease, Genetics, Molecular biology, Molecular genetics
Abstract

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Published
2023

2. Genomic profiling informs diagnoses and treatment in vascular anomalies

Author

Li, Dong, Sheppard, Sarah E., March, Michael E., Battig, Mark R., Surrey, Lea F., Srinivasan, Abhay S., Matsuoka, Leticia S., Tian, Lifeng, Wang, Fengxiang, Seiler, Christoph, Dayneka, Jill, Borst, Alexandra J., Matos, Mary C., Paulissen, Scott M., Krishnamurthy, Ganesh, Nriagu, Bede, Sikder, Tamjeed, Casey, Melissa, Williams, Lydia, Rangu, Sneha, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Hou, Cuiping, Nguyen, Kenny, Pellegrino da Silva, Renata, Chehimi, Samar N., Kao, Charlly, Biroc, Lauren, Britt, Allison D., Queenan, Maria, Reid, Janet R., Napoli, Joseph A., Low, David M., Vatsky, Seth, Treat, James, Smith, Christopher L., Cahill, Anne Marie, Snyder, Kristen M., Adams, Denise M., Dori, Yoav, and Hakonarson, Hakon

Published
2023
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4. 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

5. 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

7. 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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8. Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA

Author

Nriagu, Bede N., primary, Williams, Lydia S., additional, Brewer, Niambi, additional, Surrey, Lea F., additional, Srinivasan, Abhay S., additional, Li, Dong, additional, Britt, Allison, additional, Treat, James, additional, Crowley, T. Blaine, additional, O'Connor, Nora, additional, Ganguly, Arupa, additional, Low, David, additional, Queenan, Maria, additional, Drivas, Theodore G., additional, Zackai, Elaine H., additional, Adams, Denise M., additional, Hakonarson, Hakon, additional, Snyder, Kristen M., additional, and Sheppard, Sarah E., additional

Published
2023
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9. Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.

Author

Nriagu, Bede N., Williams, Lydia S., Brewer, Niambi, Surrey, Lea F., Srinivasan, Abhay S., Li, Dong, Britt, Allison, Treat, James, Crowley, T. Blaine, O'Connor, Nora, Ganguly, Arupa, Low, David, Queenan, Maria, Drivas, Theodore G., Zackai, Elaine H., Adams, Denise M., Hakonarson, Hakon, Snyder, Kristen M., and Sheppard, Sarah E.

Abstract

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co‐occur in individuals with Turner syndrome. [ABSTRACT FROM AUTHOR]

Published
2024
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10. O27: Utility of cfDNA in comprehensive genomic profiling of complex vascular anomalies: Informing decision making in medical therapy

Author

Li, Dong, Sheppard, Sarah, March, Michael, Battig, Mark, Surrey, Lea, Srinivasan, Abhay, Borst, Alexandra, Wang, Fengxiang, Sikder, Tamjeed, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Britt, Allison, Napoli, Joseph, Low, David, Vatsky, Seth, Treat, James, Reid, Janet, Smith, Christopher, Snyder, Kristen, Cahill, Anne Marie, Dori, Yoav, Adams, Denise, and Hakonarson, Hakon

Published
2024
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11. Genomic profiling informs diagnoses and treatment in vascular anomalies

Author

Li, Dong, Sheppard, Sarah E., March, Michael E., Battig, Mark R., Surrey, Lea F., Srinivasan, Abhay S., Matsuoka, Leticia S., Tian, Lifeng, Wang, Fengxiang, Seiler, Christoph, Dayneka, Jill, Borst, Alexandra J., Matos, Mary C., Paulissen, Scott M., Krishnamurthy, Ganesh, Nriagu, Bede, Sikder, Tamjeed, Casey, Melissa, Williams, Lydia, Rangu, Sneha, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Hou, Cuiping, Nguyen, Kenny, Pellegrino da Silva, Renata, Chehimi, Samar N., Kao, Charlly, Biroc, Lauren, Britt, Allison D., Queenan, Maria, Reid, Janet R., Napoli, Joseph A., Low, David M., Vatsky, Seth, Treat, James, Smith, Christopher L., Cahill, Anne Marie, Snyder, Kristen M., Adams, Denise M., Dori, Yoav, and Hakonarson, Hakon

Abstract

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype–phenotype associations and guide medical therapy in individuals with vascular anomalies.

