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1. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Commerce, Management, Tourism and Services, SPARK Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

2. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Basic Helix-Loop-Helix Transcription Factors, CCCTC-Binding Factor, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein U, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel, Male, Mutation, Neurodevelopmental Disorders, RNA-Binding Proteins, Repressor Proteins, Transcription Factors, SPARK Consortium
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

Published
2020

3. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, Holly AF, Xiong, Bo, Coe, Bradley P, Wang, Tianyun, Hoekzema, Kendra, Fenckova, Michaela, Kvarnung, Malin, Gerdts, Jennifer, Trinh, Sandy, Cosemans, Nele, Vives, Laura, Lin, Janice, Turner, Tychele N, Santen, Gijs, Ruivenkamp, Claudia, Kriek, Marjolein, van Haeringen, Arie, Aten, Emmelien, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Haan, Eric, Shaw, Marie, Gecz, Jozef, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Schwartz, Charles, Kooy, R Frank, Vandeweyer, Geert, Helsmoortel, Celine, Romano, Corrado, Alberti, Antonino, Vinci, Mirella, Avola, Emanuela, Giusto, Stefania, Courchesne, Eric, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Amaral, David G, Scheffer, Ingrid E, Delatycki, Martin B, Lockhart, Paul J, Hormozdiari, Fereydoun, Harich, Benjamin, Castells-Nobau, Anna, Xia, Kun, Peeters, Hilde, Nordenskjöld, Magnus, Schenck, Annette, Bernier, Raphael A, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Behavioral and Social Science, Genetic Testing, Intellectual and Developmental Disabilities (IDD), Mental Health, Neurosciences, Pediatric, Autism, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autistic Disorder, Developmental Disabilities, Female, Humans, Intellectual Disability, Male, Mutation, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

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

6. 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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7. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., Ozanturk, Aysegul, Rodríguez Criado, Germán, Grasshoff, Ute, de Hoon, Bas, Field, Michael, Manouvrier-Hanu, Sylvie, E. Hickey, Scott, Kammoun, Molka, Gripp, Karen W., Bauer, Claudia, Schroeder, Christopher, Toutain, Annick, Mihalic Mosher, Theresa, Kelly, Benjamin J., White, Peter, Dufke, Andreas, Rentmeester, Eveline, Moon, Sungjin, Koboldt, Daniel C, van Roozendaal, Kees E. P., Hu, Hao, Haas, Stefan A., Ropers, Hans-Hilger, Murray, Lucinda, Haan, Eric, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Liebelt, Jan, Hobson, Lynne, De Rademaeker, Marjan, Geraedts, Joep, Fryns, Jean-Pierre, Vermeesch, Joris, Raynaud, Martine, Riess, Olaf, Gribnau, Joost, Katsanis, Nicholas, Devriendt, Koen, Bauer, Peter, Gecz, Jozef, Golzio, Christelle, Gontan, Cristina, and Kalscheuer, Vera M.

Published
2019
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8. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Author

Girirajan, Santhosh, Rosenfeld, Jill A, Cooper, Gregory M, Antonacci, Francesca, Siswara, Priscillia, Itsara, Andy, Vives, Laura, Walsh, Tom, McCarthy, Shane E, Baker, Carl, Mefford, Heather C, Kidd, Jeffrey M, Browning, Sharon R, Browning, Brian L, Dickel, Diane E, Levy, Deborah L, Ballif, Blake C, Platky, Kathryn, Farber, Darren M, Gowans, Gordon C, Wetherbee, Jessica J, Asamoah, Alexander, Weaver, David D, Mark, Paul R, Dickerson, Jennifer, Garg, Bhuwan P, Ellingwood, Sara A, Smith, Rosemarie, Banks, Valerie C, Smith, Wendy, McDonald, Marie T, Hoo, Joe J, French, Beatrice N, Hudson, Cindy, Johnson, John P, Ozmore, Jillian R, Moeschler, John B, Surti, Urvashi, Escobar, Luis F, El-Khechen, Dima, Gorski, Jerome L, Kussmann, Jennifer, Salbert, Bonnie, Lacassie, Yves, Biser, Alisha, McDonald-McGinn, Donna M, Zackai, Elaine H, Deardorff, Matthew A, Shaikh, Tamim H, Haan, Eric, Friend, Kathryn L, Fichera, Marco, Romano, Corrado, Gécz, Jozef, DeLisi, Lynn E, Sebat, Jonathan, King, Mary-Claire, Shaffer, Lisa G, and Eichler, Evan E

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Neurosciences, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, Family, Gene Frequency, Humans, Infant, Models, Genetic, Oligonucleotide Array Sequence Analysis, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Recurrence, Severity of Illness Index, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Published
2010

9. Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Author

Henden, Lyndal, primary, Fearnley, Liam G., additional, Grima, Natalie, additional, McCann, Emily P., additional, Dobson-Stone, Carol, additional, Fitzpatrick, Lauren, additional, Friend, Kathryn, additional, Hobson, Lynne, additional, Chan Moi Fat, Sandrine, additional, Rowe, Dominic B., additional, D’Silva, Susan, additional, Kwok, John B., additional, Halliday, Glenda M., additional, Kiernan, Matthew C., additional, Mazumder, Srestha, additional, Timmins, Hannah C., additional, Zoing, Margaret, additional, Pamphlett, Roger, additional, Adams, Lorel, additional, Bahlo, Melanie, additional, Blair, Ian P., additional, and Williams, Kelly L., additional

Published
2023
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10. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Author

Corbett, Mark A., Kroes, Thessa, Veneziano, Liana, Bennett, Mark F., Florian, Rahel, Schneider, Amy L., Coppola, Antonietta, Licchetta, Laura, Franceschetti, Silvana, Suppa, Antonio, Wenger, Aaron, Mei, Davide, Pendziwiat, Manuela, Kaya, Sabine, Delledonne, Massimo, Straussberg, Rachel, Xumerle, Luciano, Regan, Brigid, Crompton, Douglas, van Rootselaar, Anne-Fleur, Correll, Anthony, Catford, Rachael, Bisulli, Francesca, Chakraborty, Shreyasee, Baldassari, Sara, Tinuper, Paolo, Barton, Kirston, Carswell, Shaun, Smith, Martin, Berardelli, Alfredo, Carroll, Renee, Gardner, Alison, Friend, Kathryn L., Blatt, Ilan, Iacomino, Michele, Di Bonaventura, Carlo, Striano, Salvatore, Buratti, Julien, Keren, Boris, Nava, Caroline, Forlani, Sylvie, Rudolf, Gabrielle, Hirsch, Edouard, Leguern, Eric, Labauge, Pierre, Balestrini, Simona, Sander, Josemir W., Afawi, Zaid, Helbig, Ingo, Ishiura, Hiroyuki, Tsuji, Shoji, Sisodiya, Sanjay M., Casari, Giorgio, Sadleir, Lynette G., van Coller, Riaan, Tijssen, Marina A. J., Klein, Karl Martin, van den Maagdenberg, Arn M. J. M., Zara, Federico, Guerrini, Renzo, Berkovic, Samuel F., Pippucci, Tommaso, Canafoglia, Laura, Bahlo, Melanie, Striano, Pasquale, Scheffer, Ingrid E., Brancati, Francesco, Depienne, Christel, and Gecz, Jozef

Published
2019
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11. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Author

Geisheker, Madeleine R, Heymann, Gabriel, Wang, Tianyun, Coe, Bradley P, Turner, Tychele N, Stessman, Holly A F, Hoekzema, Kendra, Kvarnung, Malin, Shaw, Marie, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Thompson, Elizabeth M, Haan, Eric, Guo, Hui, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Vandeweyer, Geert, Alberti, Antonino, Avola, Emanuela, Vinci, Mirella, Giusto, Stefania, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Michaelson, Jacob J, Sedlacek, Zdenek, Santen, Gijs W E, Peeters, Hilde, Hakonarson, Hakon, Courchesne, Eric, Romano, Corrado, Kooy, R Frank, Bernier, Raphael A, Nordenskjöld, Magnus, Gecz, Jozef, Xia, Kun, Zweifel, Larry S, and Eichler, Evan E

Published
2017
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12. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation

