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5. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Denomme-Pichon A. -S., Bruel A. -L., Duffourd Y., Safraou H., Thauvin-Robinet C., Tran Mau-Them F., Philippe C., Vitobello A., Jean-Marcais N., Moutton S., Thevenon J., Faivre L., Matalonga L., de Boer E., Gilissen C., Hoischen A., Kleefstra T., Pfundt R., de Vries B. B. A., Willemsen M. H., Vissers L. E. L. M., Jackson A., Banka S., Clayton-Smith J., Benetti E., Fallerini C., Renieri A., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Ellwanger K., Graessner H., Haack T. B., Zurek B., Havlovicova M., Macek M., Ryba L., Schwarz M., Votypka P., Lopez-Martin E., Posada M., Mencarelli M. A., Rooryck C., Trimouille A., Verloes A., Abbott K. M., Kerstjens M., Martin E. L., Maystadt I., Morleo M., Nigro V., Pinelli M., Riess O., Agathe J. -M. D. S., Santen G. W. E., Thauvin C., Torella A., Vissers L., Zguro K., Boer E. D., Cohen E., Danis D., Gao F., Horvath R., Johari M., Johanson L., Li S., Morsy H., Nelson I., Paramonov I., te Paske I. B. A. W., Robinson P., Savarese M., Steyaert W., Topf A., van der Velde J. K., Vandrovcova J., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Schule R., Xu J., Kessler C., Wayand M., Synofzik M., Wilke C., Traschutz A., Schols L., Hengel H., Lerche H., Kegele J., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., 't Hoen P. A. C., Sablauskas K., de Voer R. M., Kamsteeg E. -J., van de Warrenburg B., van Os N., Paske I. T., Janssen E., Steehouwer M., Yaldiz B., Brookes A. J., Veal C., Gibson S., Maddi V., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Straub V., Bettolo C. M., Manera J. D., Hambleton S., Engelhardt K., Alexander E., Peyron C., Pelissier A., Beltran S., Gut I. G., Laurie S., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Fernandez-Callejo M., Hernandez C., Pico D., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Lagorce D., Hongnat O., Chahdil M., Lebreton E., Stevanin G., Durr A., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Ben Yaou R., Metay C., Eymard B., Atalaia A., Stojkovic T., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Liskova P., Dolezalova P., Parkinson H., Keane T., Freeberg M., Thomas C., Spalding D., Robert G., Costa A., Patch C., Hanna M., Houlden H., Reilly M., Efthymiou S., Cali E., Magrinelli F., Sisodiya S. M., Rohrer J., Muntoni F., Zaharieva I., Sarkozy A., Timmerman V., Baets J., de Vries G., De Winter J., Beijer D., de Jonghe P., Van de Vondel L., De Ridder W., Weckhuysen S., Mutarelli M., Varavallo A., Banfi S., Musacchia F., Piluso G., Ferlini A., Selvatici R., Gualandi F., Bigoni S., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Vries G., Neerincx P. B., Ruvolo D., Kerstjens Frederikse W. S., Zonneveld-Huijssoon E., Roelofs-Prins D., van Gijn M., Kohler S., Metcalfe A., Drunat S., Heron D., Mignot C., Keren B., Lacombe D., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Cilio M. -R., Carpancea E., Depondt C., Lederer D., Sznajer Y., Duerinckx S., Mary S., Macaya A., Cazurro-Gutierrez A., Perez-Duenas B., Munell F., Jarava C. F., Maso L. B., Marce-Grau A., Colobran R., Hackman P., Udd B., Hemelsoet D., Dermaut B., Schuermans N., Poppe B., Verdin H., Osorio A. N., Depienne C., Roos A., Cordts I., Deschauer M., Striano P., Zara F., Riva A., Iacomino M., Uva P., Scala M., Scudieri P., Basak A. N., Claeys K., Boztug K., Haimel M., W. E G., Ruivenkamp C. A. L., Natera de Benito D., Thompson