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2. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

Author

Yap, Zheng Yie, Efthymiou, Stephanie, Seiffert, Simone, Parra, Karen Vargas, Lee, Sukyeong, Nasca, Alessia, Maroofian, Reza, Schrauwen, Isabelle, Pendziwiat, Manuela, Jung, Sunhee, Bhoj, Elizabeth, Striano, Pasquale, Mankad, Kshitij, Vona, Barbara, Cuddapah, Sanmati, Wagner, Anja, Alvi, Javeria Raza, Davoudi-Dehaghani, Elham, Fallah, Mohammad-Sadegh, Gannavarapu, Srinitya, Lamperti, Costanza, Legati, Andrea, Murtaza, Bibi Nazia, Nadeem, Muhammad Shahid, Rehman, Mujaddad Ur, Saeidi, Kolsoum, Salpietro, Vincenzo, von Spiczak, Sarah, Sandoval, Abigail, Zeinali, Sirous, Zeviani, Massimo, Reich, Adi, Group, SYNaPS Study, Genomics, University of Washington Center for Mendelian, Jang, Cholsoon, Helbig, Ingo, Barakat, Tahsin Stefan, Ghezzi, Daniele, Leal, Suzanne M, Weber, Yvonne, Houlden, Henry, and Yoon, Wan Hee

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Clinical Research, Brain Disorders, Neurosciences, Neurodegenerative, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alleles, Animals, Ataxia, Cells, Cultured, Child, Cohort Studies, DNA Mutational Analysis, Drosophila melanogaster, Epilepsy, Family Health, Female, Fibroblasts, Hearing Loss, Humans, Ketoglutarate Dehydrogenase Complex, Male, Mutation, Neurodevelopmental Disorders, RNA Splicing, Vision Disorders, SYNaPS Study Group, University of Washington Center for Mendelian Genomics, CRISPR-Cas9 gene editing, DEE, Drosophila, OGDHL, bi-allelic, developmental and epileptic encephalopathy, exome sequencing, mitochondria, neurodevelopmental disease, α-ketoglutarate, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.

Published
2021

3. Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies

Author

Galer, Peter D, Ganesan, Shiva, Lewis-Smith, David, McKeown, Sarah E, Pendziwiat, Manuela, Helbig, Katherine L, Ellis, Colin A, Rademacher, Annika, Smith, Lacey, Poduri, Annapurna, Seiffert, Simone, von Spiczak, Sarah, Muhle, Hiltrud, van Baalen, Andreas, Group, NCEE Study, Investigators, EPGP, Consortium, EuroEPINOMICS-RES, Network, Genomics Research and Innovation, Thomas, Rhys H, Krause, Roland, Weber, Yvonne, and Helbig, Ingo

Subjects
Biological Sciences, Genetics, Neurodegenerative, Epilepsy, Prevention, Neurosciences, Brain Disorders, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Child, Preschool, Cohort Studies, Female, GABA Plasma Membrane Transport Proteins, Gene Expression, Gene Ontology, Humans, Male, Munc18 Proteins, Mutation, NAV1.1 Voltage-Gated Sodium Channel, Phenotype, Seizures, Semantics, Shab Potassium Channels, Spasms, Infantile, Speech Disorders, Terminology as Topic, Exome Sequencing, NCEE Study Group, EPGP Investigators, EuroEPINOMICS-RES Consortium, Genomics Research and Innovation Network, Human Phenotype Ontology, childhood epilepsies, computational phenotypes, developmental and epileptic encephalopathies, electronic medical records, neurogenetic disorders, whole-exome sequencing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

Published
2020

4. A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.

Author

Helbig, Ingo, Lopez-Hernandez, Tania, Shor, Oded, Galer, Peter, Ganesan, Shiva, Pendziwiat, Manuela, Rademacher, Annika, Ellis, Colin, Hümpfer, Nadja, Schwarz, Niklas, Seiffert, Simone, Peeden, Joseph, Štěrbová, Katalin, Hammer, Trine, Møller, Rikke, Shinde, Deepali, Tang, Sha, Smith, Lacey, Poduri, Annapurna, Krause, Roland, Benninger, Felix, Helbig, Katherine, Haucke, Volker, Weber, Yvonne, and Shen, Joseph

