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1. Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Author

Zawerton, Ash, Mignot, Cyril, Sigafoos, Ashley, Blackburn, Patrick R, Haseeb, Abdul, McWalter, Kirsty, Ichikawa, Shoji, Nava, Caroline, Keren, Boris, Charles, Perrine, Marey, Isabelle, Tabet, Anne-Claude, Levy, Jonathan, Perrin, Laurence, Hartmann, Andreas, Lesca, Gaetan, Schluth-Bolard, Caroline, Monin, Pauline, Dupuis-Girod, Sophie, Guillen Sacoto, Maria J, Schnur, Rhonda E, Zhu, Zehua, Poisson, Alice, El Chehadeh, Salima, Alembik, Yves, Bruel, Ange-Line, Lehalle, Daphné, Nambot, Sophie, Moutton, Sébastien, Odent, Sylvie, Jaillard, Sylvie, Dubourg, Christèle, Hilhorst-Hofstee, Yvonne, Barbaro-Dieber, Tina, Ortega, Lucia, Bhoj, Elizabeth J, Masser-Frye, Diane, Bird, Lynne M, Lindstrom, Kristin, Ramsey, Keri M, Narayanan, Vinodh, Fassi, Emily, Willing, Marcia, Cole, Trevor, Salter, Claire G, Akilapa, Rhoda, Vandersteen, Anthony, Canham, Natalie, Rump, Patrick, Gerkes, Erica H, Klein Wassink-Ruiter, Jolien S, Bijlsma, Emilia, Hoffer, Mariëtte JV, Vargas, Marcelo, Wojcik, Antonina, Cherik, Florian, Francannet, Christine, Rosenfeld, Jill A, Machol, Keren, Scott, Daryl A, Bacino, Carlos A, Wang, Xia, Clark, Gary D, Bertoli, Marta, Zwolinski, Simon, Thomas, Rhys H, Akay, Ela, Chang, Richard C, Bressi, Rebekah, Sanchez Russo, Rossana, Srour, Myriam, Russell, Laura, Goyette, Anne-Marie E, Dupuis, Lucie, Mendoza-Londono, Roberto, Karimov, Catherine, Joseph, Maries, Nizon, Mathilde, Cogné, Benjamin, Kuechler, Alma, Piton, Amélie, Klee, Eric W, Lefebvre, Véronique, Clark, Karl J, and Depienne, Christel

Subjects
Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Brain Disorders, Clinical Research, Rare Diseases, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Animals, Child, Child, Preschool, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Mutation, Missense, Neurodevelopmental Disorders, Pedigree, Phenotype, SOXD Transcription Factors, Young Adult, autism, developmental delay, intellectual disability, epilepsy, missense variants, Deciphering Developmental DisorderStudy, missense variants., Clinical Sciences, Genetics & Heredity
Abstract

PurposeLamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.MethodsClinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated.ResultsMicrodeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.ConclusionsThis study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

Published
2020

2. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

Author

Bell, Scott, Rousseau, Justine, Peng, Huashan, Aouabed, Zahia, Priam, Pierre, Theroux, Jean-Francois, Jefri, Malvin, Tanti, Arnaud, Wu, Hanrong, Kolobova, Ilaria, Silviera, Heika, Manzano-Vargas, Karla, Ehresmann, Sophie, Hamdan, Fadi, Hettige, Nuwan, Zhang, Xin, Antonyan, Lilit, Nassif, Christina, Ghaloul-Gonzalez, Lina, Sebastian, Jessica, Vockley, Jerry, Begtrup, Amber, Wentzensen, Ingrid, Crunk, Amy, Nicholls, Robert, Deignan, Joshua, Al-Hertani, Walla, Efthymiou, Stephanie, Salpietro, Vincenzo, Miyake, Noriko, Makita, Yoshio, Matsumoto, Naomichi, Østern, Rune, Houge, Gunnar, Hafström, Maria, Fassi, Emily, Houlden, Henry, Klein Wassink-Ruiter, Jolien, Nelson, Dominic, Goldstein, Amy, Dabir, Tabib, van Gils, Julien, Bourgeron, Thomas, Delorme, Richard, Cooper, Gregory, Martinez, Jose, Finnila, Candice, Carmant, Lionel, Lortie, Anne, Oegema, Renske, van Gassen, Koen, Mehta, Sarju, Huhle, Dagmar, Abou Jamra, Rami, Martin, Sonja, Brunner, Han, Lindhout, Dick, Au, Margaret, Graham, John, Coubes, Christine, Turecki, Gustavo, Gravel, Simon, Mechawar, Naguib, Rossignol, Elsa, Michaud, Jacques, Lessard, Julie, Ernst, Carl, Campeau, Philippe, and Herman, Kristin

Subjects
ACTL6B, genetic engineering, intellectual disability, neurodevelopment, seizure, stem cells, Actins, Adult, Child, Child, Preschool, Chromatin, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Dendrites, Epilepsy, Female, Humans, Induced Pluripotent Stem Cells, Infant, Male, Mutation, Neurodevelopmental Disorders, Neurons, Young Adult
Abstract

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Published
2019

3. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, Holly K., Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S., Soucy, Aubrie, Genetti, Casie A., Suslovitch, Victoria, Rodan, Lance H., Tiller, George E., Lesca, Gaetan, Gripp, Karen W., Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D., Turnpenny, Peter D., Simon, Marleen E.H., Volker-Touw, Catharina M.L., Gassen, Koen L.I. van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B.A. de, Immken, LaDonna L., Buchanan, Catherine, Willing, Marcia, Toler, Tomi L., Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L., Jr., Fannemel, Madeleine, Posey, Jennifer E., Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R., Larsen, Martin J., Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K., Walsh, Laurence E., Aldinger, Kimberly A., Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P., Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B., Cohen, Lilian L., Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B., Beggs, Alan H., and Yu, Timothy W.