Author

Tudini, Emma, primary, Andrews, James, additional, Lawrence, David M., additional, King-Smith, Sarah L., additional, Baker, Naomi, additional, Baxter, Leanne, additional, Beilby, John, additional, Bennetts, Bruce, additional, Beshay, Victoria, additional, Black, Michael, additional, Boughtwood, Tiffany F., additional, Brion, Kristian, additional, Cheong, Pak Leng, additional, Christie, Michael, additional, Christodoulou, John, additional, Chong, Belinda, additional, Cox, Kathy, additional, Davis, Mark R., additional, Dejong, Lucas, additional, Dinger, Marcel E., additional, Doig, Kenneth D., additional, Douglas, Evelyn, additional, Dubowsky, Andrew, additional, Ellul, Melissa, additional, Fellowes, Andrew, additional, Fisk, Katrina, additional, Fortuno, Cristina, additional, Friend, Kathryn, additional, Gallagher, Renee L., additional, Gao, Song, additional, Hackett, Emma, additional, Hadler, Johanna, additional, Hipwell, Michael, additional, Ho, Gladys, additional, Hollway, Georgina, additional, Hooper, Amanda J., additional, Kassahn, Karin S., additional, Krishnaraj, Rahul, additional, Lau, Chiyan, additional, Le, Huong, additional, San Leong, Huei, additional, Lundie, Ben, additional, Lunke, Sebastian, additional, Marty, Anthony, additional, McPhillips, Mary, additional, Nguyen, Lan T., additional, Nones, Katia, additional, Palmer, Kristen, additional, Pearson, John V., additional, Quinn, Michael C.J., additional, Rawlings, Lesley H., additional, Sadedin, Simon, additional, Sanchez, Louisa, additional, Schreiber, Andreas W., additional, Sigalas, Emanouil, additional, Simsek, Aygul, additional, Soubrier, Julien, additional, Stark, Zornitza, additional, Thompson, Bryony A., additional, U, James, additional, Vakulin, Cassandra G., additional, Wells, Amanda V., additional, Wise, Cheryl A., additional, Woods, Rick, additional, Ziolkowski, Andrew, additional, Brion, Marie-Jo, additional, Scott, Hamish S., additional, Thorne, Natalie P., additional, Spurdle, Amanda B., additional, Akesson, Lauren, additional, Allcock, Richard, additional, Ashton, Katie, additional, Bell, Damon A., additional, Brown, Anna, additional, Buckley, Michael, additional, Burnett, John R., additional, Burrows, Linda, additional, Byrne, Alicia, additional, Chan, Eva, additional, Cliffe, Corrina, additional, Clifton-Bligh, Roderick, additional, Dooley, Susan, additional, Fernandez, Miriam Fanjul, additional, Farnsworth, Elizabeth, additional, Ha, Thuong, additional, Henry, Denae, additional, Holds, Duncan, additional, Holman, Katherine, additional, Jackson, Matilda, additional, Kang, Sinlay, additional, Luxford, Catherine, additional, McManus, Sam, additional, Mehrtens, Rachael, additional, Meldrum, Cliff, additional, Mossman, David, additional, Pantaleo, Sarah-Jane, additional, Phelan, Dean, additional, Pontikinas, Electra, additional, Ravine, Anja, additional, Roscioli, Tony, additional, Scott, Rodney, additional, Simons, Keryn, additional, and Vanwageningen, Oliver, additional

Published
2022
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13. Epilepsy and Mental Retardation Limited to Females: An Under-Recognized Disorder

Author

Scheffer, Ingrid E., Turner, Samantha J., Dibbens, Leanne M., Bayly, Marta A., Friend, Kathryn, Hodgson, Bree, Burrows, Linda, Shaw, Marie, Wei, Chen, Ullmann, Reinhard, Ropers, Hans-Hilger, Szepetowski, Pierre, Haan, Eric, Mazarib, Aziz, Afawi, Zaid, Neufeld, Miriam Y., Andrews, P. Ian, Wallace, Geoffrey, Kivity, Sara, Lev, Dorit, Lerman-Sagie, Tally, Derry, Christopher P., Korczyn, Amos D., Gecz, Jozef, Mulley, John C., and Berkovic, Samuel F.

Abstract

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at [theta] = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.

Published
2008
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14. Clefting and cancer: A complex CDH1 case

Author

Phan, Jennifer, primary, Kulkarni, Abhijit, additional, Dubowsky, Andrew, additional, Rawlings, Lesley, additional, Friend, Kathryn, additional, Hardy, Tristan, additional, and Yu, Sui, additional

Published
2022
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15. Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, Raman, Corbett, Mark A., Van Bon, Bregje W.M., Gardner, Alison, Woenig, Joshua A., Jolly, Lachlan A., Douglas, Evelyn, Friend, Kathryn, Tan, Chuan, Van Esch, Hilde, Holvoet, Maureen, Raynaud, Martine, Field, Michael, Leffler, Melanie, Budny, Bartłomiej, Wisniewska, Marzena, Badura-Stronka, Magdalena, Latos-Bieleńska, Anna, Batanian, Jacqueline, Rosenfeld, Jill A., Basel-Vanagaite, Lina, Jensen, Corinna, Bienek, Melanie, Froyen, Guy, Ullmann, Reinhard, Hu, Hao, Love, Michael I., Haas, Stefan A., Stankiewicz, Pawel, Cheung, Sau Wai, Baxendale, Anne, Nicholl, Jillian, Thompson, Elizabeth M., Haan, Eric, Kalscheuer, Vera M., and Gecz, Jozef

Published
2015
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16. Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability

Author

Grozeva, Detelina, Carss, Keren, Spasic-Boskovic, Olivera, Tejada, Maria-Isabel, Gecz, Jozef, Shaw, Marie, Corbett, Mark, Haan, Eric, Thompson, Elizabeth, Friend, Kathryn, Hussain, Zaamin, Hackett, Anna, Field, Michael, Renieri, Alessandra, Stevenson, Roger, Schwartz, Charles, Floyd, James A.B., Bentham, Jamie, Cosgrove, Catherine, Keavney, Bernard, Bhattacharya, Shoumo, Hurles, Matthew, and Raymond, Lucy F.