Subjects
Human Phenotype Ontology, clathrin-mediated endocytosis, computational phenotypes, developmental and epileptic encephalopathy, neurodevelopmental disorders, synaptic transmission, Adaptor Protein Complex 2, Adaptor Protein Complex mu Subunits, Adolescent, Animals, Brain Diseases, Child, Child, Preschool, Clathrin, Endocytosis, Epilepsy, Female, Humans, Infant, Mice, Mice, Knockout, Mutation, Missense, Neurodevelopmental Disorders, Exome Sequencing
Abstract

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Published
2019

6. Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons

Author

Catanese, Alberto, primary, Lehmann, Johannes, additional, Aly, Amr, additional, Fabbio, Luca, additional, Mayer, Valentin, additional, Dikwella, Natalie, additional, roselli, francesco, additional, Seiffert, Simone, additional, Boeckers, Tobias, additional, Brenner, David, additional, Mulaw, Medhanie, additional, and Ho, Ritchie, additional

Published
2024
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8. ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks

Author

Teunissen, Maria W A, primary, Lewerissa, Elly, additional, van Hugte, Eline J H, additional, Wang, Shan, additional, Ockeloen, Charlotte W, additional, Koolen, David A, additional, Pfundt, Rolph, additional, Marcelis, Carlo L M, additional, Brilstra, Eva, additional, Howe, Jennifer L, additional, Scherer, Stephen W, additional, Le Guillou, Xavier, additional, Bilan, Frédéric, additional, Primiano, Michelle, additional, Roohi, Jasmin, additional, Piton, Amelie, additional, de Saint Martin, Anne, additional, Baer, Sarah, additional, Seiffert, Simone, additional, Platzer, Konrad, additional, Jamra, Rami Abou, additional, Syrbe, Steffen, additional, Doering, Jan H, additional, Lakhani, Shenela, additional, Nangia, Srishti, additional, Gilissen, Christian, additional, Vermeulen, R Jeroen, additional, Rouhl, Rob P W, additional, Brunner, Han G, additional, Willemsen, Marjolein H, additional, and Nadif Kasri, Nael, additional

Published
2023
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9. ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks

Author

Genetica Klinische Genetica, Brain, Teunissen, Maria W A, Lewerissa, Elly, van Hugte, Eline J H, Wang, Shan, Ockeloen, Charlotte W, Koolen, David A, Pfundt, Rolph, Marcelis, Carlo L M, Brilstra, Eva, Howe, Jennifer L, Scherer, Stephen W, Le Guillou, Xavier, Bilan, Frédéric, Primiano, Michelle, Roohi, Jasmin, Piton, Amelie, de Saint Martin, Anne, Baer, Sarah, Seiffert, Simone, Platzer, Konrad, Jamra, Rami Abou, Syrbe, Steffen, Doering, Jan Henje, Lakhani, Shenela, Nangia, Srishti, Gilissen, Christian, Vermeulen, R Jeroen, Rouhl, Rob P W, Brunner, Han G, Willemsen, Marjolein H, Kasri, Nael Nadif, Genetica Klinische Genetica, Brain, Teunissen, Maria W A, Lewerissa, Elly, van Hugte, Eline J H, Wang, Shan, Ockeloen, Charlotte W, Koolen, David A, Pfundt, Rolph, Marcelis, Carlo L M, Brilstra, Eva, Howe, Jennifer L, Scherer, Stephen W, Le Guillou, Xavier, Bilan, Frédéric, Primiano, Michelle, Roohi, Jasmin, Piton, Amelie, de Saint Martin, Anne, Baer, Sarah, Seiffert, Simone, Platzer, Konrad, Jamra, Rami Abou, Syrbe, Steffen, Doering, Jan Henje, Lakhani, Shenela, Nangia, Srishti, Gilissen, Christian, Vermeulen, R Jeroen, Rouhl, Rob P W, Brunner, Han G, Willemsen, Marjolein H, and Kasri, Nael Nadif

Published
2023

10. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Epilepsy Patients With KCNC2 Pathogenic Variants 10.1212/WNL.0000000000200660

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, BrÃ\textonequarternger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, BrÃ\textonequarternger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Abstract

Background: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Published
2022

11. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brunger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brunger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Abstract

Background and Objectives KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. Discussion These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K(V)3.2 in the regulation of brain excitability.