Published
2021
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4. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, Enrico D.H., Nardini, Niels, Caliebe, Almuth, Nagel, Inga, Young, Dana, Horvath, Gabriella, Santoro, Stephanie L., Shuss, Christine, Ziegler, Alban, Bonneau, Dominique, Kempers, Marlies, Pfundt, Rolph, Legius, Eric, Bouman, Arjan, Stuurman, Kyra E., Õunap, Katrin, Pajusalu, Sander, Wojcik, Monica H., Vasileiou, Georgia, Le Guyader, Gwenaël, Schnelle, Hege M., Berland, Siren, Zonneveld-Huijssoon, Evelien, Kersten, Simone, Gupta, Aditi, Blackburn, Patrick R., Ellingson, Marissa S., Ferber, Matthew J., Dhamija, Radhika, Klee, Eric W., McEntagart, Meriel, Lichtenbelt, Klaske D., Kenney, Amy, Vergano, Samantha A., Abou Jamra, Rami, Platzer, Konrad, Ella Pierpont, Mary, Khattar, Divya, Hopkin, Robert J., Martin, Richard J., Jongmans, Marjolijn C.J., Chang, Vivian Y., Martinez-Agosto, Julian A., Kuismin, Outi, Kurki, Mitja I., Pietiläinen, Olli, Palotie, Aarno, Maarup, Timothy J., Johnson, Diana S., Venborg Pedersen, Katja, Laulund, Lone W., Lynch, Sally A., Blyth, Moira, Prescott, Katrina, Canham, Natalie, Ibitoye, Rita, Brilstra, Eva H., Shinawi, Marwan, Fassi, Emily, Sticht, Heinrich, Gregor, Anne, Van Esch, Hilde, and Zweier, Christiane

Published
2019
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5. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Hamdan, Fadi F., Myers, Candace T., Cossette, Patrick, Lemay, Philippe, Spiegelman, Dan, Laporte, Alexandre Dionne, Nassif, Christina, Diallo, Ousmane, Monlong, Jean, Cadieux-Dion, Maxime, Dobrzeniecka, Sylvia, Meloche, Caroline, Retterer, Kyle, Cho, Megan T., Rosenfeld, Jill A., Bi, Weimin, Massicotte, Christine, Miguet, Marguerite, Brunga, Ledia, Regan, Brigid M., Mo, Kelly, Tam, Cory, Schneider, Amy, Hollingsworth, Georgie, FitzPatrick, David R., Donaldson, Alan, Canham, Natalie, Blair, Edward, Kerr, Bronwyn, Fry, Andrew E., Thomas, Rhys H., Shelagh, Joss, Hurst, Jane A., Brittain, Helen, Blyth, Moira, Lebel, Robert Roger, Gerkes, Erica H., Davis-Keppen, Laura, Stein, Quinn, Chung, Wendy K., Dorison, Sara J., Benke, Paul J., Fassi, Emily, Corsten-Janssen, Nicole, Kamsteeg, Erik-Jan, Mau-Them, Frederic T., Bruel, Ange-Line, Verloes, Alain, Õunap, Katrin, Wojcik, Monica H., Albert, Dara V.F., Venkateswaran, Sunita, Ware, Tyson, Jones, Dean, Liu, Yu-Chi, Mohammad, Shekeeb S., Bizargity, Peyman, Bacino, Carlos A., Leuzzi, Vincenzo, Martinelli, Simone, Dallapiccola, Bruno, Tartaglia, Marco, Blumkin, Lubov, Wierenga, Klaas J., Purcarin, Gabriela, O’Byrne, James J., Stockler, Sylvia, Lehman, Anna, Keren, Boris, Nougues, Marie-Christine, Mignot, Cyril, Auvin, Stéphane, Nava, Caroline, Hiatt, Susan M., Bebin, Martina, Shao, Yunru, Scaglia, Fernando, Lalani, Seema R., Frye, Richard E., Jarjour, Imad T., Jacques, Stéphanie, Boucher, Renee-Myriam, Riou, Emilie, Srour, Myriam, Carmant, Lionel, Lortie, Anne, Major, Philippe, Diadori, Paola, Dubeau, François, D’Anjou, Guy, Bourque, Guillaume, Berkovic, Samuel F., Sadleir, Lynette G., Campeau, Philippe M., Kibar, Zoha, Lafrenière, Ronald G., Girard, Simon L., Mercimek-Mahmutoglu, Saadet, Boelman, Cyrus, Rouleau, Guy A., Scheffer, Ingrid E., Mefford, Heather C., Andrade, Danielle M., Rossignol, Elsa, Minassian, Berge A., and Michaud, Jacques L.