Published
2015
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19. Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH

Author

Nicholl, Jillian, Waters, Wendy, Mulley, John C., Suwalski, Shanna, Brown, Sue, Hull, Yvonne, Barnett, Christopher, Haan, Eric, Thompson, Elizabeth M., Liebelt, Jan, Mcgregor, Lesley, Harbord, Michael G., Entwistle, John, Munt, Chris, White, Dierdre, Chitti, Anthony, Baulderstone, David, Ketteridge, David, Consortium, Array Referral, Friend, Kathryn, Bain, Sharon M., and Yu, Sui

Published
2014
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21. Mutations in the BRWD3 gene cause X- linked mental retardation associated with macrocephaly

Author

Field, Michael, Smith, Raffaella, Edkins, Sarah, O'Meara, Sarah, Stevens, Claire, Tarpey, Patrick S., Tofts, Calli, Butler, Adam, Dicks, Ed, Barthorpe, Syd, Buck, Gemma, Cole, Jennifer, Halliday, Kelly, Gray, Kristian, Hills, Katy, Jenkinson, Andrew, Jones, David, Menzies, Andrew, Perry, Janet, Mironenko, Tatiana, Raine, Keiran, Richardson, David, Shepherd, Rebacca, Teague, Jon, Widaa, Sara, Mallya, Uma, Wooster, Richard, Moon, Jenny, Small, Alexandra, Varian, Jennifer, West, Sofie, Luo, Ying, Shaw, Marie, Friend, Kathryn L., Corbett, Mark, Turner, Gillian, Hughes, Helen, Partington, Michael, Schwartz, Charles, Stevenson, Roger, Gecz, Jozef, Mulley, John, Bobrow , Martin, Stratton, Michael R., Futreal, P. Andrew, and Raymond, F. Lucy

Subjects
Mental retardation -- Genetic aspects, Gene mutations -- Research, Cell proliferation -- Research, Biological sciences
Abstract

The article discusses about the new BRWD3 gene, which is implicated in the etiology of XLMR, linked with macrocephaly that can cause disease by altering intracellular signaling pathways affecting cellular proliferation.

Published
2007

26. A recurrent missense variant inSLC9A7causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation

Author

Khayat, Wujood, primary, Hackett, Anna, additional, Shaw, Marie, additional, Ilie, Alina, additional, Dudding-Byth, Tracy, additional, Kalscheuer, Vera M, additional, Christie, Louise, additional, Corbett, Mark A, additional, Juusola, Jane, additional, Friend, Kathryn L, additional, Kirmse, Brian M, additional, Gecz, Jozef, additional, Field, Michael, additional, and Orlowski, John, additional

Published
2018
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27. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Frints, Suzanna G. M., primary, Ozanturk, Aysegul, additional, Rodríguez Criado, Germán, additional, Grasshoff, Ute, additional, de Hoon, Bas, additional, Field, Michael, additional, Manouvrier-Hanu, Sylvie, additional, E. Hickey, Scott, additional, Kammoun, Molka, additional, Gripp, Karen W., additional, Bauer, Claudia, additional, Schroeder, Christopher, additional, Toutain, Annick, additional, Mihalic Mosher, Theresa, additional, Kelly, Benjamin J., additional, White, Peter, additional, Dufke, Andreas, additional, Rentmeester, Eveline, additional, Moon, Sungjin, additional, Koboldt, Daniel C, additional, van Roozendaal, Kees E. P., additional, Hu, Hao, additional, Haas, Stefan A., additional, Ropers, Hans-Hilger, additional, Murray, Lucinda, additional, Haan, Eric, additional, Shaw, Marie, additional, Carroll, Renee, additional, Friend, Kathryn, additional, Liebelt, Jan, additional, Hobson, Lynne, additional, De Rademaeker, Marjan, additional, Geraedts, Joep, additional, Fryns, Jean-Pierre, additional, Vermeesch, Joris, additional, Raynaud, Martine, additional, Riess, Olaf, additional, Gribnau, Joost, additional, Katsanis, Nicholas, additional, Devriendt, Koen, additional, Bauer, Peter, additional, Gecz, Jozef, additional, Golzio, Christelle, additional, Gontan, Cristina, additional, and Kalscheuer, Vera M., additional

Published
2018
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30. A non-coding variant in the 5ʹ UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability

Author

Kumar, Raman, primary, Ha, Thuong, additional, Pham, Duyen, additional, Shaw, Marie, additional, Mangelsdorf, Marie, additional, Friend, Kathryn L, additional, Hobson, Lynne, additional, Turner, Gillian, additional, Boyle, Jackie, additional, Field, Michael, additional, Hackett, Anna, additional, Corbett, Mark, additional, and Gecz, Jozef, additional

