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1. Solving unsolved rare neurological diseases-a Solve-RD viewpoint

Author

Schüle, Rebecca, Timmann, Dagmar, Erasmus, Corrie E., Reichbauer, Jennifer, Wayand, Melanie, Solve-RD-DITF-RND Baets Jonathan Balicza Peter Chinnery Patrick Dürr Alexandra Haack Tobias Hengel Holger Horvath Rita Houlden Henry Kamsteeg Erik-Jan Kamsteeg Christoph Lohmann Katja Macaya Alfons Marcé-Grau Anna Maver Ales Molnar Judit Münchau Alexander Peterlin Borut Riess Olaf Schöls Ludger European Reference Network for Rare Neurological Diseases, Tübingen, Germany Schüle Rebecca European Reference Network for Rare Neurological Diseases, Tübingen, Germany Stevanin Giovanni Synofzik Matthis European Reference Network for Rare Neurological Diseases, Tübingen, Germany Timmerman Vincent van de Warrenburg Bart Department of Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands van Os Nienke Vandrovcova Jana Wayand Melanie German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany Wilke Carlo German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany, Baets, Jonathan, Balicza, Peter, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Horvath, Rita, Houlden, Henry, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, van de Warrenburg, Bart, van Os, Nienke, Vandrovcova, Jana, Wilke, Carlo, Bevot, Andrea, Zuchner, Stephan, Beltran, Sergi, Laurie, Steven, Matalonga, Leslie, Graessner, Holm, The Solve-RD Consortium Graessner Holm Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany Zurek Birte Ellwanger Kornelia Ossowski Stephan Demidov German Sturm Marc Schulze-Hentrich Julia M. Heutink Peter Brunner Han Scheffer Hans Hoogerbrugge Nicoline Hoischen Alexander ’t Hoen Peter A. C. Vissers Lisenka E. L. M. Gilissen Christian Steyaert Wouter Sablauskas Karolis de Voer Richarda M. Janssen Erik de Boer Elke Steehouwer Marloes Yaldiz Burcu Kleefstra Tjitske Brookes Anthony J. Veal Colin Gibson Spencer Wadsley Marc Mehtarizadeh Mehdi Riaz Umar Warren Greg Dizjikan Farid Yavari Shorter Thomas Töpf Ana Straub Volker Bettolo Chiara Marini Specht Sabine Clayton-Smith Jill Banka Siddharth Alexander Elizabeth Jackson Adam Faivre Laurence Thauvin Christel Vitobello Antonio Denommé-Pichon Anne-Sophie Duffourd Yannis Tisserant Emilie Bruel Ange-Line Peyron Christine Pélissier Aurore Beltran Sergi Facultat de Biologia, Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona (UB), Barcelona, Spain Gut Ivo Glynne Laurie Steven CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Piscia Davide Matalonga Leslie CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Papakonstantinou Anastasios Bullich Gemma Corvo Alberto Garcia Carles Fernandez-Callejo Marcos Hernández Carles Picó Daniel Paramonov Ida Lochmüller Hanns Gumus Gulcin Bros-Facer Virginie Rath Ana Hanauer Marc Olry Annie Lagorce David Havrylenko Svitlana Izem Katia Rigour Fanny Durr Alexandra Davoine Claire-Sophie Guillot-Noel Léna Heinzmann Anna Coarelli Giulia Bonne Gisèle Evangelista Teresinha Allamand Valérie Nelson Isabelle Yaou Rabah Ben Metay Corinne Eymard Bruno Cohen Enzo Atalaia Antonio Stojkovic Tanya Macek Milan Jr. Turnovec Marek Thomasová Dana Kremliková Radka Pourová Franková Vera Havlovicová Markéta Kremlik Vlastimil Parkinson Helen Keane Thomas Spalding Dylan Senf Alexander Robinson Peter Danis Daniel Robert Glenn Costa Alessia Patch Christine Hanna Mike Houlden Henry Reilly Mary Vandrovcova Jana Muntoni Francesco Zaharieva Irina Sarkozy Anna de Jonghe Peter Nigro Vincenzo Banfi Sandro Torella Annalaura Musacchia Francesco Piluso Giulio Ferlini Alessandra Selvatici Rita Rossi Rachele Neri Marcella Aretz Stefan Spier Isabel Sommer Anna Katharina Peters Sophia Oliveira Carla Pelaez Jose Garcia Matos Ana Rita José Celina São Ferreira Marta Gullo Irene Fernandes Susana Garrido Luzia Ferreira Pedro Carneiro Fátima Swertz Morris A. Johansson Lennart van der Velde Joeri K. van der Vries Gerben Neerincx Pieter B. Roelofs-Prins Dieuwke Köhler Sebastian Metcalfe Alison Verloes Alain Drunat Séverine Rooryck Caroline Trimouille Aurelien Castello Raffaele Morleo Manuela Pinelli Michele Varavallo Alessandra De la Paz Manuel Posada Sánchez Eva Bermejo Martín Estrella López Delgado Beatriz Martínez de la Rosa F. Javier Alonso García Ciolfi Andrea Dallapiccola Bruno Pizzi Simone Radio Francesca Clementina Tartaglia Marco Renieri Alessandra Benetti Elisa Balicza Peter Molnar Maria Judit Maver Ales Peterlin Borut Münchau Alexander Lohmann Katja Herzog Rebecca Pauly Martje Macaya Alfons Marcé-Grau Anna Osorio Andres Nascimiento de Benito Daniel Natera Lochmüller Hanns Thompson Rachel Polavarapu Kiran Beeson David Cossins Judith Cruz Pedro M. Rodriguez Hackman Peter Johari Mridul Savarese Marco Udd Bjarne Horvath Rita Capella Gabriel Valle Laura Holinski-Feder Elke Laner Andreas Steinke-Lange Verena Schröck Evelin Rump Andreas, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoischen, Alexander, ’t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Gilissen, Christian, Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Spalding, Dylan, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Solve-RD-DITF-RND, Solve-RD Consortium, Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., van de Warrenburg, B., Schols, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Synofzik, M., Nigro, V., Banfi, S., Torella, A., Piluso, G., Medicum, University of Helsinki, Department of Medical and Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Wilke, Carlo [0000-0002-7250-8597], Beltran, Sergi [0000-0002-2810-3445], Laurie, Steven [0000-0003-3913-5829], Graessner, Holm [0000-0001-9803-7183], Synofzik, Matthis [0000-0002-2280-7273], and Apollo - University of Cambridge Repository