Published
2017
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7. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, Vincenzo, Dixon, Christine L., Guo, Hui, Bello, Oscar D., Vandrovcova, Jana, Efthymiou, Stephanie, Maroofian, Reza, Heimer, Gali, Burglen, Lydie, Valence, Stephanie, Torti, Erin, Hacke, Moritz, Rankin, Julia, Tariq, Huma, Colin, Estelle, Procaccio, Vincent, Striano, Pasquale, Mankad, Kshitij, Lieb, Andreas, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, Roope, Manole, Andreea, Brusco, Alfredo, Grosso, Enrico, Ferrero, Giovanni Battista, Armstrong-Moron, Judith, Gueden, Sophie, Bar-Yosef, Omer, Tzadok, Michal, Monaghan, Kristin G., Santiago-Sim, Teresa, Person, Richard E., Cho, Megan T., Willaert, Rebecca, Yoo, Yongjin, Chae, Jong-Hee, Quan, Yingting, Wu, Huidan, Wang, Tianyun, Bernier, Raphael A., Xia, Kun, Blesson, Alyssa, Jain, Mahim, Motazacker, Mohammad M., Jaeger, Bregje, Schneider, Amy L., Boysen, Katja, Muir, Alison M., Myers, Candace T., Gavrilova, Ralitza H., Gunderson, Lauren, Schultz-Rogers, Laura, Klee, Eric W., Dyment, David, Osmond, Matthew, Parellada, Mara, Llorente, Cloe, Gonzalez-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, SYNAPS Study Group, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N., De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Boris, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C., Scheffer, Ingrid E., Clayton-Smith, Jill, Macaya, Alfons, Rothman, James E., Eichler, Evan E., Kullmann, Dimitri M., and Houlden, Henry

Published
2019
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9. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, Yu, Timothy W, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, and Yu, Timothy W

Published
2021

11. Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, Holly K., primary, Nakayama, Tojo, additional, Lai, Jenny, additional, Zhao, Boxun, additional, Argyrou, Nikoleta, additional, Gubbels, Cynthia S., additional, Soucy, Aubrie, additional, Genetti, Casie A., additional, Rodan, Lance H., additional, Tiller, George E., additional, Lesca, Gaetan, additional, Gripp, Karen W., additional, Asadollahi, Reza, additional, Hamosh, Ada, additional, Applegate, Carolyn D., additional, Turnpenny, Peter D., additional, Simon, Marleen E.H., additional, Volker-Touw, Catharina (Nienke) M.L., additional, van Gassen, Koen L.I., additional, van Binsbergen, Ellen, additional, Pfundt, Rolph, additional, Gardeitchik, Thatjana, additional, de Vries, Bert B.A., additional, Imken, Ladonna L., additional, Buchanan, Catherine, additional, Willing, Marcia, additional, Toler, Tomi L., additional, Fassi, Emily, additional, Baker, Laura, additional, Vansenne, Fleur, additional, Wang, Xiadong, additional, Ambrus, Julian L., additional, Fannemel, Madeleine, additional, Posey, Jennifer E., additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Rauch, Anita, additional, Boonsawat, Paranchai, additional, Fagerberg, Christina R., additional, Larsen, Martin J., additional, Kibaek, Maria, additional, Labalme, Audrey, additional, Poisson, Alice, additional, Payne, Katelyn K., additional, Walsh, Laurence E., additional, Aldinger, Kimberly, additional, Balciuniene, Jorune, additional, Skraban, Cara, additional, Gray, Christopher, additional, Murrell, Jill, additional, Bupp, Caleb P., additional, Pascolini, Giulia, additional, Grammatico, Paola, additional, Broly, Martin, additional, Küry, Sébastien, additional, Nizon, Mathilde, additional, Rasool, Iqra Ghulam, additional, Zahoor, Muhammad Yasir, additional, Kraus, Cornelia, additional, Reis, André, additional, Iqbal, Muhammad, additional, Uguen, Kevin, additional, Audebert-Bellanger, Severine, additional, Ferec, Claude, additional, Redon, Sylvia, additional, Baker, Janice, additional, Wu, Yunhong, additional, Zampino, Guiseppe, additional, Syrbe, Steffan, additional, Brosse, Ines, additional, Jamra, Rami Abou, additional, Dobyns, William B., additional, Cohen, Lilian L., additional, Agrawal, Pankaj B., additional, Beggs, Alan, additional, and Yu, Timothy W., additional

Published
2020
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12. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, Tucci Arianna, Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, and Tucci Arianna