Published
2016
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31. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study

Author

Mirzaa, Ghayda M, primary, Conti, Valerio, additional, Timms, Andrew E, additional, Smyser, Christopher D, additional, Ahmed, Sarah, additional, Carter, Melissa, additional, Barnett, Sarah, additional, Hufnagel, Robert B, additional, Goldstein, Amy, additional, Narumi-Kishimoto, Yoko, additional, Olds, Carissa, additional, Collins, Sarah, additional, Johnston, Kathreen, additional, Deleuze, Jean-François, additional, Nitschké, Patrick, additional, Friend, Kathryn, additional, Harris, Catharine, additional, Goetsch, Allison, additional, Martin, Beth, additional, Boyle, Evan August, additional, Parrini, Elena, additional, Mei, Davide, additional, Tattini, Lorenzo, additional, Slavotinek, Anne, additional, Blair, Ed, additional, Barnett, Christopher, additional, Shendure, Jay, additional, Chelly, Jamel, additional, Dobyns, William B, additional, and Guerrini, Renzo, additional

Published
2015
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32. IncreasedSTAG2dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, Raman, primary, Corbett, Mark A., additional, Van Bon, Bregje W.M., additional, Gardner, Alison, additional, Woenig, Joshua A., additional, Jolly, Lachlan A., additional, Douglas, Evelyn, additional, Friend, Kathryn, additional, Tan, Chuan, additional, Van Esch, Hilde, additional, Holvoet, Maureen, additional, Raynaud, Martine, additional, Field, Michael, additional, Leffler, Melanie, additional, Budny, Bartłomiej, additional, Wisniewska, Marzena, additional, Badura-Stronka, Magdalena, additional, Latos-Bieleńska, Anna, additional, Batanian, Jacqueline, additional, Rosenfeld, Jill A., additional, Basel-Vanagaite, Lina, additional, Jensen, Corinna, additional, Bienek, Melanie, additional, Froyen, Guy, additional, Ullmann, Reinhard, additional, Hu, Hao, additional, Love, Michael I., additional, Haas, Stefan A., additional, Stankiewicz, Pawel, additional, Cheung, Sau Wai, additional, Baxendale, Anne, additional, Nicholl, Jillian, additional, Thompson, Elizabeth M., additional, Haan, Eric, additional, Kalscheuer, Vera M., additional, and Gecz, Jozef, additional

Published
2015
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33. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Author

Kumar, Raman, primary, Corbett, Mark A., additional, van Bon, Bregje W.M., additional, Woenig, Joshua A., additional, Weir, Lloyd, additional, Douglas, Evelyn, additional, Friend, Kathryn L., additional, Gardner, Alison, additional, Shaw, Marie, additional, Jolly, Lachlan A., additional, Tan, Chuan, additional, Hunter, Matthew F., additional, Hackett, Anna, additional, Field, Michael, additional, Palmer, Elizabeth E., additional, Leffler, Melanie, additional, Rogers, Carolyn, additional, Boyle, Jackie, additional, Bienek, Melanie, additional, Jensen, Corinna, additional, Van Buggenhout, Griet, additional, Van Esch, Hilde, additional, Hoffmann, Katrin, additional, Raynaud, Martine, additional, Zhao, Huiying, additional, Reed, Robin, additional, Hu, Hao, additional, Haas, Stefan A., additional, Haan, Eric, additional, Kalscheuer, Vera M., additional, and Gecz, Jozef, additional

Published
2015
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34. Phenotypic variation ofTTC19-deficient mitochondrial complex III deficiency: A case report and literature review

Author

Mordaunt, Dylan A., primary, Jolley, Alexandra, additional, Balasubramaniam, Shanti, additional, Thorburn, David R., additional, Mountford, Hayley S., additional, Compton, Alison G., additional, Nicholl, Jillian, additional, Manton, Nicholas, additional, Clark, Damian, additional, Bratkovic, Drago, additional, Friend, Kathryn, additional, and Yu, Sui, additional

Published
2015
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35. Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach

Author

Marques, Isabel, primary, Sá, Maria João, additional, Soares, Gabriela, additional, Mota, Maria do Céu, additional, Pinheiro, Carla, additional, Aguiar, Lisa, additional, Amado, Marta, additional, Soares, Christina, additional, Calado, Angelina, additional, Dias, Patrícia, additional, Sousa, Ana Berta, additional, Fortuna, Ana Maria, additional, Santos, Rosário, additional, Howell, Katherine B., additional, Ryan, Monique M., additional, Leventer, Richard J, additional, Sachdev, Rani, additional, Catford, Rachael, additional, Friend, Kathryn, additional, Mattiske, Tessa R., additional, Shoubridge, Cheryl, additional, and Jorge, Paula, additional

Published
2015
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36. Refining analyses of copy number variation identifies specific genes associated with developmental delay