Published
2022

12. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

Author

Genetica Klinische Genetica, Brain, Child Health, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brà Nger, Tobias, Hedrich, Ulrike B S, Augustijn, Paul B, Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J, Bruria, Ben Zeev, Doyle, Michael G, Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S, Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S, Ragona, Francesca, Granata, Tiziana, Reif, Phillip S, Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A, Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Genetica Klinische Genetica, Brain, Child Health, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brà Nger, Tobias, Hedrich, Ulrike B S, Augustijn, Paul B, Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J, Bruria, Ben Zeev, Doyle, Michael G, Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S, Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S, Ragona, Francesca, Granata, Tiziana, Reif, Phillip S, Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A, Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Published
2022

13. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Author

Schwarz, Niklas, primary, Seiffert, Simone, additional, Pendziwiat, Manuela, additional, Rademacher, Annika Verena, additional, Brünger, Tobias, additional, Hedrich, Ulrike B.S., additional, Augustijn, Paul B., additional, Baier, Hartmut, additional, Bayat, Allan, additional, Bisulli, Francesca, additional, Buono, Russell J., additional, Bruria, Ben Zeev, additional, Doyle, Michael G., additional, Guerrini, Renzo, additional, Heimer, Gali, additional, Iacomino, Michele, additional, Kearney, Hugh, additional, Klein, Karl Martin, additional, Kousiappa, Ioanna, additional, Kunz, Wolfram S., additional, Lerche, Holger, additional, Licchetta, Laura, additional, Lohmann, Ebba, additional, Minardi, Raffaella, additional, McDonald, Marie, additional, Montgomery, Sarah, additional, Mulahasanovic, Lejla, additional, Oegema, Renske, additional, Ortal, Barel, additional, Papacostas, Savvas S., additional, Ragona, Francesca, additional, Granata, Tiziana, additional, Reif, Phillip S., additional, Rosenow, Felix, additional, Rothschild, Annick, additional, Scudieri, Paolo, additional, Striano, Pasquale, additional, Tinuper, Paolo, additional, Tanteles, George A., additional, Vetro, Annalisa, additional, Zahnert, Felix, additional, Goldberg, Ethan M., additional, Zara, Federico, additional, Lal, Dennis, additional, May, Patrick, additional, Muhle, Hiltrud, additional, Helbig, Ingo, additional, and Weber, Yvonne, additional

Published
2022
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14. Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

Author

Seiffert, Simone, primary, Pendziwiat, Manuela, additional, Bierhals, Tatjana, additional, Goel, Himanshu, additional, Schwarz, Niklas, additional, van der Ven, Amelie, additional, Boßelmann, Christian Malte, additional, Willemsen, Marjolein H., additional, Hedrich, Ulrike B.S., additional, Helbig, Ingo, additional, and Weber, Yvonne G., additional

Published
2021
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15. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations 2021.05.21.21257099

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Philipp S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, BMBF Treat-ION grant (01GM1907). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
KCNC2, Neurologie [D14] [Sciences de la santé humaine], Neurology [D14] [Human health sciences], epilepsy, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], potassium channel
Abstract

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

Published
2021

16. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations 2021.05.21.21257099

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF Treat-ION grant (01GM1907). [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Philipp S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF Treat-ION grant (01GM1907). [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Philipp S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Abstract

Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

Published
2021

17. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

Author

Schwarz, Niklas, primary, Seiffert, Simone, additional, Pendziwiat, Manuela, additional, Rademacher, Annika, additional, Brünger, Tobias, additional, Hedrich, Ulrike B.S., additional, Augustijn, Paul B, additional, Baier, Hartmut, additional, Bayat, Allan, additional, Bisulli, Francesca, additional, Buono, Russell J, additional, Bruria, Ben Zeev, additional, Doyle, Michael G, additional, Guerrini, Renzo, additional, Heimer, Gali, additional, Iacomino, Michele, additional, Kearney, Hugh, additional, Klein, Karl Martin, additional, Kousiappa, Ioanna, additional, Kunz, Wolfram S., additional, Lerche, Holger, additional, Licchetta, Laura, additional, Lohmann, Ebba, additional, Minardi, Raffaella, additional, McDonald, Marie, additional, Montgomery, Sarah, additional, Mulahasanovic, Lejla, additional, Oegema, Renske, additional, Ortal, Barel, additional, Papacostas, Savvas S., additional, Ragona, Francesca, additional, Granata, Tiziana, additional, Reif, Philipp S., additional, Rosenow, Felix, additional, Rothschild, Annick, additional, Scudieri, Paolo, additional, Striano, Pasquale, additional, Tinuper, Paolo, additional, Tanteles, George A., additional, Vetro, Annalisa, additional, Zahnert, Felix, additional, Zara, Federico, additional, Lal, Dennis, additional, May, Patrick, additional, Muhle, Hiltrud, additional, Helbig, Ingo, additional, and Weber, Yvonne, additional