Published
2019

13. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

Author

Genetica, Genetica Klinische Genetica, Brain, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Sectie Genomics and Bioinformatics, Bell, Scott, Rousseau, Justine, Peng, Huashan, Aouabed, Zahia, Priam, Pierre, Theroux, Jean Francois, Jefri, Malvin, Tanti, Arnaud, Wu, Hanrong, Kolobova, Ilaria, Silviera, Heika, Manzano-Vargas, Karla, Ehresmann, Sophie, Hamdan, Fadi F., Hettige, Nuwan, Zhang, Xin, Antonyan, Lilit, Nassif, Christina, Ghaloul-Gonzalez, Lina, Sebastian, Jessica, Vockley, Jerry, Begtrup, Amber G., Wentzensen, Ingrid M., Crunk, Amy, Nicholls, Robert D., Herman, Kristin C., Deignan, Joshua L., Al-Hertani, Walla, Efthymiou, Stephanie, Salpietro, Vincenzo, Miyake, Noriko, Makita, Yoshio, Matsumoto, Naomichi, Østern, Rune, Houge, Gunnar, Hafström, Maria, Fassi, Emily, Houlden, Henry, Klein Wassink-Ruiter, Jolien S., Nelson, Dominic, Goldstein, Amy, Dabir, Tabib, van Gils, Julien, Bourgeron, Thomas, Delorme, Richard, Cooper, Gregory M., Martinez, Jose E., Finnila, Candice R., Carmant, Lionel, Lortie, Anne, Oegema, Renske, van Gassen, Koen, Mehta, Sarju G., Huhle, Dagmar, Abou Jamra, Rami, Martin, Sonja, Brunner, Han G., Lindhout, Dick, Au, Margaret, Graham, John M., Coubes, Christine, Turecki, Gustavo, Gravel, Simon, Mechawar, Naguib, Rossignol, Elsa, Michaud, Jacques L., Lessard, Julie, Ernst, Carl, Campeau, Philippe M., Genetica, Genetica Klinische Genetica, Brain, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Sectie Genomics and Bioinformatics, Bell, Scott, Rousseau, Justine, Peng, Huashan, Aouabed, Zahia, Priam, Pierre, Theroux, Jean Francois, Jefri, Malvin, Tanti, Arnaud, Wu, Hanrong, Kolobova, Ilaria, Silviera, Heika, Manzano-Vargas, Karla, Ehresmann, Sophie, Hamdan, Fadi F., Hettige, Nuwan, Zhang, Xin, Antonyan, Lilit, Nassif, Christina, Ghaloul-Gonzalez, Lina, Sebastian, Jessica, Vockley, Jerry, Begtrup, Amber G., Wentzensen, Ingrid M., Crunk, Amy, Nicholls, Robert D., Herman, Kristin C., Deignan, Joshua L., Al-Hertani, Walla, Efthymiou, Stephanie, Salpietro, Vincenzo, Miyake, Noriko, Makita, Yoshio, Matsumoto, Naomichi, Østern, Rune, Houge, Gunnar, Hafström, Maria, Fassi, Emily, Houlden, Henry, Klein Wassink-Ruiter, Jolien S., Nelson, Dominic, Goldstein, Amy, Dabir, Tabib, van Gils, Julien, Bourgeron, Thomas, Delorme, Richard, Cooper, Gregory M., Martinez, Jose E., Finnila, Candice R., Carmant, Lionel, Lortie, Anne, Oegema, Renske, van Gassen, Koen, Mehta, Sarju G., Huhle, Dagmar, Abou Jamra, Rami, Martin, Sonja, Brunner, Han G., Lindhout, Dick, Au, Margaret, Graham, John M., Coubes, Christine, Turecki, Gustavo, Gravel, Simon, Mechawar, Naguib, Rossignol, Elsa, Michaud, Jacques L., Lessard, Julie, Ernst, Carl, and Campeau, Philippe M.

Published
2019

14. Breast cancer polygenic risk scores in the clinical cancer genetic counseling setting: Current practices and impact on patient management.

Author

McGuinness, Molly, Fassi, Emily, Wang, Catharine, Hacking, Claire, and Ellis, Victoria

Abstract

Multivariate risk models are commonly used in clinical practice to estimate a woman's lifetime risk for breast cancer and assist in implementation of appropriate screening and risk reduction strategies. More recently, breast cancer polygenic risk scores (PRS) have been derived and integrated into these models to further improve risk estimation. While breast cancer PRS have been offered by two clinical diagnostic laboratories since 2017, little is known about the extent to which genetic counselors are ordering breast cancer PRS or incorporating the results into patient management. This study surveyed U.S. cancer genetic counselors from October 2019 to January 2020 to identify and understand their current practices with breast cancer PRS, to determine the impact of breast cancer PRS on patient management, and to anticipate future genetic counselor practices with breast cancer PRS. Fewer than half of respondents (43%, 51/120) had ordered breast cancer PRS and approximately one‐third (35%, 16/46) reported that the PRS had changed their medical management recommendations. The majority of cancer genetic counselors had not ordered PRS, most commonly due to (a) lack of clinical guidelines (90%, 60/67), (b) insufficient evidence of clinical utility (88%, 59/67), and (c) lack of availability for patients of non‐European ancestry (70%, 47/67). Of genetic counselors who had not ordered breast cancer PRS, only 10% (7/68) did not believe they would order PRS in the future. This is the first study to characterize genetic counselors' experiences with breast cancer PRS. Results from this study indicate that although breast cancer PRS have been clinically available for patients for several years, most cancer genetic counselors are not yet convinced they are ready to be incorporated into patient care. [ABSTRACT FROM AUTHOR]

Published
2021
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15. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Author

Chemin, Jean, primary, Siquier-Pernet, Karine, additional, Nicouleau, Michaël, additional, Barcia, Giulia, additional, Ahmad, Ali, additional, Medina-Cano, Daniel, additional, Hanein, Sylvain, additional, Altin, Nami, additional, Hubert, Laurence, additional, Bole-Feysot, Christine, additional, Fourage, Cécile, additional, Nitschké, Patrick, additional, Thevenon, Julien, additional, Rio, Marlène, additional, Blanc, Pierre, additional, vidal, Céline, additional, Bahi-Buisson, Nadia, additional, Desguerre, Isabelle, additional, Munnich, Arnold, additional, Lyonnet, Stanislas, additional, Boddaert, Nathalie, additional, Fassi, Emily, additional, Shinawi, Marwan, additional, Zimmerman, Holly, additional, Amiel, Jeanne, additional, Faivre, Laurence, additional, Colleaux, Laurence, additional, Lory, Philippe, additional, and Cantagrel, Vincent, additional

Published
2018
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17. Mutations in the PH Domain of <italic>DNM1</italic> are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities.