Subjects
genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Datasets as Topic, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, Genetics (clinical), 0303 health sciences, methods [Genomics], Management science, Neurodevelopmental disorders, Neurodegenerative diseases, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetics [Nervous System Diseases], 3. Good health, Chemistry, Practice Guidelines as Topic, Malalties rares, pathology [Rare Diseases], methods [Genetic Testing], Movement disorders, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Socio-culturale, standards [Exome Sequencing], standards [Genetic Testing], pathology [Nervous System Diseases], 03 medical and health sciences, Rare Diseases, Viewpoint, Exome Sequencing, Genetics, Humans, Genetic Testing, ddc:610, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Sistema nerviós -- Malalties, methods [Exome Sequencing], standards [Genomics], 3111 Biomedicine, Human medicine, Nervous System Diseases, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

Rare genetic neurological disorders (RND; ORPHA:71859) are a heterogeneous group of disorders comprising >1700 distinct genetic disease entities. However, genetic discoveries have not yet translated into dramatic increases of diagnostic yield and indeed rates of molecular genetic diagnoses have been stuck at about 30–50% across NGS modalities and RND phenotypes [1, 2]. Existence of yet unknown disease genes as well as shortcomings of commonly employed NGS technologies and analysis pipelines in detecting certain variant types are typically cited to explain the low diagnosis rates. To increase the diagnostic yield in RNDs - one of the four focus disease groups in Solve-RD - we follow two major approaches, that we will here present and exemplify: (i) systematic state-of the art re-analysis of large cohorts of unsolved whole-exome/genome sequencing (WES/WGS) RND datasets; and (ii) novel-omics approaches. Based on the way Solve-RD systematically organizes researchers’ expertise to channel this approach [3], the European Reference Network for Rare Neurological Diseases (ERN-RND) has established its own Data Interpretation Task Force (DITF) within SOLVE-RD, which is currently composed of clinical and genetic experts from 29 sites in 15 European countries. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (Grant Numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (Grant Numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. The study was further funded by the Federal Ministry of Education and Research, Germany, through the TreatHSP network (01GM1905 to RS and LS), the National Institute of Neurological Diseases and Stroke (R01NS072248 to SZ and RS), the European Joint Program on Rare Diseases-EJP-RD COFUND-EJP N° 825575 through funding for the PROSPAX consortium (441409627 to MS, RS and BvW). CW was supported by the PATE program of the Medical Faculty, University of Tübingen. CEE received support from the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund. Authors on this paper are members of the European Reference Network for Rare Neurological Diseases (ERN-RND, Project ID 739510)

Published
2021

2. Additional file 5 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 5: Table S2. Seizure and seizure-like episodes in affected individuals with at least one afebrile seizure.

Published
2022
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3. Additional file 6 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 6: Figure S1. TASK3 conformational changes define PC motions and channel gating. Figure S2. Detailed view of the TASK3 selectivity filter and surrounding residues. Figure S3. Distributions of K+ ions for selected positions along the transport process, and across variants. Figure S4. Genomic variants lead to changes in K+ concentration at the selectivity filter. Figure S5. Cellular localization of labelled TASK3 variants. Figure S6. Comparison of whole cell current density for Tyr205Cys in the presence of various cysteine-modifying agents.

Published
2022
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4. Additional file 1 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 1: Supplementary Note. Clinical Histories. Written clinical histories including genetic testing for each novel family in this study. Molecular Modeling Reveals Mutation-Specific Effects on Channel Mechanics. Molecular Dynamics Simulations Show Changes in Potassium Ion Distribution.

Published
2022
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5. Additional file 9 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 9: Table S5. A comparison of GPCRs regulation between TASK3 clinical variants and WT controls.

Published
2022
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6. Additional file 7 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 7: Table S3. A comparison of whole cell current density and reversal potentials between TASK3 clinical variants and matched WT controls.

Published
2022
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7. Additional file 8 of Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Author

Cousin, Margot A., Veale, Emma L., Dsouza, Nikita R., Tripathi, Swarnendu, Holden, Robyn G., Arelin, Maria, Beek, Geoffrey, Bekheirnia, Mir Reza, Beygo, Jasmin, Bhambhani, Vikas, Bialer, Martin, Bigoni, Stefania, Boelman, Cyrus, Carmichael, Jenny, Courtin, Thomas, Cogne, Benjamin, Dabaj, Ivana, Doummar, Diane, Fazilleau, Laura, Ferlini, Alessandra, Gavrilova, Ralitza H., Graham, John M., Haack, Tobias B., Juusola, Jane, Kant, Sarina G., Kayani, Saima, Keren, Boris, Ketteler, Petra, Klöckner, Chiara, Koopmann, Tamara T., Kruisselbrink, Teresa M., Kuechler, Alma, Lambert, Laëtitia, Latypova, Xénia, Lebel, Robert Roger, Leduc, Magalie S., Leonardi, Emanuela, Lewis, Andrea M., Liew, Wendy, Machol, Keren, Mardini, Samir, McWalter, Kirsty, Mignot, Cyril, McLaughlin, Julie, Murgia, Alessandra, Narayanan, Vinodh, Nava, Caroline, Neuser, Sonja, Nizon, Mathilde, Ognibene, Davide, Park, Joohyun, Platzer, Konrad, Poirsier, Céline, Radtke, Maximilian, Ramsey, Keri, Runke, Cassandra K., Guillen Sacoto, Maria J., Scaglia, Fernando, Shinawi, Marwan, Spranger, Stephanie, Tan, Ee Shien, Taylor, John, Trentesaux, Anne-Sophie, Vairo, Filippo, Willaert, Rebecca, Zadeh, Neda, Urrutia, Raul, Babovic-Vuksanovic, Dusica, Zimmermann, Michael T., Mathie, Alistair, and Klee, Eric W.

