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4. 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, Jr, 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.

Published
2022
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6. Genome Sequencing for Diagnosing Rare Diseases

Author

Wojcik, Monica H., primary, Lemire, Gabrielle, additional, Berger, Eva, additional, Zaki, Maha S., additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Susan M., additional, Weisburd, Ben, additional, Wieczorek, Dagmar, additional, Waddell, Leigh B., additional, Verboon, Jeffrey M., additional, VanNoy, Grace E., additional, Töpf, Ana, additional, Tan, Tiong Yang, additional, Syrbe, Steffen, additional, Strehlow, Vincent, additional, Straub, Volker, additional, Stenton, Sarah L., additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G., additional, Schneider, Ronen, additional, Sankaran, Vijay G., additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A., additional, Reinson, Karit, additional, Ravenscroft, Gianina, additional, Radtke, Maximilian, additional, Popp, Denny, additional, Polster, Tilman, additional, Platzer, Konrad, additional, Pierce, Eric A., additional, Place, Emily M., additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Õunap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Opperman, Henry, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Morel, Chantal F., additional, Merkenschlager, Andreas, additional, Marchant, Rhett G., additional, Mangilog, Brian E., additional, Madden, Jill A., additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P., additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Hentschel, Julia, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G., additional, Ghaoui, Roula, additional, Genetti, Casie A., additional, Gburek-Augustat, Janina, additional, Gazda, Hanna T., additional, Ganesh, Vijay S., additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack M., additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T., additional, Chung, Wendy K., additional, Christodoulou, John, additional, Chao, Katherine R., additional, Cato, Liam D., additional, Bujakowska, Kinga M., additional, Bryen, Samantha J., additional, Brand, Harrison, additional, Bönnemann, Carsten G., additional, Beggs, Alan H., additional, Baxter, Samantha M., additional, Bartolomaeus, Tobias, additional, Agrawal, Pankaj B., additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Abou Jamra, Rami, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional

Published
2024
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7. Molecular and Phenotypic Characterization of the RORB-Related Disorder

Author

Neurologen, Brain, Metabole ziekten patientenzorg, Gokce-Samar, Zeynep, Vetro, Annalisa, De Bellescize, Julitta, Pisano, Tiziana, Monteiro, Laloe, Penaud, Noémie, Korff, Christian M., Fluss, Joel, Marini, Carla, Cesaroni, Elisabetta, Alvarez, Blanca Mercedes, Sanlaville, Damien, Chatron, Nicolas, Arzimanoglou, Alexis A., Labalme, Audrey, Cuddapah, Vishnu A., Ruggiero, Sarah M., Lecoquierre, Francois, Nicolas, Gael, Marie, Guerrot Anne, Lebas, Axel, Testard, Herve O., Helbig, Katherine L., Ruiz, Anna, Ngoh, Adeline, Kurian, Manju A., Reid, Kimberley, Spaull, Robert, Joset, Pascal, Ramantani, Georgia, Steindl, Katharina, Krenn, Martin, Gerstl, Lucia, Vieker, Silvia, Craiu, Dana, Pendziwiat, Manuela, Haldeman-Englert, Chad, Kanivets, Ilya, Romanova, Irina, Rajan, Deepa S., Rosenfeld, Jill A., Au, Margaret, Grand, Katheryn, Graham, John M., Isapof, Arnaud, Villeneuve, Nathalie, Smol, Thomas, Caumes, Roseline, Zacher, Pia, Neuser, Sonja, Tinschert, Sigrid, Platzer, Konrad, Bartolomaeus, Tobias, Mohnke, Ines, Radtke, Maximilian, Jamra, Rami Abou, Helbig, Ingo, Jansen, Floortje E., Koop, Klaas, Rudolf, Gabrielle, Küry, Sebastien, Courchet, Julien, Guerrini, Renzo, Lesca, Gaetan, Neurologen, Brain, Metabole ziekten patientenzorg, Gokce-Samar, Zeynep, Vetro, Annalisa, De Bellescize, Julitta, Pisano, Tiziana, Monteiro, Laloe, Penaud, Noémie, Korff, Christian M., Fluss, Joel, Marini, Carla, Cesaroni, Elisabetta, Alvarez, Blanca Mercedes, Sanlaville, Damien, Chatron, Nicolas, Arzimanoglou, Alexis A., Labalme, Audrey, Cuddapah, Vishnu A., Ruggiero, Sarah M., Lecoquierre, Francois, Nicolas, Gael, Marie, Guerrot Anne, Lebas, Axel, Testard, Herve O., Helbig, Katherine L., Ruiz, Anna, Ngoh, Adeline, Kurian, Manju A., Reid, Kimberley, Spaull, Robert, Joset, Pascal, Ramantani, Georgia, Steindl, Katharina, Krenn, Martin, Gerstl, Lucia, Vieker, Silvia, Craiu, Dana, Pendziwiat, Manuela, Haldeman-Englert, Chad, Kanivets, Ilya, Romanova, Irina, Rajan, Deepa S., Rosenfeld, Jill A., Au, Margaret, Grand, Katheryn, Graham, John M., Isapof, Arnaud, Villeneuve, Nathalie, Smol, Thomas, Caumes, Roseline, Zacher, Pia, Neuser, Sonja, Tinschert, Sigrid, Platzer, Konrad, Bartolomaeus, Tobias, Mohnke, Ines, Radtke, Maximilian, Jamra, Rami Abou, Helbig, Ingo, Jansen, Floortje E., Koop, Klaas, Rudolf, Gabrielle, Küry, Sebastien, Courchet, Julien, Guerrini, Renzo, and Lesca, Gaetan