Author

Brereton, Emily, Fassi, Emily, Araujo, Gabriel C., Dodd, Jonathan, Telegrafi, Aida, Pathak, Sheel J., and Shinawi, Marwan

Subjects
*GENETIC mutation, *PHENOTYPES, *DEVELOPMENTAL delay, *NEUROBEHAVIORAL disorders, *NEUROTRANSMITTERS
Abstract

Abstract: Background: Dynamin 1 is a protein involved in the synaptic vesicle cycle, which facilitates the exocytosis of neurotransmitters necessary for normal signaling and development in the central nervous system. Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy. All previously reported DNM1 pathogenic variants causing this severe phenotype occur in the GTPase and Middle domains of the dynamin 1 protein. Methods: We used whole‐exome sequencing to characterize the molecular basis of DD and autistic symptoms in two identical siblings. Results: The twin siblings exhibit mild to moderate ID and autistic symptoms but no epileptic encephalopathy. Exome sequencing revealed a genetic variant, c.1603A>G (p.Lys535Glu), in the PH domain of dynamin 1. Previous in vitro studies showed that mutations at Lys535 inhibit endocytosis and impair PH loop binding to PIP2. Conclusions: Our data suggest a previously undescribed milder phenotype associated with a missense genetic variant in the PH domain of dynamin 1. [ABSTRACT FROM AUTHOR]