R., Polavarapu K., Grimbacher B., Zaganas I., Kokosali E., Lambros M., Evangeliou A., Spilioti M., Kapaki E., Bourbouli M., Balicza P., Molnar M. J., De la Paz M. P., Sanchez E. B., Delgado B. M., Alonso Garcia de la Rosa F. J., Schrock E., Rump A., Mei D., Vetro A., Balestrini S., Guerrini R., Chinnery P. F., Ratnaike T., Schon K., Maver A., Peterlin B., Munchau A., Lohmann K., Herzog R., Pauly M., May P., Beeson D., Cossins J., Furini S., Afenjar A., Goldenberg A., Masurel A., Phan A., Dieux-Coeslier A., Fargeot A., Guerrot A. -M., Toutain A., Molin A., Sorlin A., Putoux A., Jouret B., Laudier B., Demeer B., Doray B., Bonniaud B., Isidor B., Gilbert-Dussardier B., Leheup B., Reversade B., Paul C., Vincent-Delorme C., Neiva C., Poirsier C., Quelin C., Chiaverini C., Coubes C., Francannet C., Colson C., Desplantes C., Wells C., Goizet C., Sanlaville D., Amram D., Lehalle D., Genevieve D., Gaillard D., Zivi E., Sarrazin E., Steichen E., Schaefer E., Lacaze E., Jacquemin E., Bongers E., Kilic E., Colin E., Giuliano F., Prieur F., Laffargue F., Morice-Picard F., Petit F., Cartault F., Feillet F., Baujat G., Morin G., Diene G., Journel H., Perthus I., Lespinasse J., Alessandri J. -L., Amiel J., Martinovic J., Delanne J., Albuisson J., Lambert L., Perrin L., Ousager L. B., Van Maldergem L., Pinson L., Ruaud L., Samimi M., Bournez M., Bonnet-Dupeyron M. N., Vincent M., Jacquemont M. -L., Cordier-Alex M. -P., Gerard-Blanluet M., Willems M., Spodenkiewicz M., Doco-Fenzy M., Rossi M., Renaud M., Fradin M., Mathieu M., Holder-Espinasse M. H., Houcinat N., Hanna N., Leperrier N., Chassaing N., Philip N., Boute O., Van Kien P. K., Parent P., Bitoun P., Sarda P., Vabres P., Jouk P. -S., Touraine R., El Chehadeh S., Whalen S., Marlin S., Passemard S., Grotto S., Bellanger S. A., Blesson S., Nambot S., Naudion S., Lyonnet S., Odent S., Attie-Bitach T., Busa T., Drouin-Garraud V., Layet V., Bizaoui V., Cusin V., Capri Y., Alembik Y., Unión Europea. Comisión Europea. H2020, Unión Europea. Comisión Europea. 7 Programa Marco, Instituto de Salud Carlos III, Instituto Nacional de Bioinformatica (España), Ministry of Health (República Checa), Ministry of Education, Youth and Sports (República Checa), Denomme-Pichon, A. -S., Bruel, A. -L., Duffourd, Y., Safraou, H., Thauvin-Robinet, C., Tran Mau-Them, F., Philippe, C., Vitobello, A., Jean-Marcais, N., Moutton, S., Thevenon, J., Faivre, L., Matalonga, L., de Boer, E., Gilissen, C., Hoischen, A., Kleefstra, T., Pfundt, R., de Vries, B. B. A., Willemsen, M. H., Vissers, L. E. L. M., Jackson, A., Banka, S., Clayton-Smith, J., Benetti, E., Fallerini, C., Renieri, A., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Ellwanger, K., Graessner, H., Haack, T. B., Zurek, B., Havlovicova, M., Macek, M., Ryba, L., Schwarz, M., Votypka, P., Lopez-Martin, E., Posada, M., Mencarelli, M. A., Rooryck, C., Trimouille, A., Verloes, A., Abbott, K. M., Kerstjens, M., Martin, E. L., Maystadt, I., Morleo, M., Nigro, V., Pinelli, M., Riess, O., Agathe, J. -M. D. S., Santen, G. W. E., Thauvin, C., Torella, A., Vissers, L., Zguro, K., Boer, E. D., Cohen, E., Danis, D., Gao, F., Horvath, R., Johari, M., Johanson, L., Li, S., Morsy, H., Nelson, I., Paramonov, I., te Paske, I. B. A. W., Robinson, P., Savarese, M., Steyaert, W., Topf, A., van der Velde, J. K., Vandrovcova, J., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Xu, J., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Lerche, H., Kegele, J., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., 