Published
2021
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18. Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies

Author

Galer, Peter D., Ganesan, Shiva, Lewis-Smith, David, McKeown, Sarah E., Pendziwiat, Manuela, Helbig, Katherine L., Ellis, Colin A., Rademacher, Annika, Smith, Lacey, Poduri, Annapurna, Seiffert, Simone, Spiczak, Sarah Von, Muhle, Hiltrud, Baalen, Andreas Van, Thomas, Rhys H., Krause, Roland, Weber, Yvonne, Helbig, Ingo, Galer, Peter D., Ganesan, Shiva, Lewis-Smith, David, McKeown, Sarah E., Pendziwiat, Manuela, Helbig, Katherine L., Ellis, Colin A., Rademacher, Annika, Smith, Lacey, Poduri, Annapurna, Seiffert, Simone, Spiczak, Sarah Von, Muhle, Hiltrud, Baalen, Andreas Van, Thomas, Rhys H., Krause, Roland, Weber, Yvonne, and Helbig, Ingo

Abstract

Summary 2.1 × 10−5) and “focal clonic seizures” (HP: 0002266; p = 8.9 × 10−6), STXBP1 with “absent speech” (HP: 0001344; p = 1.3 × 10−11), and SLC6A1 with “EEG with generalized slow activity” (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

Published
2020

19. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With Pathogenic Variants.

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B.S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, and Kunz, Wolfram S.

Published
2022
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21. A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Helbig, Ingo, Lopez-Hernandez, Tania, Shor, Oded, Galer, Peter, Ganesan, Shiva, Pendziwiat, Manuela, Rademacher, Annika, Ellis, Colin A., Humpfer, Nadja, Schwarz, Niklas, Seiffert, Simone, Peeden, Joseph, Shen, Joseph, Sterbova, Katalin, Hammer, Trine Bjorg, Moller, Rikke S., Shinde, Deepali N., Tang, Sha, Smith, Lacey, Poduri, Annapurna, Krause, Roland, Benninger, Felix, Helbig, Katherine L., Haucke, Volker, Weber, Yvonne G., EuroEPINOMICS-RES Consortium, Balling, Rudi, May, Patrick, GRIN consortium, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Helbig, Ingo, Lopez-Hernandez, Tania, Shor, Oded, Galer, Peter, Ganesan, Shiva, Pendziwiat, Manuela, Rademacher, Annika, Ellis, Colin A., Humpfer, Nadja, Schwarz, Niklas, Seiffert, Simone, Peeden, Joseph, Shen, Joseph, Sterbova, Katalin, Hammer, Trine Bjorg, Moller, Rikke S., Shinde, Deepali N., Tang, Sha, Smith, Lacey, Poduri, Annapurna, Krause, Roland, Benninger, Felix, Helbig, Katherine L., Haucke, Volker, Weber, Yvonne G., EuroEPINOMICS-RES Consortium, Balling, Rudi, May, Patrick, and GRIN consortium

Abstract

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Published
2019

22. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2Pathogenic Variants

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B.S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Published
2022
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23. Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy.

Author

Rademacher, Annika, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rohr, Axel, van Baalen, Andreas, Helbig, Ingo, Weber, Yvonne, and Muhle, Hiltrud

Subjects
EPILEPSY, POTASSIUM channels, INFANTILE spasms, ETIOLOGY of diseases, SYNDROMES, NEUROFIBROMATOSIS 1
Abstract

Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype–phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done. [ABSTRACT FROM AUTHOR]

Published
2020
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24. Co-occurrence of schwannomatosis and rhabdoid tumor predisposition syndrome 1

Author

Kehrer-Sawatzki, Hildegard, primary, Kordes, Uwe, additional, Seiffert, Simone, additional, Summerer, Anna, additional, Hagel, Christian, additional, Schüller, Ulrich, additional, Farschtschi, Said, additional, Schneppenheim, Reinhard, additional, Bendszus, Martin, additional, Godel, Tim, additional, and Mautner, Victor-Felix, additional

Published
2018
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