Published
2018
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18. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo Salpietro1, 2 3, 140, Christine L. Dixon4, Hui Guo5, 6 140, Oscar D. Bello Stephanie Efthymiou 1, 4, Reza Maroofian1, Gali Heimer7, Lydie Burglen 8, Stephanie Valence 9, Erin Torti 10, Moritz Hacke11, Julia Rankin12, Huma Tariq1, Estelle Colin13, Vincent Procaccio13, Pasquale Striano2, 3, Kshitij Mankad15, Andreas Lieb 4, Sharon Chen16, Laura Pisani16, Conceicao Bettencourt 17, Roope Männikkö 1, Andreea Manole1, Alfredo Brusco 18, Enrico Grosso18, Giovanni Battista Ferrero19, Judith Armstrong-Moron20, Sophie Gueden21, Omer Bar-Yosef7, Michal Tzadok7, Kristin G. Monaghan10, Teresa Santiago-Sim10, Richard E. Person10, Megan T. Cho10, Rebecca Willaert10, Yongjin Yoo22, Jong-Hee Chae23, Yingting Quan6, Huidan Wu6, Tianyun Wang5, 6, Raphael A. Bernier24, Kun Xia6, Alyssa Blesson25, Mahim Jain25, Mohammad M. Motazacker26, Bregje Jaeger27, Amy L. Schneider 28, Katja Boysen28, Alison M. Muir 29, Candace T. Myers30, Ralitza H. Gavrilova31, Lauren Gunderson31, Laura Schultz-Rogers 31, Eric W. Klee31, David Dyment32, Matthew Osmond32, 33 34, Mara Parellada35, Cloe Llorente36, Javier Gonzalez-Peñas37, Angel Carracedo38, Arie Van Haeringen40, Claudia Ruivenkamp40, Caroline Nava41, Delphine Heron41, Rosaria Nardello42, Michele Iacomino43, Carlo Minetti2, Aldo Skabar44, Antonella Fabretto44, SYNAPS Study GroupMiquel Raspall-Chaure45, Michael Chez46, Anne Tsai47, Emily Fassi48, Marwan Shinawi48, John N. Constantino49, Rita De Zorzi50, Sara Fortuna 50, Fernando Kok51, Boris Keren41, Dominique Bonneau13, Murim Choi 22, Bruria Benzeev7, Federico Zara43, Heather C. Mefford29, Ingrid E. Scheffer28, Jill Clayton-Smith53, Alfons Macaya45, James E. Rothman4, Evan E. Eichler 5, Dimitri M. Kullmann 4, Henry Houlden 1, SYNAPS Study Group Michael G. Hanna1, Enrico Bugiardini1, Isabel Hostettler1, Benjamin O’Callaghan1, Alaa Khan1, Andrea Cortese1, Emer O’Connor1, Wai Y. Yau1, Thomas Bourinaris1, Rauan Kaiyrzhanov1, Viorica Chelban1, Monika Madej1, Maria C. Diana2, Maria S. Vari2, Marina Pedemonte2, Claudio Bruno2, Ganna Balagura3, Marcello Scala3, Chiara Fiorillo3, Lino Nobili3, Nancy T. Malintan4, Maria N. Zanetti4, Shyam S. Krishnakumar4, Gabriele Lignani4, James E. C. Jepson4, Paolo Broda43, Simona Baldassari43, Pia Rossi43, Floriana Fruscione43, Francesca Madia43, Monica Traverso43, Patrizia De-Marco43, Belen Pérez-Dueñas45, Francina Munell45, Yamna Kriouile57, Mohamed El-Khorassani57, Blagovesta Karashova58, Daniela Avdjieva58, Hadil Kathom58, Radka Tincheva58, Lionel Van-Maldergem59, Wolfgang Nachbauer60, Sylvia Boesch60, Antonella Gagliano61, Elisabetta Amadori62, Jatinder S. Goraya63, Tipu Sultan64, Salman Kirmani65, Shahnaz Ibrahim66, Farida Jan66, Jun Mine67, Selina Banu68, Pierangelo Veggiotti69, Gian V. Zuccotti69, Michel D. Ferrari70, Arn M. J. Van Den Maagdenberg70, Alberto Verrotti71, Gian L. Marseglia72, Salvatore Savasta72, Miguel A. Soler73, Carmela Scuderi74, Eugenia Borgione74, Roberto Chimenz75, Eloisa Gitto75, Valeria Dipasquale75, Alessia Sallemi75, Monica Fusco75, Caterina Cuppari75, Maria C. Cutrupi75, Martino Ruggieri76, Armando Cama77, Valeria Capra77, Niccolò E. Mencacci78, Richard Boles79, Neerja Gupta80, Madhulika Kabra80, Savvas Papacostas81, Eleni Zamba-Papanicolaou81, Efthymios Dardiotis82, Shazia Maqbool83, Nuzhat Rana84, Osama Atawneh85, Shen Y. Lim86, Farooq Shaikh87, George Koutsis88, Marianthi Breza88, Domenico A. Coviello89, Yves A. Dauvilliers90, Issam AlKhawaja91, Mariam AlKhawaja92, Fuad Al-Mutairi93, Tanya Stojkovic94, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya96, Maria Kinali97, Hamed Sherifa98, Hanene Benrhouma99, Ilhem B. Y. Turki99, Meriem Tazir100, Makram Obeid101, Sophia Bakhtadze102, Nebal W. Saadi103, Maha S. Zaki104, Chahnez C. Triki105, Fabio Benfenati106, Stefano Gustincich106, Majdi Kara107, Vincenzo Belcastro108, Nicola Specchio109, Giuseppe Capovilla110, Ehsan G. Karimiani111, Ahmed M. Salih112, Njideka U. Okubadejo113, Oluwadamilola O. Ojo113, Olajumoke O. Oshinaike113, Olapeju Oguntunde113, Kolawole Wahab114, Abiodun H. Bello114, Sanni Abubakar115, Yahaya Obiabo116, Ernest Nwazor117, Oluchi Ekenze118, Uduak Williams119, Alagoma Iyagba120, Lolade Taiwo121, Morenikeji Komolafe122, Konstantin Senkevich123, Chingiz Shashkin124, Nazira Zharkynbekova125, Kairgali Koneyev126, Ganieva Manizha127, Maksud Isrofilov127, Ulviyya Guliyeva128, Kamran Salayev129, Samson Khachatryan130, Salvatore Rossi131, Gabriella Silvestri131, Nourelhoda Haridy132, Luca A. Ramenghi133, Georgia Xiromerisiou134, Emanuele David135, Mhammed Aguennouz136, Liana Fidani137, Cleanthe Spanaki138, Arianna Tucci139, University College of London [London] (UCL), Instituto Giannina Gaslini, Genoa, University of Genoa (UNIGE), University of Washington [Seattle], Institute of Neurology, Queen Square, London, King‘s College London, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), GeneDx [Gaithersburg, MD, USA], Heidelberg University Hospital [Heidelberg], Royal Devon and Exeter NHS Foundation Trust [UK], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Universita degli studi di Genova, Great Ormond Street Hospital for Children [London] (GOSH), The University of Sydney, Hofstra University [Hempstead], Università degli studi di Torino (UNITO), Hospital Sant Joan de Déu [Barcelona], Safra Children's Hospital, Seoul National University Hospital, Central South University [Changsha], Kennedy Krieger Institute [Baltimore], University of Amsterdam [Amsterdam] (UvA), University of Melbourne, Mayo Clinic [Rochester], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Ottawa [Ottawa], University of British Columbia (UBC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Leiden [Leiden], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Palermo - University of Palermo, University of Trieste, Universitat Autònoma de Barcelona (UAB), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California-University of California, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Washington University in Saint Louis (WUSTL), Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Psychiatry, Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, University of Oxford [Oxford], University of São Paulo (USP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Pédiatrie, CHUR Poitiers, Seoul National University [Seoul] (SNU), Pediatric Neurology and Neuromuscular Diseases Unit, University of Manchester [Manchester], Yale University School of Medicine, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Salvy-Córdoba, Nathalie, Università degli studi di Genova = University of Genoa (UniGe), Tel Aviv University (TAU), Università degli studi di Torino = University of Turin (UNITO), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Trieste = University of Trieste, University of California (UC)-University of California (UC), University of Oxford, Universidade de São Paulo = University of São Paulo (USP), Yale School of Medicine [New Haven, Connecticut] (YSM), Salpietro V, Dixon CL, Guo