Published
2024

8. altAFplotter: a web app for reliable UPD detection in NGS diagnostics.

Author

Radtke, Maximilian, Moch, Johanna, Hentschel, Julia, and Schumann, Isabell

Subjects
*WEB-based user interfaces, *SOURCE code, *HUMAN genetics, *SINGLE parents, *DATA science
Abstract

Background: The detection of uniparental disomies (the inheritance of both chromosome homologues from a single parent, UPDs) is not part of most standard or commercial NGS-pipelines in human genetics and thus a common gap in NGS diagnostics. To address this we developed a tool for UPD-detection based on panel or exome data which is easy to use and publicly available. Results: The app is freely available at https://altafplotter.uni-leipzig.de/ and implemented in Python, using the Streamlit framework for data science web apps. It utilizes bcftools and tabix for processing vcf files. The source code is available at https://github.com/HUGLeipzig/altafplotter and can be used to host your own instance of the tool. Conclusion: We believe the app to be a great benefit for research and diagnostic labs, which struggle identifying and interpreting UPDs in their NGS diagnostic setup. The information provided allows a quick interpretation of the results and thus is suitable for usage in a high throughput manner by clinicians and biologists. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Molecular and Phenotypic Characterization of the RORB-Related Disorder

Author

Gokce-Samar, Zeynep, primary, Vetro, Annalisa, additional, De Bellescize, Julitta, additional, Pisano, Tiziana, additional, Monteiro, Laloe, additional, Penaud, Noémie, additional, Korff, Christian M., additional, Fluss, Joel, additional, Marini, Carla, additional, Cesaroni, Elisabetta, additional, Alvarez, Blanca Mercedes, additional, Sanlaville, Damien, additional, Chatron, Nicolas, additional, Arzimanoglou, Alexis A., additional, Labalme, Audrey, additional, Cuddapah, Vishnu A., additional, Ruggiero, Sarah M., additional, Lecoquierre, Francois, additional, Nicolas, Gael, additional, Marie, Guerrot Anne, additional, Lebas, Axel, additional, Testard, Herve O., additional, Helbig, Katherine L., additional, Ruiz, Anna, additional, Ngoh, Adeline, additional, Kurian, Manju A., additional, Reid, Kimberley, additional, Spaull, Robert, additional, Joset, Pascal, additional, Ramantani, Georgia, additional, Steindl, Katharina, additional, Krenn, Martin, additional, Gerstl, Lucia, additional, Vieker, Silvia, additional, Craiu, Dana, additional, Pendziwiat, Manuela, additional, Haldeman-Englert, Chad, additional, Kanivets, Ilya, additional, Romanova, Irina, additional, Rajan, Deepa S., additional, Rosenfeld, Jill A., additional, Au, Margaret, additional, Grand, Katheryn, additional, Graham, John M., additional, Isapof, Arnaud, additional, Villeneuve, Nathalie, additional, Smol, Thomas, additional, Caumes, Roseline, additional, Zacher, Pia, additional, Neuser, Sonja, additional, Tinschert, Sigrid, additional, Platzer, Konrad, additional, Bartolomaeus, Tobias, additional, Mohnke, Ines, additional, Radtke, Maximilian, additional, Jamra, Rami Abou, additional, Helbig, Ingo, additional, Jansen, Floortje E., additional, Koop, Klaas, additional, Rudolf, Gabrielle, additional, Küry, Sebastien, additional, Courchet, Julien, additional, Guerrini, Renzo, additional, and Lesca, Gaetan, additional

Published
2023
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14. Case report: Complete paternal isodisomy on chromosome 18 induces methylation changes in PARD6G-AS1 promotor in a case with arthrogryposis.