Abstract

Additional file 8: Table S4. A comparison of inhibition by extracellular acidification (pH 6.4) between TASK3 clinical variants and WT controls.

Published
2022
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8. Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

Author

Zurek, Birte, Ellwanger, Kornelia, Vissers, Lisenka E. L. M., Schüle, Rebecca, Synofzik, Matthis, Töpf, Ana, de Voer, Richarda M., Laurie, Steven, Matalonga, Leslie, Gilissen, Christian, Ossowski, Stephan, ’t Hoen, Peter A. C., Vitobello, Antonio, Schulze-Hentrich, Julia M., Riess, Olaf, Brunner, Han G., Brookes, Anthony J., Rath, Ana, Bonne, Gisèle, Gumus, Gulcin, Verloes, Alain, Hoogerbrugge, Nicoline, Evangelista, Teresinha, Harmuth, Tina, Swertz, Morris, Spalding, Dylan, Hoischen, Alexander, Beltran, Sergi, Graessner, Holm, Haack, Tobias B., Demidov, German, Sturm, Marc, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, Brunner, Han, Scheffer, Hans, Steyaert, Wouter, Sablauskas, Karolis, Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Bros-Facer, Virginie, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, Van de Vondel, Liedewei, Beijer, Danique, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Marcé-Grau, Anna, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), Zurek, Birte [0000-0002-8200-7542], Ellwanger, Kornelia [0000-0003-4845-5795], Vissers, Lisenka ELM [0000-0001-6470-5497], Synofzik, Matthis [0000-0002-2280-7273], de Voer, Richarda M [0000-0002-8222-0343], Laurie, Steven [0000-0003-3913-5829], Gilissen, Christian [0000-0003-1693-9699], 't Hoen, Peter AC [0000-0003-4450-3112], Vitobello, Antonio [0000-0003-3717-8374], Brookes, Anthony J [0000-0001-8686-0017], Rath, Ana [0000-0003-4308-6337], Bonne, Gisèle [0000-0002-2516-3258], Verloes, Alain [0000-0003-4819-0264], Hoogerbrugge, Nicoline [0000-0003-2393-8141], Harmuth, Tina [0000-0002-4833-8057], Spalding, Dylan [0000-0002-4285-2493], Beltran, Sergi [0000-0002-2810-3445], Graessner, Holm [0000-0001-9803-7183], Apollo - University of Cambridge Repository, Zurek, B., Ellwanger, K., Vissers, L. E. L. M., Schule, R., Synofzik, M., Topf, A., de Voer, R. M., Laurie, S., Matalonga, L., Gilissen, C., Ossowski, S., 't Hoen, P. A. C., Vitobello, A., Schulze-Hentrich, J. M., Riess, O., Brunner, H. G., Brookes, A. J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Beltran, S., Graessner, H., Nigro, V., Banfi, S., Torella, A., Piluso, G., Dürr, Alexandra, Lohmann, Katja, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschuetz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, University of Tübingen, Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Leicester, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), EURORDIS-Rare Diseases Europe (Bureau de Paris), EURORDIS - Plateforme Maladies Rares [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center Groningen [Groningen] (UMCG), European Molecular Biology Laboratory [Hinxton], Universitat de Barcelona (UB), SOLVE-RD Consortium, Projekt DEAL, Unión Europea. Comisión Europea. H2020, European Reference Network for Rare Neurological Diseases (ERN-RND), Haack, T. B., Demidov, G., Sturm, M., Kessler, C., Wayand, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Heutink, P., Brunner, H., Scheffer, H., Steyaert, W., Sablauskas, K., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., te Paske, I., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Bros-Facer, V., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Vandrovcova, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., Van de Vondel, L., Beijer, D., de Jonghe, P., Musacchia, F., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Balicza, P., Molnar, M. J., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., Macaya, A., Marce-Grau, A., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Horvath, R., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., Rump, A., Gestionnaire, HAL Sorbonne Université 5, Centre de Recherche en Myologie, Medicum, University of Helsinki, and Department of Medical and Clinical Genetics

Subjects
Computer science, Consensus Development Conferences as Topic, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Diseases, Pan european, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Intersectoral Collaboration, Genetics (clinical), Exome sequencing, 0303 health sciences, 030305 genetics & heredity, Medical genetics, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, diagnosis [Rare Diseases], Europe, GENOME, Chemistry, New disease, Patient representatives, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], methods [Genetic Testing], MEDLINE, Socio-culturale, 03 medical and health sciences, Viewpoint, Rare Diseases, Exome Sequencing, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, genetics [Genetic Diseases, Inborn], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Information Dissemination, Genetic Diseases, Inborn, Correction, Data science, diagnosis [Genetic Diseases, Inborn], Data sharing, methods [Exome Sequencing], 3111 Biomedicine, Human medicine, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Rare disease
Abstract

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. This research is supported (not financially) by four ERNs: (1) The ERN for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA)-Project ID No 869189; (2) The ERN on Rare Neurological Diseases (ERN-RND)-Project ID No 739510; (3) The ERN for Neuromuscular Diseases (ERN Euro-NMD)-Project ID No 870177; (4) The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS)-Project ID No 739547. The ERNs are co-funded by the European Union within the framework of the Third Health Programme. Open Access funding enabled and organized by Projekt DEAL. Sí