H, Bello OD, Vandrovcova J, Efthymiou S, Maroofian R, Heimer G, Burglen L, Valence S, Torti E, Hacke M, Rankin J, Tariq H, Colin E, Procaccio V, Striano P, Mankad K, Lieb A, Chen S, Pisani L, Bettencourt C, Männikkö R, Manole A, Brusco A, Grosso E, Ferrero GB, Armstrong-Moron J, Gueden S, Bar-Yosef O, Tzadok M, Monaghan KG, Santiago-Sim T, Person RE, Cho MT, Willaert R, Yoo Y, Chae JH, Quan Y, Wu H, Wang T, Bernier RA, Xia K, Blesson A, Jain M, Motazacker MM, Jaeger B, Schneider AL, Boysen K, Muir AM, Myers CT, Gavrilova RH, Gunderson L, Schultz-Rogers L, Klee EW, Dyment D, Osmond M, Parellada M, Llorente C, Gonzalez-Peñas J, Carracedo A, Van Haeringen A, Ruivenkamp C, Nava C, Heron D, Nardello R, Iacomino M, Minetti C, Skabar A, Fabretto A, SYNAPS Study Group, Raspall-Chaure M, Chez M, Tsai A, Fassi E, Shinawi M, Constantino JN, De Zorzi R, Fortuna S, Kok F, Keren B, Bonneau D, Choi M, Benzeev B, Zara F, Mefford HC, Scheffer IE, Clayton-Smith J, Macaya A, Rothman JE, Eichler EE, Kullmann DM, Houlden H, Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Maroofian, Reza, Heimer, Gali, Burglen, Lydie, Valence, Stephanie, Torti, Erin, Hacke, Moritz, Rankin, Julia, Tariq, Huma, Colin, Estelle, Procaccio, Vincent, Striano, Pasquale, Mankad, Kshitij, Lieb, Andrea, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, Roope, Manole, Andreea, Brusco, Alfredo, Grosso, Enrico, Ferrero, Giovanni Battista, Armstrong-Moron, Judith, Gueden, Sophie, Bar-Yosef, Omer, Tzadok, Michal, Monaghan, Kristin G, Santiago-Sim, Teresa, Person, Richard E, Cho, Megan T, Willaert, Rebecca, Yoo, Yongjin, Chae, Jong-Hee, Quan, Yingting, Wu, Huidan, Wang, Tianyun, Bernier, Raphael A, Xia, Kun, Blesson, Alyssa, Jain, Mahim, Motazacker, Mohammad M, Jaeger, Bregje, Schneider, Amy L, Boysen, Katja, Muir, Alison M, Myers, Candace T, Gavrilova, Ralitza H, Gunderson, Lauren, Schultz-Rogers, Laura, Klee, Eric W, Dyment, David, Osmond, Matthew, Parellada, Mara, Llorente, Cloe, Gonzalez-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N, De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Bori, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C, Scheffer, Ingrid E, Clayton-Smith, Jill, Macaya, Alfon, Rothman, James E, Eichler, Evan E, Kullmann, Dimitri M, Houlden, Henry, Salpietro1, Vincenzo, 3, 2, Dixon4, Christine L., Guo5, Hui, 140, 6, Bello Stephanie Efthymiou 1, Oscar D., Maroofian1, Reza, Heimer7, Gali, 8, Lydie Burglen, 9, Stephanie Valence, Torti 10, Erin, Hacke11, Moritz, Rankin12, Julia, Tariq1, Huma, Colin13, Estelle, Procaccio13, Vincent, Striano2, Pasquale, Mankad15, Kshitij, 4, Andreas Lieb, Chen16, Sharon, Pisani16, Laura, Bettencourt 17, Conceicao, 1, Roope Männikkö, Manole1, Andreea, Brusco 18, Alfredo, Grosso18, Enrico, Battista Ferrero19, Giovanni, Armstrong-Moron20, Judith, Gueden21, Sophie, Bar-Yosef7, Omer, Tzadok7, Michal, Monaghan10, Kristin G., Santiago-Sim10, Teresa, Person10, Richard E., Cho10, Megan T., Willaert10, Rebecca, Yoo22, Yongjin, Chae23, Jong-Hee, Quan6, Yingting, Wu6, Huidan, Wang5, Tianyun, Bernier24, Raphael A., Xia6, Kun, Blesson25, Alyssa, Jain25, Mahim, Motazacker26, Mohammad M., Jaeger27, Bregje, Schneider 28, Amy L., Boysen28, Katja, Muir 29, Alison M., Myers30, Candace T., Gavrilova31, Ralitza H., Gunderson31, Lauren, Schultz-Rogers 31, Laura, Klee31, Eric W., Dyment32, David, Osmond32, Matthew, 34, 33, Parellada35, Mara, Llorente36, Cloe, Gonzalez-Peñas37, Javier, Carracedo38, Angel, Van Haeringen40, Arie, Ruivenkamp40, Claudia, Nava41, Caroline, Heron41, Delphine, Nardello42, Rosaria, Iacomino43, Michele, Minetti2, Carlo, Skabar44, Aldo, Fabretto44, Antonella, Study GroupMiquel Raspall-Chaure45, Synap, Chez46, Michael, Tsai47, Anne, Fassi48, Emily, Shinawi48, Marwan, Constantino49, John N., De Zorzi50, Rita, Fortuna 50, Sara, Kok51, Fernando, Keren41, Bori, Bonneau13, Dominique, Choi 22, Murim, Benzeev7, Bruria, Zara43, Federico, Mefford29, Heather C., Scheffer28, Ingrid E., Clayton-Smith53, Jill, Macaya45, Alfon, Rothman4, James E., Eichler 5, Evan E., Kullmann 4 &amp, Dimitri M., 1, Henry Houlden, Hanna1, SYNAPS Study Group Michael G., Bugiardini1, Enrico, Hostettler1, Isabel, O’Callaghan1, Benjamin, Khan1, Alaa, Cortese1, Andrea, O’Connor1, Emer, Yau1, Wai Y., Bourinaris1, Thoma, Kaiyrzhanov1, Rauan, Chelban1, Viorica, Madej1, Monika, Diana2, Maria C., Vari2, Maria S., Pedemonte2, Marina, Bruno2, Claudio, Balagura3, Ganna, Scala3, Marcello, Fiorillo3, Chiara, Nobili3, Lino, Malintan4, Nancy T., Zanetti4, Maria N., Krishnakumar4, Shyam S., Lignani4, Gabriele, Jepson4, James E. C., Broda43, Paolo, Baldassari43, Simona, Rossi43, Pia, Fruscione43, Floriana, Madia43, Francesca, Traverso43, Monica, De-Marco43, Patrizia, Pérez-Dueñas45, Belen, Munell45, Francina, Kriouile57, Yamna, El-Khorassani57, Mohamed, Karashova58, Blagovesta, Avdjieva58, Daniela, Kathom58, Hadil, Tincheva58, Radka, Van-Maldergem59, Lionel, Nachbauer60, Wolfgang, Boesch60, Sylvia, Gagliano61, Antonella, Amadori62, Elisabetta, Goraya63, Jatinder S., Sultan64, Tipu, Kirmani65, Salman, Ibrahim66, Shahnaz, Jan66, Farida, Mine67, Jun, Banu68, Selina, Veggiotti69, Pierangelo, Zuccotti69, Gian V., Ferrari70, Michel D., Van Den Maagdenberg70, Arn M. J., Verrotti71, Alberto, Marseglia72, Gian L., Savasta72, Salvatore, Soler73, Miguel A., Scuderi74, Carmela, Borgione74, Eugenia, Chimenz75, Roberto, Gitto75, Eloisa, Dipasquale75, Valeria, Sallemi75, Alessia, Fusco75, Monica, Cuppari75, Caterina, Cutrupi75, Maria C., Ruggieri76, Martino, Cama77, Armando, Capra77, Valeria, Mencacci78, Niccolò E., Boles79, Richard, Gupta80, Neerja, Kabra80, Madhulika, Papacostas81, Savva, Zamba-Papanicolaou81, Eleni, Dardiotis82, Efthymio, Maqbool83, Shazia, Rana84, Nuzhat, Atawneh85, Osama, Lim86, Shen Y., Shaikh87, Farooq, Koutsis88, George, Breza88, Marianthi, Coviello89, Domenico A., Dauvilliers90, Yves A., Alkhawaja91, Issam, Alkhawaja92, Mariam, Al-Mutairi93, Fuad, Stojkovic94, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya96, Fowzan S., Kinali97, Maria, Sherifa98, Hamed, Benrhouma99, Hanene, Turki99, Ilhem B. Y., Tazir100, Meriem, Obeid101, Makram, Bakhtadze102, Sophia, Saadi103, Nebal W., Zaki104, Maha S., Triki105, Chahnez C., Benfenati106, Fabio, Gustincich106, Stefano, Kara107, Majdi, Belcastro108, Vincenzo, Specchio109, Nicola, Capovilla110, Giuseppe, Karimiani111, Ehsan G., Salih112, Ahmed M., Okubadejo113, Njideka U., Ojo113, Oluwadamilola O., Oshinaike113, Olajumoke O., Oguntunde113, Olapeju, Wahab114, Kolawole, Bello114, Abiodun H., Abubakar115, Sanni, Obiabo116, Yahaya, Nwazor117, Ernest, Ekenze118, Oluchi, Williams119, Uduak, Iyagba120, Alagoma, Taiwo121, Lolade, Komolafe122, Morenikeji, Senkevich123, Konstantin, Shashkin124, Chingiz, Zharkynbekova125, Nazira, Koneyev126, Kairgali, Manizha127, Ganieva, Isrofilov127, Maksud, Guliyeva128, Ulviyya, Salayev129, Kamran, Khachatryan130, Samson, Rossi131, Salvatore, Silvestri131, Gabriella, Haridy132, Nourelhoda, Ramenghi133, Luca A., Xiromerisiou134, Georgia, David135, Emanuele, Aguennouz136, Mhammed, Fidani137, Liana, Spanaki138 &amp, Cleanthe, and Tucci139, Arianna