Author

Moch, Johanna, Radtke, Maximilian, Gburek-Augustat, Janina, Karnstedt, Maike, Schönnagel, Senta, Drukewitz, Stephan H., Pilgram, Laura, Hentschel, Julia, and Schumann, Isabell

Subjects
ARTHROGRYPOSIS, GENETIC variation, METHYLATION, MUSCLE weakness, PANEL analysis, CHROMOSOMES, MOTOR learning
Abstract

Uniparental disomy (UPD) is the inheritance of both alleles of a chromosome from only one parent. So far, the detection of UPDs in sequencing data is not well established and a known gap in next-generation sequencing (NGS) diagnostics. By developing a new tool for UPD detection, we re-evaluated an eight-year-old individual presenting with scoliosis, muscle weakness and global developmental delay. Previous panel analysis identified a homozygous likely pathogenic loss-of- function variant in the PIEZO2-gene associated with arthrogryposis (OMIM # 617146). Interestingly, during a re-evaluation process, we identified a region of homozygosity (ROH) covering over 95% of chromosome 18. Segregation and microsatellite analysis within the family revealed that only the father is a heterozygous carrier of the variant in PIEZO2 and confirmed paternal uniparental isodisomy (iUPD) on chromosome 18 in the individual. Further methylation analysis indicated demethylation of the promotor region of PARD6G-AS1, which is described to be maternally imprinted and could possibly influence the individuals’ phenotype. Our report describes the first complete iUPD on chromosome 18 and highlights that UPDs can be a cause for homozygous pathogenic variants, which reduces the risk of reoccurrence in case of a new pregnancy in comparison to an autosomal recessive inheritance trait significantly. [ABSTRACT FROM AUTHOR]

Published
2024
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15. CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Author

Macnee, Marie, primary, Pérez-Palma, Eduardo, additional, Brünger, Tobias, additional, Klöckner, Chiara, additional, Platzer, Konrad, additional, Stefanski, Arthur, additional, Montanucci, Ludovica, additional, Bayat, Allan, additional, Radtke, Maximilian, additional, Collins, Ryan L, additional, Talkowski, Michael, additional, Blankenberg, Daniel, additional, Møller, Rikke S, additional, Lemke, Johannes R, additional, Nothnagel, Michael, additional, May, Patrick, additional, and Lal, Dennis, additional

Published
2023
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16. CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], DFG [sponsor], BMBF [sponsor], Macnee, Marie, Pérez-Palma, Eduardo, Brünger, Tobias, Klöckner, Chiara, Platzer, Konrad, Stefanski, Arthur, Montanucci, Ludovica, Bayat, Allan, Radtke, Maximilian, Collins, Ryan L., Talkowski, Michael, Blankenberg, Daniel, Møller, Rikke S., Lemke, Johannes R., Nothnagel, Michael, May, Patrick, Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], DFG [sponsor], BMBF [sponsor], Macnee, Marie, Pérez-Palma, Eduardo, Brünger, Tobias, Klöckner, Chiara, Platzer, Konrad, Stefanski, Arthur, Montanucci, Ludovica, Bayat, Allan, Radtke, Maximilian, Collins, Ryan L., Talkowski, Michael, Blankenberg, Daniel, Møller, Rikke S., Lemke, Johannes R., Nothnagel, Michael, May, Patrick, and Lal, Dennis

Abstract

Pathogenic copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.Here, we introduce the CNV-ClinViewer, an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.The web-application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.Supplementary data are available at Bioinformatics online.