Author

Coe, Bradley P, primary, Witherspoon, Kali, additional, Rosenfeld, Jill A, additional, van Bon, Bregje W M, additional, Vulto-van Silfhout, Anneke T, additional, Bosco, Paolo, additional, Friend, Kathryn L, additional, Baker, Carl, additional, Buono, Serafino, additional, Vissers, Lisenka E L M, additional, Schuurs-Hoeijmakers, Janneke H, additional, Hoischen, Alex, additional, Pfundt, Rolph, additional, Krumm, Nik, additional, Carvill, Gemma L, additional, Li, Deana, additional, Amaral, David, additional, Brown, Natasha, additional, Lockhart, Paul J, additional, Scheffer, Ingrid E, additional, Alberti, Antonino, additional, Shaw, Marie, additional, Pettinato, Rosa, additional, Tervo, Raymond, additional, de Leeuw, Nicole, additional, Reijnders, Margot R F, additional, Torchia, Beth S, additional, Peeters, Hilde, additional, Thompson, Elizabeth, additional, O'Roak, Brian J, additional, Fichera, Marco, additional, Hehir-Kwa, Jayne Y, additional, Shendure, Jay, additional, Mefford, Heather C, additional, Haan, Eric, additional, Gécz, Jozef, additional, de Vries, Bert B A, additional, Romano, Corrado, additional, and Eichler, Evan E, additional

Published
2014
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37. Epilepsy with cognitive deficit and autism spectrum disorders: Prospective diagnosis by array CGH

Author

Nicholl, Jillian, primary, Waters, Wendy, additional, Suwalski, Shanna, additional, Brown, Sue, additional, Hull, Yvonne, additional, Harbord, Michael G., additional, Entwistle, John, additional, Thompson, Suzanna, additional, Clark, Damian, additional, Pridmore, Claire, additional, Haan, Eric, additional, Barnett, Christopher, additional, McGregor, Lesley, additional, Liebelt, Jan, additional, Thompson, Elizabeth M., additional, Friend, Kathryn, additional, Bain, Sharon M., additional, Yu, Sui, additional, and Mulley, John C., additional

Published
2012
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38. Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations

Author

Field, Michael, primary, Scheffer, Ingrid E, additional, Gill, Deepak, additional, Wilson, Meredith, additional, Christie, Louise, additional, Shaw, Marie, additional, Gardner, Alison, additional, Glubb, Georgie, additional, Hobson, Lynne, additional, Corbett, Mark, additional, Friend, Kathryn, additional, Willis-Owen, Saffron, additional, and Gecz, Jozef, additional

Published
2012
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39. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia

Author

Hahn, Christopher N, primary, Chong, Chan-Eng, additional, Carmichael, Catherine L, additional, Wilkins, Ella J, additional, Brautigan, Peter J, additional, Li, Xiao-Chun, additional, Babic, Milena, additional, Lin, Ming, additional, Carmagnac, Amandine, additional, Lee, Young K, additional, Kok, Chung H, additional, Gagliardi, Lucia, additional, Friend, Kathryn L, additional, Ekert, Paul G, additional, Butcher, Carolyn M, additional, Brown, Anna L, additional, Lewis, Ian D, additional, To, L Bik, additional, Timms, Andrew E, additional, Storek, Jan, additional, Moore, Sarah, additional, Altree, Meryl, additional, Escher, Robert, additional, Bardy, Peter G, additional, Suthers, Graeme K, additional, D'Andrea, Richard J, additional, Horwitz, Marshall S, additional, and Scott, Hamish S, additional

Published
2011
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40. GATA2 is a New Predisposition Gene for Familial Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Author

Scott, Hamish S, primary, Hahn, Christopher N, additional, Carmichael, Catherine L, additional, Wilkins, Ella J, additional, Chong, Chan-Eng, additional, Brautigan, Peter J, additional, Li, Xiao-Chun, additional, Stankovic, Milena, additional, Lin, Ming, additional, Carmagnac, Amandine, additional, Butcher, Carolyn M, additional, Friend, Kathryn L, additional, Ekert, Paul G, additional, Kok, Chung H, additional, Brown, Anna L, additional, Lewis, Ian D, additional, To, L. Bik, additional, Timms, Andrew E, additional, Storek, Jan, additional, Moore, Sarah, additional, Altree, Meryl, additional, Escher, Robert, additional, Bardy, Peter G, additional, Suthers, Graeme K, additional, D'Andrea, Richard J, additional, and Horwitz, Marshall S, additional

Published
2010
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41. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Author