Published
2021

9. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Author

Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara–Schmidt, Ulrike, Hentschel, Andreas, Chinnery, Patrick F., Kölbel, Heike, Roos, Andreas, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Paramonov, Ida, Peters, Sophia, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Van Der Velde, Joeri K., Vitobello, Antonio, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G., Houlden, Henry, Lau, Jarred, Lochmüller, Hanns, Macken, William L., Musacchia, Francesco, Nascimento, Andres, Natera-De Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D. S., Polavarapu, Kiran, Cruz, Pedro M. Rodriguez, Sarkozy, Anna, Selvatici, Rita, Thompson, Rachel, Torella, Annalaura, Udd, Bjarne, Van De Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Schon, Katherine [0000-0001-8054-8954], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), University of Cambridge [UK] (CAM), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Aberdeen, Ruhr-Universität Bochum [Bochum], University Children's Hospital of Essen [Essen, Germany], Enzo Cohen, Isabel Cuesta, Daniel Danis, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Christian Gilissen, Mridul Johari, Steven Laurie, Shuang Li, Isabelle Nelson, Ida Paramonov, Sophia Peters, Sivakumar Prasanth, Peter Robinson, Karolis Sablauskas, Marco Savarese, Wouter Steyaert, Joeri K van der Velde, Antonio Vitobello, Jonathan Baets, Danique Beijer, Gisèle Bonne, Judith Cossins, Teresinha Evangelista, Alessandra Ferlini, Peter Hackman, Michael G Hanna, Henry Houlden, Jarred Lau, Hanns Lochmüller, William L Macken, Francesco Musacchia, Andres Nascimento, Daniel Natera-de Benito, Vincenzo Nigro, Giulio Piluso, Veronica Pini, Robert D S Pitceathly, Kiran Polavarapu, Pedro M Rodriguez Cruz, Anna Sarkozy, Rita Selvatici, Rachel Thompson, Annalaura Torella, Bjarne Udd, Liedewei Van de Vondel, Jana Vandrovcova, Irina Zaharieva, Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara-Schmidt, Ulrike, Hentschel, Andrea, Chinnery, Patrick F, Kölbel, Heike, Roos, Andrea, Horvath, Rita, Nigro, Vincenzo, Torella, Annalaura, and Piluso, Giulio

Subjects
0301 basic medicine, Male, Proteome, 45/41, Developmental Disabilities, Medizin, 45/22, Biology, Bioinformatics, Nervous System Malformations, Brief Communication, 82/80, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Cerebellum, 38/23, Genetics research, Genetics, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Exome, Genetic Testing, Gene, Cerebellar hypoplasia, Genetics (clinical), Exome sequencing, Proteomic Profile, Proteomic Profiling, 82/58, 631/208/514/2254, brief-communication, 692/308/2056, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Spinal muscular atrophy, medicine.disease, 3. Good health, 030104 developmental biology, Congenital muscular dystrophy, Next-generation sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Several authors of this study are members of the European Reference Network for Neuromuscular disease, Project ID No 739543. This study was supported by the AFM (grant 21644 to AR), the framework of the NME-GPS project by the European Regional Development Fund (AR/US/AS), the support by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung (AH and AS), the European Research Council (RH), the Wellcome Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH) and the Evelyn Trust (RH). This research was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Published
2020

10. Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure

Author

Gagliardi, Christian, Perfetto, Federico, Lorenzini, Massimiliano, Ferlini, Alessandra, Salvi, Fabrizio, Milandri, Agnese, Quarta, Cristina Candida, Taborchi, Giulia, Bartolini, Simone, Frusconi, Sabrina, Martone, Raffaele, Cinelli, Michele Mario, Foffi, Serena, Reggiani, Maria Letizia Bacchi, Fabbri, Gioele, Cataldo, Paolo, Cappelli, Francesco, Rapezzi, Claudio, Gagliardi, Christian, Perfetto, Federico, Lorenzini, Massimiliano, Ferlini, Alessandra, Salvi, Fabrizio, Milandri, Agnese, Quarta, Cristina Candida, Taborchi, Giulia, Bartolini, Simone, Frusconi, Sabrina, Martone, Raffaele, Cinelli, Michele Mario, Foffi, Serena, Reggiani, Maria Letizia Bacchi, Fabbri, Gioele, Cataldo, Paolo, Cappelli, Francesco, and Rapezzi, Claudio

Subjects
Male, Cardiomyopathy, Heart Ventricles, Left, DNA Mutational Analysis, Amyloid Neuropathies, Transthyretin, Ventricular Function, Left, NO, Electrocardiography, Familial, Amyloidosi, 80 and over, Ventricular Function, Humans, LS2_6, Aged, Retrospective Studies, Aged, 80 and over, Heart Failure, Amyloid Neuropathies, Familial, Incidence, Amyloidosis, Heart failure, Cardiomyopathies, Echocardiography, Female, Follow-Up Studies, Italy, Mutation, Phenotype, Survival Rate, Cardiology and Cardiovascular Medicine
Abstract

Aims: Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin-related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild-type transthyretin amyloidosis (ATTRwt). Methods and results: Data of 67 Ile68Leu ATTRm patients from two Italian referral centres (Bologna and Florence) were retrospectively analysed and compared to those of 82 ATTRwt patients. Fifty-five unaffected mutation carriers were also analysed. Cumulative disease onset was 50% at age 71. A total of 56/67 (84%) patients had a predominantly cardiac phenotype at presentation with concentric increase in left ventricular wall thickness [median 17 mm], and normal or near normal left ventricular ejection fraction (79% of patients). Low QRS voltages were present only in 29% of patients but voltage/mass ratio was low (0.5). Carpal tunnel syndrome was noted in 43%. The overall phenotypic profile was similar to ATTRwt but Ile68Leu ATTRm patients typically presented younger (median 71 vs. 78 years) and were more likely to have (mild) symptomatic neurological involvement (19% vs. 2%). Male prevalence was 44% in unaffected mutation carriers and 78% in affected patients. Age-adjusted survival was comparable between groups. Conclusions: Ile68Leu ATTRm is a cause of familial amyloidotic cardiomyopathy endemic in central-northern Italy and presents as hypertrophic/restrictive cardiomyopathy quite similar to ATTRwt. Male preponderance is present in affected patients but not in unaffected mutation carriers. Age-adjusted survival is similar to ATTRwt.