Published
2023

18. The constitutional gain‐of‐function variant p. Glu1099Lys in NSD2 is associated with a novel syndrome

Author

Popp, Bernt, primary, Brugger, Melanie, additional, Poschmann, Sibylle, additional, Bartolomaeus, Tobias, additional, Radtke, Maximilian, additional, Hentschel, Julia, additional, Di Donato, Nataliya, additional, Rump, Andreas, additional, Gburek‐Augustat, Janina, additional, Graf, Elisabeth, additional, Wagner, Matias, additional, Sorge, Ina, additional, Lemke, Johannes R, additional, Meitinger, Thomas, additional, Abou Jamra, Rami, additional, Strehlow, Vincent, additional, and Brunet, Theresa, additional

Published
2022
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19. CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR; BMBF [sponsor], Macnee, Marie, Perez-Palma, Eduardo, Brünger, Tobias, Klöckner, Chiara, Platzer, Konrad, Stefanski, Arthur, Montanucci, Ludovica, Bayat, Allan, Radtke, Maximilian, Collins, Ryan L., Talkowski, Michael, Blankenberg, Daniel, Møller, Rikke S., Lemke, Johannes R., Nothnagel, Michael, May, Patrick, Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR; BMBF [sponsor], Macnee, Marie, Perez-Palma, Eduardo, Brünger, Tobias, Klöckner, Chiara, Platzer, Konrad, Stefanski, Arthur, Montanucci, Ludovica, Bayat, Allan, Radtke, Maximilian, Collins, Ryan L., Talkowski, Michael, Blankenberg, Daniel, Møller, Rikke S., Lemke, Johannes R., Nothnagel, Michael, May, Patrick, and Lal, Dennis

Abstract

Purpose Large copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. Methods We developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses. Results Here, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface. Conclusion Overall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.

Published
2022

22. Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Author

Körner, Marek B, primary, Velluva, Akhil, additional, Bundalian, Linnaeus, additional, Radtke, Maximilian, additional, Lin, Chen-Ching, additional, Zacher, Pia, additional, Bartolomaeus, Tobias, additional, Kirstein, Anna, additional, Mrestani, Achmed, additional, Scholz, Nicole, additional, Platzer, Konrad, additional, Teichmann, Anne-Christin, additional, Hentschel, Julia, additional, Langenhan, Tobias, additional, Lemke, Johannes R, additional, Garten, Antje, additional, Abou Jamra, Rami, additional, and Le Duc, Diana, additional

Published
2022
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23. 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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24. 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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25. 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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26. 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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27. 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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28. 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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29. CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online

Author

Macnee, Marie, primary, Pérez-Palma, Eduardo, additional, Brünger, Tobias, additional, Klöckner, Chiara, additional, Platzer, Konrad, additional, Stefanski, Arthur, additional, Montanucci, Ludovica, additional, Bayat, Allan, additional, Radtke, Maximilian, additional, Collins, Ryan L, additional, Talkowski, Michael, additional, Blankenberg, Daniel, additional, Møller, Rikke S, additional, Lemke, Johannes R, additional, Nothnagel, Michael, additional, May, Patrick, additional, and Lal, Dennis, additional

Published
2022
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30. A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2

Author

Popp, Bernt, primary, Brugger, Melanie, additional, Poschmann, Sibylle, additional, Bartolomaeus, Tobias, additional, Radtke, Maximilian, additional, Hentschel, Julia, additional, Di Donato, Nataliya, additional, Rump, Andreas, additional, Gburek-Augustat, Janina, additional, Graf, Elisabeth, additional, Wagner, Matias, additional, Lemke, Johannes, additional, Meitinger, Thomas, additional, Jamra, Rami Abou, additional, Strehlow, Vincent, additional, and Brunet, Theresa, additional

Published
2022
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31. The constitutional gain‐of‐function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome.

Author

Popp, Bernt, Brugger, Melanie, Poschmann, Sibylle, Bartolomaeus, Tobias, Radtke, Maximilian, Hentschel, Julia, Di Donato, Nataliya, Rump, Andreas, Gburek‐Augustat, Janina, Graf, Elisabeth, Wagner, Matias, Sorge, Ina, Lemke, Johannes R, Meitinger, Thomas, Abou Jamra, Rami, Strehlow, Vincent, and Brunet, Theresa

Subjects
GENE expression, MISSENSE mutation, DNA methylation, SYNDROMES, INTELLECTUAL disabilities, BETAINE
Abstract

NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf‐Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss‐of‐function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain‐of‐function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch–Steindl syndrome (RAUST). [ABSTRACT FROM AUTHOR]

Published
2023
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32. Approach to Cohort-Wide Re-Analysis of Exome Data in 1000 Individuals with Neurodevelopmental Disorders.