Dibbens, Leanne M, primary, Tarpey, Patrick S, additional, Hynes, Kim, additional, Bayly, Marta A, additional, Scheffer, Ingrid E, additional, Smith, Raffaella, additional, Bomar, Jamee, additional, Sutton, Edwina, additional, Vandeleur, Lucianne, additional, Shoubridge, Cheryl, additional, Edkins, Sarah, additional, Turner, Samantha J, additional, Stevens, Claire, additional, O'Meara, Sarah, additional, Tofts, Calli, additional, Barthorpe, Syd, additional, Buck, Gemma, additional, Cole, Jennifer, additional, Halliday, Kelly, additional, Jones, David, additional, Lee, Rebecca, additional, Madison, Mark, additional, Mironenko, Tatiana, additional, Varian, Jennifer, additional, West, Sofie, additional, Widaa, Sara, additional, Wray, Paul, additional, Teague, John, additional, Dicks, Ed, additional, Butler, Adam, additional, Menzies, Andrew, additional, Jenkinson, Andrew, additional, Shepherd, Rebecca, additional, Gusella, James F, additional, Afawi, Zaid, additional, Mazarib, Aziz, additional, Neufeld, Miriam Y, additional, Kivity, Sara, additional, Lev, Dorit, additional, Lerman-Sagie, Tally, additional, Korczyn, Amos D, additional, Derry, Christopher P, additional, Sutherland, Grant R, additional, Friend, Kathryn, additional, Shaw, Marie, additional, Corbett, Mark, additional, Kim, Hyung-Goo, additional, Geschwind, Daniel H, additional, Thomas, Paul, additional, Haan, Eric, additional, Ryan, Stephen, additional, McKee, Shane, additional, Berkovic, Samuel F, additional, Futreal, P Andrew, additional, Stratton, Michael R, additional, Mulley, John C, additional, and Gécz, Jozef, additional

Published
2008
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43. GATA2is a New Predisposition Gene for Familial Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Author

Scott, Hamish S, Hahn, Christopher N, Carmichael, Catherine L, Wilkins, Ella J, Chong, Chan-Eng, Brautigan, Peter J, Li, Xiao-Chun, Stankovic, Milena, Lin, Ming, Carmagnac, Amandine, Butcher, Carolyn M, Friend, Kathryn L, Ekert, Paul G, Kok, Chung H, Brown, Anna L, Lewis, Ian D, To, L. Bik, Timms, Andrew E, Storek, Jan, Moore, Sarah, Altree, Meryl, Escher, Robert, Bardy, Peter G, Suthers, Graeme K, D'Andrea, Richard J, and Horwitz, Marshall S

Abstract

Abstract LBA-3

Published
2010
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44. Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability

Author

Shoumo Bhattacharya, Olivera Spasic-Boskovic, Charles E. Schwartz, Catherine Cosgrove, Kathryn Friend, Keren J. Carss, F. Lucy Raymond, Roger E. Stevenson, Anna Hackett, Eric Haan, Zaamin B. Hussain, Matthew E. Hurles, Michael Field, Detelina Grozeva, James A B Floyd, Jozef Gecz, Maria-Isabel Tejada, Jamie Bentham, Mark A. Corbett, Bernard Keavney, Elizabeth Thompson, Marie Shaw, Alessandra Renieri, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Department of Haematology, Hospital Universitario Cruces = Cruces University Hospital, University of Adelaide, Women’s and Children’s Hospital [Adelaide], Università degli Studi di Siena = University of Siena (UNISI), The Greenwood Genetic Center, Grozeva, Detelina, Carss, Keren, Spasic Boskovic, Olivera, Tejada, Maria Isabel, Gecz, Jozef, Shaw, Marie, Corbett, Mark, Haan, Eric, Thompson, Elizabeth, Friend, Kathryn, Hussain, Zaamin, Hackett, Anna, Field, Michael, Renieri, Alessandra, Stevenson, Roger, Schwartz, Charle, Floyd, James A. B., Bentham, Jamie, Cosgrove, Catherine, Keavney, Bernard, Bhattacharya, Shoumo, Hurles, Matthew, Raymond, F. Lucy, and Franco, Brunella

Subjects
Male, Proband, Developmental delay, Intellectual disability, Mendelian disease, Next-generation sequencing, Genetics, Genetics (clinical), Sequence analysis, Alleles, Cohort Studies, Computational Biology, Female, Humans, Inheritance Patterns, Intellectual Disability, Mutation, Polymorphism, Single Nucleotide, Genetic Association Studies, High-Throughput Nucleotide Sequencing, next‐generation sequencing, Biology, Bioinformatics, DNA sequencing, Genetic, medicine, Missense mutation, Polymorphism, Allele, developmental delay, intellectual disability, next-generation sequencing, Research Articles, ATRX, Single Nucleotide, medicine.disease, Settore MED/03 - Genetica Medica, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, CUL4B, Research Article
Abstract

International audience; To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ß11% of the cases (113 variants in 107/986 individuals: ß8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ß3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%–15% yield from array CGH alone.