Published
2018

11. A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield

Author

Ankala, Arunkanth, da Silva, Cristina, Gualandi, Francesca, Ferlini, Alessandra, Bean, Lora J. H, Collins, Christin, Tanner, Alice K, and Hegde, Madhuri R.

Subjects
Computational Biology, Humans, Single Nucleotide, Genetic Testing, Genomics, Neuromuscular Diseases, Polymorphism, Polymorphism, Single Nucleotide, NO
Abstract

Neuromuscular diseases (NMDs) are a group of200 highly genetically as well as clinically heterogeneous inherited genetic disorders that affect the peripheral nervous and muscular systems, resulting in gross motor disability. The clinical and genetic heterogeneities of NMDs make disease diagnosis complicated and expensive, often involving multiple tests.To expedite the molecular diagnosis of NMDs, we designed and validated several next generation sequencing (NGS)-based comprehensive gene panel tests that include complementary deletion and duplication testing through comparative genomic hybridization arrays. Our validation established the targeted gene panel test to have 100% sensitivity and specificity for single nucleotide variant detection. To compare the clinical diagnostic yields of single gene (NMD-associated) tests with the various NMD NGS panel tests, we analyzed data from all clinical tests performed at the Emory Genetics Laboratory from October 2009 through May 2014. We further compared the clinical utility of the targeted NGS panel test with that of exome sequencing (ES).We found that NMD comprehensive panel testing has a 3-fold greater diagnostic yield (46%) than single gene testing (15-19%). Sanger fill-in of low-coverage exons, copy number variation analysis, and thorough in-house validation of the assay all complement panel testing and allow the detection of all types of causative pathogenic variants, some of which (about 18%) may be missed by ES.Our results strongly indicate that for molecular diagnosis of heterogeneous disorders such as NMDs, targeted panel testing has the highest clinical yield and should therefore be the preferred first-tier approach.

Published
2014

12. Prenatal genetic counseling referrals for advanced maternal age: still room for improvement

Author

Pompilii, E., Astolfi, Gianni, Calabrese, Olga, Calzolari, Elisa, Ferlini, Alessandra, Lucci, M., Parmeggiani, Giulia, Seri, M., Baroncini, A., Pompilii, E, Astolfi, G, Calabrese, O, Calzolari, E, Ferlini, A, Lucci, M, Parmeggiani, G, Seri, M, and Baroncini, A.

Subjects
Adult, Chromosome Disorders, Genetic Counseling, Prenatal genetic counseling, advanced maternal age, Pedigree, Pregnancy Complications, Consanguinity, Italy, Pregnancy, Risk Factors, Prenatal Diagnosis, Surveys and Questionnaires, Humans, Female, Genetic Testing, Referral and Consultation, Maternal Age, Retrospective Studies
Abstract

OBJECTIVE: The objective of this study is to evaluate genetic risks already present before pregnancy in a cohort of pregnant women referred for prenatal genetic counseling exclusively for advanced maternal age (AMA). METHOD: We retrospectively reviewed the records of 1353 women referred over 1 year (2010) for pre-test genetic counseling with the only indication of AMA at three Italian Clinical Genetic Services. RESULTS: Of the 1353 women fulfilling the inclusion criteria of the study, 87 (6.4%) had cumulatively 94 genetic risk factors not previously identified (one risk factor in 80 patients and two risk factors in seven). Twenty-six risk factors (27.7%) concerned heterogeneous or multifactorial conditions and 68 (72.3%) Mendelian or chromosomal disorders and consanguinity.In nine out of these 87 women, the estimated risk for the offspring of a genetic disease or a significant structural anomaly was >5%. Additional testing according to the identified risks was performed in 36 of these 87 women/families. CONCLUSIONS: The proportion of cases with additional risk factors is smaller than reported in previous studies, but it remains substantial and confirms the need for strategies to increase awareness of the public and health professionals responsible for the care of women in childbearing age.

Published
2013

13. Osteopontin in Duchenne Muscular Dystrophy

Author

Pegoraro, Elena, Bello, Luca, Piva, Luisa, Barp, Andrea, Ermani, Mario, Politano, Luisa, Mercuri, Eugenio, Previtali, Stefano, Torrente, Yvan, Bruno, Claudio, Minetti, Carlo, Berardinelli, Angela, Comi, Giacomo, D Amico, Adele, Soraru, Gianni, Messina, Sonia, Mongini, Tiziana, Bertini, Enrico, Ferlini, Alessandra, Gualandi, Francesca, Battini, Roberta, Boffi, Patrizia, Pane, Marika, Vita, Giuseppe, Hoffman, Eric, and Corrado Angelini

14. Nanoparticle-Mediated Delivery of Antisense Oligoribonucleotides Allows Restoration of Dystrophin Expression in the mdx Mouse