Author

Halfmeyer, Insa, Bartolomaeus, Tobias, Popp, Bernt, Radtke, Maximilian, Helms, Tobias, Hentschel, Julia, Popp, Denny, and Jamra, Rami Abou

Subjects
NEURAL development, RARE diseases, CURRICULUM, WORKFLOW
Abstract

The re-analysis of nondiagnostic exome sequencing (ES) has the potential to increase diagnostic yields in individuals with rare diseases, but its implementation in the daily routines of laboratories is limited due to restricted capacities. Here, we describe a systematic approach to re-analyse the ES data of a cohort consisting of 1040 diagnostic and nondiagnostic samples. We applied a strict filter cascade to reveal the most promising single-nucleotide variants (SNVs) of the whole cohort, which led to an average of 0.77 variants per individual that had to be manually evaluated. This variant set revealed seven novel diagnoses (0.8% of all nondiagnostic cases) and two secondary findings. Thirteen additional variants were identified by a scientific approach prior to this re-analysis and were also present in this variant set. This resulted in a total increase in the diagnostic yield of 2.3%. The filter cascade was optimised during the course of the study and finally resulted in sensitivity of 85%. After applying the filter cascade, our re-analysis took 20 h and enabled a workflow that can be used repeatedly. This work is intended to provide a practical recommendation for other laboratories wishing to introduce a resource-efficient re-analysis strategy into their clinical routine. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain

Author

Neuser, Sonja, primary, Krey, Ilona, additional, Schwan, Annemarie, additional, Abou Jamra, Rami, additional, Bartolomaeus, Tobias, additional, Döring, Jan, additional, Syrbe, Steffen, additional, Plassmann, Margit, additional, Rohde, Stefan, additional, Roth, Christian, additional, Rehder, Helga, additional, Radtke, Maximilian, additional, Le Duc, Diana, additional, Schubert, Susanna, additional, Bermúdez-Guzmán, Luis, additional, Leal, Alejandro, additional, Schoner, Katharina, additional, and Popp, Bernt, additional

Published
2021
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35. Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Author

Neuser, Sonja, primary, Krey, Ilona, additional, Schwan, Annemarie, additional, Bartolomaeus, Tobias, additional, Doering, Jan Henje, additional, Syrbe, Steffen, additional, Plassmann, Margit, additional, Rohde, Stefan, additional, Roth, Christian, additional, Rehder, Helga, additional, Abou Jamra, Rami, additional, Radtke, Maximilian, additional, Le Duc, Diana, additional, Schubert, Susanna, additional, Bermudez-Guzman, Luis, additional, Leal, Alejandro, additional, Schoner, Katharina, additional, and Popp, Bernt, additional

Published
2021
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36. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

Author

Oates, Stephanie, primary, Absoud, Michael, additional, Goyal, Sushma, additional, Bayley, Sophie, additional, Baulcomb, Jennifer, additional, Sims, Annemarie, additional, Riddett, Amy, additional, Allis, Katrina, additional, Brasch‐Andersen, Charlotte, additional, Balasubramanian, Meena, additional, Bai, Renkui, additional, Callewaert, Bert, additional, Hüffmeier, Ulrike, additional, Le Duc, Diana, additional, Radtke, Maximilian, additional, Korff, Christian, additional, Kennedy, Joanna, additional, Low, Karen, additional, Møller, Rikke S., additional, Nielsen, Jens Erik Klint, additional, Popp, Bernt, additional, Quteineh, Lina, additional, Rønde, Gitte, additional, Schönewolf‐Greulich, Bitten, additional, Shillington, Amelle, additional, Taylor, Matthew RG, additional, Todd, Emily, additional, Torring, Pernille M., additional, Tümer, Zeynep, additional, Vasileiou, Georgia, additional, Yates, T. Michael, additional, Zweier, Christiane, additional, Rosch, Richard, additional, Basson, M. Albert, additional, and Pal, Deb K., additional

Published
2021
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37. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