Published
2015

45. A non-coding variant in the 5ʹ UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability

Author

Raman Kumar, Jozef Gecz, Michael Field, Marie Shaw, Kathryn Friend, Marie Mangelsdorf, Lynne Hobson, Duyen H. Pham, Jackie Boyle, Anna Hackett, Mark A. Corbett, Gillian Turner, Thuong Ha, Kumar, Raman, Ha, Thuong, Pham, Duyen, Shaw, Marie, Mangelsdorf, Marie, Friend, Kathryn L, Hobson, Lynne, Turner, Gillian, Boyle, Jackie, Field, Michael, Hackett, Anna, Corbett, Mark, and Gecz, Jozef

Subjects
0301 basic medicine, Untranslated region, Adult, Male, RNA Folding, Five prime untranslated region, Short Report, Biology, 03 medical and health sciences, Genetic linkage, Cell Line, Tumor, Gene duplication, Genetics, Humans, RNA, Messenger, Nuclear protein, Gene, Genetics (clinical), X chromosome, Aged, Aged, 80 and over, Chromosomes, Human, X, Nuclear Proteins, Middle Aged, Phenotype, Pedigree, Mutagenesis, Insertional, 030104 developmental biology, HEK293 Cells, intellectual disability, Mental Retardation, X-Linked, Female, mutation, 5' Untranslated Regions, Transcription Factors
Abstract

Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may be associated with additional dysmorphic, metabolic, neuromuscular or psychiatric features. Although many coding variants have been implicated in ID, identification of pathogenic non-coding regulatory variants has only been achieved in a few cases to date. We identified a duplication of a guanine on chromosome X, NC_000023.10:g.69665044dupG 7 nucleotides upstream of the translational start site in the 5' untranslated region (UTR) of the known ID gene DLG3 that encodes synapse-associated protein 102 (SAP102). The dupG variant segregated with affected status in a large multigenerational family with non-syndromic X-linked ID and was predicted to disrupt folding of the mRNA. When tested on blood cells from the affected individuals, DLG3 mRNA levels were not altered, however, DLG3/SAP102 protein levels were. We also showed by dual luciferase reporter assay that the dupG variant interfered with translation. All currently known pathogenic DLG3 variants are predicted to be null, however the dupG variant likely leads to only a modest reduction of SAP102 levels accounting for the milder phenotype seen in this family. Refereed/Peer-reviewed

Published
2016

46. 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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47. A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.

Author

Khayat W, Hackett A, Shaw M, Ilie A, Dudding-Byth T, Kalscheuer VM, Christie L, Corbett MA, Juusola J, Friend KL, Kirmse BM, Gecz J, Field M, and Orlowski J

Subjects
Acids metabolism, Animals, CHO Cells, Cell Membrane genetics, Cricetinae, Cricetulus, Gene Expression Regulation genetics, Genetic Diseases, X-Linked metabolism, Genetic Diseases, X-Linked pathology, Glycosylation, Golgi Apparatus metabolism, Humans, Intellectual Disability metabolism, Intellectual Disability pathology, Membrane Glycoproteins genetics, Mutation, Missense genetics, Protein Transport genetics, Transfection, Viral Envelope Proteins genetics, trans-Golgi Network genetics, Genetic Diseases, X-Linked genetics, Golgi Apparatus genetics, Intellectual Disability genetics, Sodium-Hydrogen Exchangers genetics
Abstract

We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation. These data implicate a crucial role for SLC9A7 in the regulation of TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which may underlie the cellular pathophysiology and neurodevelopmental deficits associated with this particular nonsyndromic form of X-linked ID.

Published
2019
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48. A novel locus for X-linked congenital cataract on Xq24.

Author

Craig JE, Friend KL, Gecz J, Rattray KM, Troski M, Mackey DA, and Burdon KP

Subjects
Adolescent, Cataract pathology, Child, Preschool, Female, Humans, Lod Score, Male, Pedigree, Tooth pathology, Cataract congenital, Cataract genetics, Chromosomes, Human, X genetics, Genes, X-Linked, Genetic Diseases, X-Linked genetics
Abstract

Purpose: This study aimed to map the genetic locus responsible for a novel X-linked congenital cataract phenotype., Methods: A large three-generation family with lamellar and nuclear cataract in five affected males was identified. Linkage analysis was conducted by genotyping X-chromosome specific microsatellite markers at an average spacing of 5 cM. Analysis was conducted using the LINKAGE package under an X-linked recessive model., Results: A linkage was detected on Xq24 with the maximum LOD score of 2.53 at theta=0 for DXS1001. The minimal region was defined as 11.5 Mb between markers DXS8055 and DXS8009 through critical recombination events in multiple individuals., Conclusions: A gene causing this novel congenital cataract phenotype is located on the long arm of the X chromosome.

Published
2008

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