Author

Rimessi, Paola, Patrizia Sabatelli, Fabris, Marina, Braghetta, Paola, Bassi, Elena, Spitali, Pietro, Vattemi, Gaetano A., Tomelleri, Giuliano, Mari, Lara, Perrone, Daniela, Medici, Alessandro, Neri, Marcella, Bovolenta, Matteo, Martoni, Elena, Maraldi, Nadir M., Gualandi, Francesca, Merlini, Luciano, Ballestri, Marco, Tondelli, Luisa, Sparnacci, Katia, Bonaldo, Paolo, Caputo, Antonella, Laus, Michele, and Ferlini, Alessandra

Subjects
NO

15. Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results

Author

Nadir M. Maraldi, Francesca Gualandi, Enrico Bertini, Paolo Bernardi, Alessandra Ferlini, M.E. Michelini, Luciano Merlini, A. Franchella, Paolo Grumati, Alessia Angelin, Saverio Gnudi, Annarita Armaroli, Patrizia Sabatelli, Paolo Bonaldo, Merlini, Luciano, Sabatelli, Patrizia, Armaroli, Annarita, Gnudi, Saverio, Angelin, Alessia, Grumati, Paolo, Michelini, Maria Elena, Franchella, Andrea, Gualandi, Francesca, Bertini, Enrico, Maraldi, Nadir Mario, Ferlini, Alessandra, Bonaldo, Paolo, Bernardi, Paolo, Merlini L, Sabatelli P, Armaroli A, Gnudi S, Angelin A, Grumati P, Michelini ME, Franchella A, Gualandi F, Bertini E, Maraldi NM, Ferlini A, Bonaldo P, and Bernardi P.

Subjects
Male, Aging, respiratory muscles, Apoptosis, Biochemistry, Muscular Dystrophies, 0302 clinical medicine, respiratory function, Collagen VI, Enzyme Inhibitor, Respiratory function, Enzyme Inhibitors, Respiratory system, Muscular dystrophy, Child, Muscular Dystrophie, Membrane Potential, Mitochondrial, 0303 health sciences, lcsh:Cytology, motor function, General Medicine, Anatomy, Diaphragm (structural system), Clinical trial, Child, Preschool, Cyclosporine, Female, Research Article, Human, medicine.medical_specialty, Article Subject, Ullrich congenital muscular dystrophy, Urology, Collagen Type VI, Biology, Cyclosporins, 03 medical and health sciences, apoptotic, mitochondrial dysfunction, muscle rigeneration, medicine, Humans, Regeneration, Muscle Strength, lcsh:QH573-671, Muscle, Skeletal, 030304 developmental biology, Sclerosis, Apoptosi, Cell Biology, medicine.disease, Mutation, Muscle strength, 030217 neurology & neurosurgery
Abstract

Six individuals with Ullrich congenital muscular dystrophy (UCMD) and mutations in the genes-encoding collagen VI, aging 5–9, received 3–5 mg/kg of cyclosporine A (CsA) daily for 1 to 3.2 years. The primary outcome measure was the muscle strength evaluated with a myometer and expressed as megalimbs. The megalimbs score showed significant improvement (P=0.01) in 5 of the 6 patients. Motor function did not change. Respiratory function deteriorated in all. CsA treatment corrected mitochondrial dysfunction, increased muscle regeneration, and decreased the number of apoptotic nuclei. Results from this study demonstrate that long-term treatment with CsA ameliorates performance in the limbs, but not in the respiratory muscles of UCMD patients, and that it is well tolerated. These results suggest considering a trial of CsA or nonimmunosuppressive cyclosporins, that retains the PTP-desensitizing properties of CsA, as early as possible in UCMD patients when diaphragm is less compromised.

Published
2011

16. Atrial fibrillation in amyloidotic cardiomyopathy: prevalence, incidence, risk factors and prognostic role

Author

Simone Longhi, Ornella Leone, Maria Letizia Bacchi-Reggiani, Ilaria Gallelli, Christian Gagliardi, Agnese Milandri, Candida Cristina Quarta, Massimiliano Lorenzini, Antonio Russo, Lisa Manuzzi, Alessandra Ferlini, Claudio Rapezzi, Longhi, Simone, Quarta, Candida Cristina, Milandri, Agnese, Lorenzini, Massimiliano, Gagliardi, Christian, Manuzzi, Lisa, Bacchi-Reggiani, Maria Letizia, Leone, Ornella, Ferlini, Alessandra, Russo, Antonio, Gallelli, Ilaria, and Rapezzi, Claudio

Subjects
Male, Cardiomyopathy, Administration, Oral, Longitudinal Studie, Ventricular Function, Left, Retrospective Studie, Risk Factors, Atrial Fibrillation, Amyloidosi, Prevalence, Prealbumin, Longitudinal Studies, Amyloidosis, atrial fibrillation, cardiomyopathy, heart failure, Aged, 80 and over, Ejection fraction, Incidence (epidemiology), Medicine (all), Incidence, Central venous pressure, Atrial fibrillation, Middle Aged, Prognosis, Italy, Cardiology, Female, Survival Analysi, Cardiomyopathies, medicine.drug, Human, medicine.medical_specialty, Prognosi, Risk Assessment, NO, Internal medicine, Thromboembolism, medicine, Internal Medicine, Humans, Cardiomyopathie, Aged, Retrospective Studies, Heart Failure, business.industry, Risk Factor, Warfarin, Anticoagulant, Anticoagulants, Stroke Volume, medicine.disease, Survival Analysis, Heart failure, Complication, business
Abstract

Background: Although atrial fibrillation (AF) is a known complication of amyloidotic cardiomyopathy (AC), a precise pathophysiological and prognostic characterization is not available. We therefore aimed to assess prevalence, incidence, risk factors and prognostic significance of AF in light-chain (AL), hereditary transthyretin-related (m-ATTR) and non-mutant transthyretin-related (wt-ATTR) AC. Methods: Retrospective study of 262 patients with AC (123 AL, 94 m-ATTR, 45 wt-ATTR) from a single center. Results: AF prevalence was 15% (AL 9%, m-ATTR 11%, wt-ATTR 40%). During a median follow-up of 1.2 years 11 patients developed AF (2.1% person-years). Age, heart failure (HF), left ventricular (LV) ejection fraction, renal involvement, left atrial size and right atrial pressure were independently associated with AF. AF was associated with incident HF but not with increased mortality. All AF patients were prescribed warfarin and none suffered thromboembolic events. Conclusions: In AC the prevalence of AF varies widely according to etiology with a mean value of 15% that reaches 40% in wt-ATTR amyloidosis. Age, HF, LV ejection fraction, left atrial size and right atrial pressure were the main independent risk factors, while wall thickness and etiology were not the main independent risk factors. AF does not seem to impact all-cause mortality but was strongly associated with prevalent and incident HF.