Author

Oates, Stephanie, Absoud, Michael, Goyal, Sushma, Bayley, Sophie, Baulcomb, Jennifer, Sims, Annemarie, Riddett, Amy, Allis, Katrina, Brasch-Andersen, Charlotte, Balasubramanian, Meena, Bai, Renkui, Callewaert, Bert, Hüffmeier, Ulrike, Le Duc, Diana, Radtke, Maximilian, Korff, Christian, Kennedy, Joanna, Low, Karen, Møller, Rikke S., Nielsen, Jens Erik Klint, Popp, Bernt, Quteineh, Lina, Rønde, Gitte, Schönewolf-Greulich, Bitten, Shillington, Amelle, Taylor, Matthew R.G., Todd, Emily, Torring, Pernille M., DMSc, Zeynep Tümer M.D.Ph D., Vasileiou, Georgia, Yates, T. Michael, Zweier, Christiane, Rosch, Richard, Basson, M. Albert, Pal, Deb K., Oates, Stephanie, Absoud, Michael, Goyal, Sushma, Bayley, Sophie, Baulcomb, Jennifer, Sims, Annemarie, Riddett, Amy, Allis, Katrina, Brasch-Andersen, Charlotte, Balasubramanian, Meena, Bai, Renkui, Callewaert, Bert, Hüffmeier, Ulrike, Le Duc, Diana, Radtke, Maximilian, Korff, Christian, Kennedy, Joanna, Low, Karen, Møller, Rikke S., Nielsen, Jens Erik Klint, Popp, Bernt, Quteineh, Lina, Rønde, Gitte, Schönewolf-Greulich, Bitten, Shillington, Amelle, Taylor, Matthew R.G., Todd, Emily, Torring, Pernille M., DMSc, Zeynep Tümer M.D.Ph D., Vasileiou, Georgia, Yates, T. Michael, Zweier, Christiane, Rosch, Richard, Basson, M. Albert, and Pal, Deb K.

Abstract

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n = 8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n = 4); (iii) unclassified (n = 8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype–phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype–phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

Published
2021

40. The spliceosome-associated protein Nrl1 suppresses homologous recombination-dependent R-loop formation in fission yeast

Author

Aronica, Lucia, Kasparek, Torben, Ruchman, David, Marquez, Yamile, Cipak, Lubos, Cipakova, Ingrid, Anrather, Dorothea, Mikolaskova, Barbora, Radtke, Maximilian, Sarkar, Sovan, Pai, Chen-Chun, Blaikley, Elizabeth, Walker, Carol, Shen, Kuo-Fang, Schroeder, Renee, Barta, Andrea, Forsburg, Susan L., and Humphrey, Timothy C.

Subjects
Alternative Splicing, DNA Repair, Schizosaccharomyces, RNA Precursors, Spliceosomes, RNA, DNA, Rad51 Recombinase, Schizosaccharomyces pombe Proteins, Genome Integrity, Repair and Replication, Homologous Recombination, Genomic Instability, Rad52 DNA Repair and Recombination Protein
Abstract

The formation of RNA-DNA hybrids, referred to as R-loops, can promote genome instability and cancer development. Yet the mechanisms by which R-loops compromise genome instability are poorly understood. Here, we establish roles for the evolutionarily conserved Nrl1 protein in pre-mRNA splicing regulation, R-loop suppression and in maintaining genome stability. nrl1Δ mutants exhibit endogenous DNA damage, are sensitive to exogenous DNA damage, and have defects in homologous recombination (HR) repair. Concomitantly, nrl1Δ cells display significant changes in gene expression, similar to those induced by DNA damage in wild-type cells. Further, we find that nrl1Δ cells accumulate high levels of R-loops, which co-localize with HR repair factors and require Rad51 and Rad52 for their formation. Together, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites, leading to genome instability.