Published
2024
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12. Correspondence.

Author

Banks, W. R., Dearing, Ann, MacKaye, Arvia, Nernberg, M. A., Reed, Ferdinanda W., O'Connor, Nora, and Brackett, Haven D.

Subjects
LETTERS to the editor, UNIVERSITIES & colleges, ACADEMIC libraries, STUDENT activism
Abstract

Presents letters to the editor referencing articles and topics discussed in the previous issues of the periodical, The Nation. Texas College library; Students meet the U.S. President Warren G. Harding; Attitude towards soldier bonus.

Published
1922

13. Correspondence.

Author

O'Connor, Nora, Haynes, Jack, Harney, Norman H., Balch, Emily G., and Abbott, Charles D.

Subjects
LETTERS to the editor, INTERNATIONAL relations, JOURNALISM, RELIGION & marriage, CHURCH
Abstract

Presents several letters to the editor on different topics. Comments on the U.S. foreign policy; Comments on policies of the journal "The Nation"; Concerns on the Church's new decisions related to marriage.

Published
1922

14. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Author

Li D, Wang Q, Bayat A, Battig MR, Zhou Y, Bosch DG, van Haaften G, Granger L, Petersen AK, Pérez-Jurado LA, Aznar-Laín G, Aneja A, Hancarova M, Bendova S, Schwarz M, Kremlikova Pourova R, Sedlacek Z, Keena BA, March ME, Hou C, O'Connor N, Bhoj EJ, Harr MH, Lemire G, Boycott KM, Towne M, Li M, Tarnopolsky M, Brady L, Parker MJ, Faghfoury H, Parsley LK, Agolini E, Dentici ML, Novelli A, Wright M, Palmquist R, Lai K, Scala M, Striano P, Iacomino M, Zara F, Cooper A, Maarup TJ, Byler M, Lebel RR, Balci TB, Louie R, Lyons M, Douglas J, Nowak C, Afenjar A, Hoyer J, Keren B, Maas SM, Motazacker MM, Martinez-Agosto JA, Rabani AM, McCormick EM, Falk MJ, Ruggiero SM, Helbig I, Møller RS, Tessarollo L, Tomassoni Ardori F, Palko ME, Hsieh TC, Krawitz PM, Ganapathi M, Gelb BD, Jobanputra V, Wilson A, Greally J, Jacquemont S, Jizi K, Bruel AL, Quelin C, Misra VK, Chick E, Romano C, Greco D, Arena A, Morleo M, Nigro V, Seyama R, Uchiyama Y, Matsumoto N, Taira R, Tashiro K, Sakai Y, Yigit G, Wollnik B, Wagner M, Kutsche B, Hurst AC, Thompson ML, Schmidt R, Randolph L, Spillmann RC, Shashi V, Higginbotham EJ, Cordeiro D, Carnevale A, Costain G, Khan T, Funalot B, Tran Mau-Them F, Fernandez Garcia Moya L, García-Miñaúr S, Osmond M, Chad L, Quercia N, Carrasco D, Li C, Sanchez-Valle A, Kelley M, Nizon M, Jensson BO, Sulem P, Stefansson K, Gorokhova S, Busa T, Rio M, Hadj Habdallah H, Lesieur-Sebellin M, Amiel J, Pingault V, Mercier S, Vincent M, Philippe C, Fatus-Fauconnier C, Friend K, Halligan RK, Biswas S, Rosser J, Shoubridge C, Corbett M, Barnett C, Gecz J, Leppig K, Slavotinek A, Marcelis C, Pfundt R, de Vries BB, van Slegtenhorst MA, Brooks AS, Cogne B, Rambaud T, Tümer Z, Zackai EH, Akizu N, Song Y, and Hakonarson H

Subjects
Humans, Gene Regulatory Networks, Mutation, Missense, RNA Splicing, RNA Splicing Factors genetics, Nuclear Proteins genetics, DNA Repair Enzymes genetics, Spliceosomes genetics, Neurodevelopmental Disorders genetics
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 U2af50-deficient 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
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