Published
2015

17. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking

Author

Hui Jiang, Francesca Romana Di Raimo, Subreena Simrick, Giorgio Tasca, Jianguo Zhang, Fabiana Fattori, C. Scotton, Claudio Rapezzi, Thomas Brand, Bruno Dallapiccola, Rita Selvatici, Niels Decher, Alexander Froese, Viacheslav O. Nikolaev, Antonello Pietrangelo, Roland F.R. Schindler, Jun Wang, Fabrizio Drago, Enrico Bertini, Susanne Rinné, Marcella Neri, Alessandra Ferlini, Thorsten Schwerte, Kar Lai Poon, Thomas Müller, Christiane Grunert, Wenyan Li, Eloisa Arbustini, Mingyan Fang, Xun Xu, Chiara Passarelli, Beatriz Ortiz-Bonnin, Padmini Sarathchandra, Francesca Gualandi, Schindler, Roland F. R., Scotton, Chiara, Zhang, Jianguo, Passarelli, Chiara, Ortiz-Bonnin, Beatriz, Simrick, Subreena, Schwerte, Thorsten, Poon, Kar-Lai, Fang, Mingyan, Rinné, Susanne, Froese, Alexander, Nikolaev, Viacheslav O., Grunert, Christiane, Müller, Thoma, Tasca, Giorgio, Sarathchandra, Padmini, Drago, Fabrizio, Dallapiccola, Bruno, Rapezzi, Claudio, Arbustini, Eloisa, Romana Di Raimo, Francesca, Neri, Marcella, Selvatici, Rita, Gualandi, Francesca, Fattori, Fabiana, Pietrangelo, Antonello, Li, Wenyan, Jiang, Hui, Xu, Xun, Bertini, Enrico, Decher, Niel, Wang, Jun, Brand, Thoma, Ferlini, Alessandra, Medical Research Council (MRC), British Heart Foundation, and The Magdi Yacoub Institute

Subjects
0301 basic medicine, Male, Pathology, Muscle Proteins, Research & Experimental Medicine, DOMAIN-CONTAINING PROTEINS, domain containing proteins, Membrane Potentials, Cyclic AMP, Missense mutation, Muscular dystrophy, Child, Zebrafish, Membrane Protein, Cardiac muscle cell, Aged, 80 and over, biology, Medicine (all), Aged, Animals, Arrhythmias, Cardiac, Humans, Membrane Proteins, Middle Aged, Muscular Dystrophies, Limb-Girdle, Mutation, Potassium Channels, Tandem Pore Domain, Protein Transport, STRESS-MEDIATED MODULATION, General Medicine, 11 Medical And Health Sciences, medicine.anatomical_structure, Medicine, Research & Experimental, SKELETAL-MUSCLE, HEART, POTASSIUM CHANNEL, muscular dystrophy, arrhythmia, ITGA7, Life Sciences & Biomedicine, Human, Research Article, medicine.medical_specialty, HL-1 CELLS, Immunology, cardiac pacemakin, Membrane Potential, NO, HL1 cell, 03 medical and health sciences, Internal medicine, medicine, KINASE, Allele, skeletal muscle, Science & Technology, COMPLEX, Animal, Cardiac arrhythmia, Skeletal muscle, stress mediated modulation, domain containing proteins, skeletal muscle, cardiac pacemakin, potassium channel, HL1 cell, zebrafish, heart, kinase, biology.organism_classification, medicine.disease, 030104 developmental biology, Endocrinology, stress mediated modulation, CARDIAC PACEMAKING, Cell Adhesion Molecules
Abstract

The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. peerReviewed

Published
2014

18. Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of Kabuki Syndrome Patients

Author

Gioacchino Scarano, Alessandra Ferlini, Gigliola Serra, Maria Teresa Pellico, Bartolomeo Augello, Loredana Boccone, Lucia Micale, Federica Zucchetti, Angelo Selicorni, Livia Garavelli, Leopoldo Zelante, Elisabetta Lapi, Alessandra Vancini, Giuseppe Merla, Alba Pilotta, Laura Mazzanti, Leonardo Salviati, Carmela Fusco, Francesca Faravelli, Maria Grazia Patricelli, Daniela Melis, Stefano Sotgiu, Maria Luigia Cavaliere, Matteo Della Monica, Claudia Maffeo, Chiara Perria, Francesco Benedicenti, Paolo Prontera, Eliana Di Battista, Maria Francesca Bedeschi, Benedetta Toschi, Pasquelena De Nittis, Elisa Biamino, Rita Fischetto, Pietro Chiurazzi, Paola Ferrari, Barbara Mandriani, Marcella Neri, Margherita Silengo, Micale, Lucia, Augello, Bartolomeo, Maffeo, Claudia, Selicorni, Angelo, Zucchetti, Federica, Fusco, Carmela, De Nittis, Pasquelena, Pellico, Maria Teresa, Mandriani, Barbara, Fischetto, Rita, Boccone, Loredana, Silengo, Margherita, Biamino, Elisa, Perria, Chiara, Sotgiu, Stefano, Serra, Gigliola, Lapi, Elisabetta, Neri, Marcella, Ferlini, Alessandra, Cavaliere, Maria Luigia, Chiurazzi, Pietro, Monica, Matteo Della, Scarano, Gioacchino, Faravelli, Francesca, Ferrari, Paola, Mazzanti, Laura, Pilotta, Alba, Patricelli, Maria Grazia, Bedeschi, Maria Francesca, Benedicenti, Francesco, Prontera, Paolo, Toschi, Benedetta, Salviati, Leonardo, Melis, Daniela, Di Battista, Eliana, Vancini, Alessandra, Garavelli, Livia, Zelante, Leopoldo, and Merla, Giuseppe