Published
2015

41. Exploring intra-splicing and its regulatory potential

Author

Radtke, Maximilian

Abstract

Die Diversität des menschlichen Proteoms ist das Ergebnis einer Kaskade regulativer Interaktionen, die genetisch kodierte Informationen nutzen und diesen durch einen transformativen Prozess führen. Dies erlaubt eine Maximierung der Diversität. Einer dieser Prozesse, und möglicherweise der mit dem größten Diversifikationspotential ist Transkription und die daran gekoppelten RNA Prozessierung. Viele regulative Ebenen dieser Prozesse, von Transkription bis Prozessierung, wurden bereits entdeckt und untersucht. Die führt zu einem bereits heute komplexen Gesamtbild, dieser zellulären Vorgänge. Diese Entdeckungen beinhalten molekulare Interaktionen und Interaktoren, kombinatorische Events, die das Transkriptom effektiv, als Antwort auf externe Stimuli, interne Anforderungen oder zelluläre Diversifikation formen. In der vorliegenden Arbeit präsentiere ich eine weitere regulative Ebene, welche durch den bereits intensiv erforschten Splicingmechanismus agiert. Intra-splicing, ursprünglich ein hypothetischer Mechanismus des langen-Intron-splicings wurde inzwischen experimentell verifiziert. Diesem wurde in jüngeren Studien eine weitere regulative Funktion zugeschrieben: recursive Exons. Diese erlauben eine flexible Einbindung zusätzlicher genetischer Information in langen Introns und ermöglichen außerdem, höchstwahrscheinlich, das Spleißen dieser langen Introns. Aufbauend auf diesem Ansatz habe ich weitere Intra-splicing Events genomweit identifiziert. Dies führte einerseits zu einer neuen Perspektive der RNA-Prozessierung und andererseits zu der Identifikation einiger Intra-splicing spezifischer regulativer Mechanismen. Die im Detail studierten Fälle beeinflussten Genexpression quantitativ und qualitativ. Teilweise Intronretention, beziehungsweise erhöhte RNA-Prozessierungseffizienz regulierten die Abundanz spezifischer Transkripte, während potentielle rekursive splicing Events in einer Art positioniert sind, die alternatives Splicing ermöglichen und, möglicherweise, forcieren. Die vorliegende Arbeit bildet das theoretische Grundgerüst der während des Doktorats durchgeführten praktischen Arbeiten und den daraus resultierten Publikationen., The diversity of the human proteome is the consequence of a cascade of regulatory network interactions that use the rather limited pool of direct genetically encoded information and push it through extensive transformative processes, allowing for maximum, or rather required, diversity. One of these processes, and arguably the one with the biggest diversification potential is transcription and its coupled RNA processing steps. Many regulatory layers in these processes, touching all aspects of transcription and RNA processing, have already been uncovered, drawing a complex interactive network. This includes the continuous discovery of molecular interactions and interactors and combinatorial events that allow for efficient shaping of the transcriptome in response to external stimuli, internal requirements or cellular diversification attempts. In this thesis, I want to present yet another layer of regulation via the extensively studied splicing process. Intra-splicing, previously hypothesized and later experimentally validated as a mechanism of long intron splicing, recently was accredited with a novel impact on gene expression: recursive exons. These allow for a flexible inclusion of additional genetic information in long introns and presumably facilitate long intron removal. Extending on this approach, I identified intrasplicing events on a genome-wide scale which allows for a more processing-focused approach to gene expression and additionally lead to the discovery of a number of regulatory splicing events that, in the cases studied in detail, lead to gene expression and isoform regulation. Down-regulation is achieved via partial intron retention, and increased gene expression via more efficient intron removal. The impact on isoform selection is hypothesized based on a novel intersection between recursive splicing and exon selection. This thesis provides the theoretical basis for the work performed in this doctorate and the resulting manuscripts attached.

Published
2017
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45. ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

Author

Oates, Stephanie, Absoud, Michael, Goyal, Sushma, Bayley, Sophie, Baulcomb, Jennifer, Sims, Annemarie, Riddett, Amy, Allis, Katrina, Brasch-Andersen, Charlotte, Balasubramanian, Meena, Bai, Renkui, Callewaert, Bert, H��ffmeier, Ulrike, Le Duc, Diana, Radtke, Maximilian, Korff, Christian, Kennedy, Joanna, Low, Karen, M��ller, Rikke S, Nielsen, Jens Erik Klint, Popp, Bernt, Quteineh, Lina, R��nde, Gitte, Sch��newolf-Greulich, Bitten, Shillington, Amelle, Taylor, Matthew Rg, Todd, Emily, Torring, Pernille M, T��mer, Zeynep, Vasileiou, Georgia, Yates, T Michael, Zweier, Christiane, Rosch, Richard, Basson, M Albert, and Pal, Deb K

Subjects
610 Medicine & health, 3. Good health
Abstract

ZMYND11 is the critical gene in chromosome 10p15.3 microdeletion syndrome, a syndromic cause of intellectual disability. The phenotype of ZMYND11 variants has recently been extended to autism and seizures. We expand on the epilepsy phenotype of 20 individuals with pathogenic variants in ZMYND11. We obtained clinical descriptions of 16 new and nine published individuals, plus detailed case history of two children. New individuals were identified through GeneMatcher, ClinVar and the European Network for Therapies in Rare Epilepsy (NETRE). Genetic evaluation was performed using gene panels or exome sequencing; variants were classified using American College of Medical Genetics (ACMG) criteria. Individuals with ZMYND11 associated epilepsy fell into three groups: (i) atypical benign partial epilepsy or idiopathic focal epilepsy (n��=��8); (ii) generalised epilepsies/infantile epileptic encephalopathy (n��=��4); (iii) unclassified (n��=��8). Seizure prognosis ranged from spontaneous remission to drug resistant. Neurodevelopmental deficits were invariable. Dysmorphic features were variable. Variants were distributed across the gene and mostly de novo with no precise genotype-phenotype correlation. ZMYND11 is one of a small group of chromatin reader genes associated in the pathogenesis of epilepsy, and specifically ABPE. More detailed epilepsy descriptions of larger cohorts and functional studies might reveal genotype-phenotype correlation. The epileptogenic mechanism may be linked to interaction with histone H3.3.