Subjects
Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ion channels in the nervous system, Cohort Studies, fluids and secretions, Loss of Function Mutation, Receptors, AMPA, AMPA receptor, lcsh:Science, Child, reproductive and urinary physiology, AMPA receptor, GluA2, neurodevelopmental disorders, autism spectrum disorder, glutamatergic synaptic transmission, GRIA2, neurodevelopmental disorders, Developmental disorders, Neurodevelopmental disorders, Brain, Magnetic Resonance Imaging, Settore MED/26 - NEUROLOGIA, GluA2, Child, Preschool, Female, Adult, Heterozygote, Adolescent, Science, autism spectrum disorder, Article, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Intellectual Disability/genetics, Neurodevelopmental Disorders/genetics, Receptors AMPA/genetics, Intellectual Disability, mental disorders, Humans, Infant, Neurodevelopmental Disorders, Receptors, AMPA, GRIA2, Preschool, Ion channel in the nervous system, Developmental disorders, Synaptic development, NG sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, glutamatergic synaptic transmission, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, NG sequencing, Synaptic development, Ion channel in the nervous system, Next-generation sequencing, lcsh:Q
Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission., Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

Published
2019
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19. Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

Author

Cheng H, Capponi S, Wakeling E, Marchi E, Li Q, Zhao M, Weng C, Stefan PG, Ahlfors H, Kleyner R, Rope A, Lumaka A, Lukusa P, Devriendt K, Vermeesch J, Posey JE, Palmer EE, Murray L, Leon E, Diaz J, Worgan L, Mallawaarachchi A, Vogt J, de Munnik SA, Dreyer L, Baynam G, Ewans L, Stark Z, Lunke S, Gonçalves AR, Soares G, Oliveira J, Fassi E, Willing M, Waugh JL, Faivre L, Riviere JB, Moutton S, Mohammed S, Payne K, Walsh L, Begtrup A, Guillen Sacoto MJ, Douglas G, Alexander N, Buckley MF, Mark PR, Adès LC, Sandaradura SA, Lupski JR, Roscioli T, Agrawal PB, Kline AD, Wang K, Timmers HTM, and Lyon GJ

Abstract

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Published
2019
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