Subjects
Transcription, Genetic, PREDICTION, Nonsense-mediated decay, DNA Mutational Analysis, Gene Expression, medicine.disease_cause, Settore MED/03 - GENETICA MEDICA, Cohort Studies, KDM6A, KMT2D, Kabuki syndrome, haploinsufficiency, readthrough, readthrough KeyWords Plus:HISTONE H3, DNA sequencing, Gentamicin, Vestibular Disease, MENTAL-RETARDATION, MLL2, MUTATIONS, GENES, SPECTRUM, DEMETHYLASE, GROWTH, Research Articles, Genetics (clinical), Nuclear Protein, Genetics, Histone Demethylases, Mutation, Translational readthrough, MLL2 gene, Nuclear Proteins, Homeodomain Protein, KDM6A gene, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Codon, Nonsense, RNA Splice Site, Haploinsufficiency, KDM6A, KMT2D, Kabuki syndrome, haploinsufficiency, readthrough, Human, DNA-Binding Protein, Nonsense mutation, Genetic Association Studie, Biology, MED/39 Neuropsichiatria infantile, Cell Line, DNA Mutational Analysi, Neoplasm Protein, Genetic, medicine, Humans, Abnormalities, Multiple, Multiplex ligation-dependent probe amplification, Gene, Genetic Association Studies, Homeodomain Proteins, Sequence Analysis, DNA, Hematologic Disease, medicine.disease, Hematologic Diseases, Nonsense Mediated mRNA Decay, Gene Expression Regulation, Face, Histone Demethylase, RNA Splice Sites, Gentamicins, Cohort Studie
Abstract

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients’ lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.

Published
2014

19. Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies

Author

Eugenio Mercuri, Paolo Grumati, Francesca Gualandi, Luciano Merlini, Enrico Bertini, Patrizia Sabatelli, Matteo Bovolenta, Alessandra Ferlini, Marcella Neri, Anna Urciuolo, Paolo Bonaldo, E. Martoni, M. Fabris, Bovolenta, Matteo, Neri, Marcella, Martoni, Elena, Urciuolo, Anna, Sabatelli, Patrizia, Fabris, Marina, Grumati, Paolo, Mercuri, Eugenio, Bertini, Enrico, Merlini, Luciano, Bonaldo, Paolo, Ferlini, Alessandra, and Gualandi, Francesca

Subjects
Male, Intron, Gene Dosage, Genetic mutation, Compound heterozygosity, Muscular Dystrophies, Cohort Studies, Exon, 0302 clinical medicine, Collagen VI, Genetics(clinical), Copy-number variation, Child, Muscular Dystrophie, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Allele, Genetics, Comparative Genomic Hybridization, 0303 health sciences, Bethlem myopathy, Middle Aged, Immunohistochemistry, Phenotype, Child, Preschool, Mutational analysis, Muscular dystrophy, Fibroblast, Female, Human, Research Article, Adult, lcsh:Internal medicine, Heterozygote, lcsh:QH426-470, Adolescent, Genotype, Ullrich congenital muscular dystrophy, Collagen Type VI, Biology, Genetic Heterogeneity, 03 medical and health sciences, Muscular Diseases, Intronic Mutation, medicine, Humans, lcsh:RC31-1245, Alleles, 030304 developmental biology, Muscular Disease, Oligonucleotide Array Sequence Analysi, Genetic heterogeneity, Fibroblasts, medicine.disease, Introns, lcsh:Genetics, Mutation, Cohort Studie, Gene Deletion, 030217 neurology & neurosurgery
Abstract

Background Molecular characterization of collagen-VI related myopathies currently relies on standard sequencing, which yields a detection rate approximating 75-79% in Ullrich congenital muscular dystrophy (UCMD) and 60-65% in Bethlem myopathy (BM) patients as PCR-based techniques tend to miss gross genomic rearrangements as well as copy number variations (CNVs) in both the coding sequence and intronic regions. Methods We have designed a custom oligonucleotide CGH array in order to investigate the presence of CNVs in the coding and non-coding regions of COL6A1, A2, A3, A5 and A6 genes and a group of genes functionally related to collagen VI. A cohort of 12 patients with UCMD/BM negative at sequencing analysis and 2 subjects carrying a single COL6 mutation whose clinical phenotype was not explicable by inheritance were selected and the occurrence of allelic and genetic heterogeneity explored. Results A deletion within intron 1A of the COL6A2 gene, occurring in compound heterozygosity with a small deletion in exon 28, previously detected by routine sequencing, was identified in a BM patient. RNA studies showed monoallelic transcription of the COL6A2 gene, thus elucidating the functional effect of the intronic deletion. No pathogenic mutations were identified in the remaining analyzed patients, either within COL6A genes, or in genes functionally related to collagen VI. Conclusions Our custom CGH array may represent a useful complementary diagnostic tool, especially in recessive forms of the disease, when only one mutant allele is detected by standard sequencing. The intronic deletion we identified represents the first example of a pure intronic mutation in COL6A genes.

Published
2010

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