46. Exome sequencing in Nigerian children with early-onset epilepsy syndromes.

Author

Ademuwagun IA, Adam Y, Rotimi SO, Syrbe S, Radtke M, Hentschel J, Lemke JR, and Adebiyi E

Abstract

Objective: Nigeria, along with other Sub-Saharan African countries, bears the highest burden of epilepsy worldwide. This high prevalence is attributed to a combination of factors, including a significant incidence of infectious diseases, perinatal complications, and genetic etiologies. Genetic testing is rarely available and is not typically included in the routine diagnostic work-up for individuals with infantile and childhood epilepsy syndromes in these regions. Exome sequencing (ES) offers a diagnostic yield of 24%-62%, but these figures primarily reflect data from high-income countries (HICs) and may not be applicable to low- and middle-income countries (LMICs). In this study, we employed ES to investigate the genetic basis of early-onset epilepsy in 22 affected children from Nigeria., Methods: The study involved sampling of patients diagnosed with early-onset epilepsy syndromes at the Lagos State University Teaching Hospital (LASUTH) Neurology clinic. Venous blood samples were collected, and genomic DNA was isolated and purified. Molecular analysis included DNA fragmentation, ligation, target enrichment, library preparation, and whole-exome sequencing. Computational analysis involved variant calling, curation, and classification using specialized tools and databases., Results: Pathogenic variants were identified in 6 out of 22 individuals, equaling a diagnostic yield of 27.3% and comprising variants in BPTF, NAA15, SCN1A, TUBA1A and twice in CACNA1A., Significance: In this study, we present the first exome study on early-onset epilepsy syndromes from West Africa, facilitated by a Nigerian-German research collaboration. Our findings reveal a genetic diagnostic yield comparable to that of HICs. The integration of genomic medicine into epilepsy management in Nigeria holds promising prospects for improving patient care and reducing mortality rates., Plain Language Summary: This study represents the first published exome findings in Nigerian children with early-onset epilepsy, revealing a genetic diagnosis in 27% of cases. Pathogenic variants were identified in five genes amongst 6 of 22 patients, underscoring the potential of genetic testing to enhance epilepsy management in developing nations like Nigeria., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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47. Molecular and Phenotypic Characterization of the RORB -Related Disorder.

Author

Gokce-Samar Z, Vetro A, De Bellescize J, Pisano T, Monteiro L, Penaud N, Korff CM, Fluss J, Marini C, Cesaroni E, Alvarez BM, Sanlaville D, Chatron N, Arzimanoglou AA, Labalme A, Cuddapah VA, Ruggiero SM, Lecoquierre F, Nicolas G, Marie GA, Lebas A, Testard HO, Helbig KL, Ruiz A, Ngoh A, Kurian MA, Reid K, Spaull R, Joset P, Ramantani G, Steindl K, Krenn M, Gerstl L, Vieker S, Craiu D, Pendziwiat M, Haldeman-Englert C, Kanivets I, Romanova I, Rajan DS, Rosenfeld JA, Au M, Grand K, Graham M Jr, Isapof A, Villeneuve N, Smol T, Caumes R, Zacher P, Neuser S, Tinschert S, Platzer K, Bartolomaeus T, Mohnke I, Radtke M, Jamra RA, Helbig I, Jansen FE, Koop K, Rudolf G, Küry S, Courchet J, Guerrini R, and Lesca G

Subjects
Humans, Male, Animals, Mice, Child, Preschool, Child, Adolescent, Young Adult, Adult, Infant, Seizures, Phenotype, Genotype, Nuclear Receptor Subfamily 1, Group F, Member 2, Epilepsy, Absence genetics, Epilepsy, Generalized genetics, Intellectual Disability
Abstract

Background and Objectives: Heterozygous variants in RAR-related orphan receptor B ( RORB ) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants., Methods: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB . To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology., Results: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB , including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function., Discussion: In most patients, the phenotype of the RORB -related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

Published
2024
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