't Hoen, P. A. C., Sablauskas, K., de Voer, R. M., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Maddi, V., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Manera, J. D., Hambleton, S., Engelhardt, K., Alexander, E., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Fernandez-Callejo, M., Hernandez, C., Pico, D., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Lagorce, D., Hongnat, O., Chahdil, M., Lebreton, E., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Ben Yaou, R., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Liskova, P., Dolezalova, P., Parkinson, H., Keane, T., Freeberg, M., Thomas, C., Spalding, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Efthymiou, S., Cali, E., Magrinelli, F., Sisodiya, S. M., Rohrer, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., de Vries, G., De Winter, J., Beijer, D., de Jonghe, P., Van de Vondel, L., De Ridder, W., Weckhuysen, S., Mutarelli, M., Varavallo, A., Banfi, S., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Gualandi, F., Bigoni, S., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Ruvolo, D., Kerstjens Frederikse, W. S., Zonneveld-Huijssoon, E., Roelofs-Prins, D., van Gijn, M., Kohler, S., Metcalfe, A., Drunat, S., Heron, D., Mignot, C., Keren, B., Lacombe, D., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Cilio, M. -R., Carpancea, E., Depondt, C., Lederer, D., Sznajer, Y., Duerinckx, S., Mary, S., Macaya, A., Cazurro-Gutierrez, A., Perez-Duenas, B., Munell, F., Jarava, C. F., Maso, L. B., Marce-Grau, A., Colobran, R., Hackman, P., Udd, B., Hemelsoet, D., Dermaut, B., Schuermans, N., Poppe, B., Verdin, H., Osorio, A. N., Depienne, C., Roos, A., Cordts, I., Deschauer, M., Striano, P., Zara, F., Riva, A., Iacomino, M., Uva, P., Scala, M., Scudieri, P., Basak, A. N., Claeys, K., Boztug, K., Haimel, M., W. E, G., Ruivenkamp, C. A. L., Natera de Benito, D., Thompson, R., Polavarapu, K., Grimbacher, B., Zaganas, I., Kokosali, E., Lambros, M., Evangeliou, A., Spilioti, M., Kapaki, E., Bourbouli, M., Balicza, P., Molnar, M. J., De la Paz, M. P., Sanchez, E. B., Delgado, B. M., Alonso Garcia de la Rosa, F. J., Schrock, E., Rump, A., Mei, D., Vetro, A., Balestrini, S., Guerrini, R., Chinnery, P. F., Ratnaike, T., Schon, K., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., May, P., Beeson, D., Cossins, J., Furini, S., Afenjar, A., Goldenberg, A., Masurel, A., Phan, A., Dieux-Coeslier, A., Fargeot, A., Guerrot, A. -M., Toutain, A., Molin, A., Sorlin, A., Putoux, A., Jouret, B., Laudier, B., Demeer, B., Doray, B., Bonniaud, B., Isidor, B., Gilbert-Dussardier, B., Leheup, B., Reversade, B., Paul, C., Vincent-Delorme, C., Neiva, C., Poirsier, C., Quelin, C., Chiaverini, C., Coubes, C., Francannet, C., Colson, C., Desplantes, C., Wells, C., Goizet, C., Sanlaville, D., Amram, D., Lehalle, D., Genevieve, D., Gaillard, D., Zivi, E., Sarrazin, E., Steichen, E., Schaefer, E., Lacaze, E., Jacquemin, E., Bongers, E., Kilic, E., Colin, E., Giuliano, F., Prieur, F., Laffargue, F., Morice-Picard, F., Petit, F., Cartault, F., Feillet, F., Baujat, G., Morin, G., Diene, G., Journel, H., Perthus, I., Lespinasse, J., Alessandri, J. -L., Amiel, J., Martinovic, J., Delanne, J., Albuisson, J., Lambert, L., Perrin, L., Ousager, L. B., Van Maldergem, L., Pinson, L., Ruaud, L., Samimi, M., Bournez, M., Bonnet-Dupeyron, M. N., Vincent, M., Jacquemont, M. -L., Cordier-Alex, M. -P., Gerard-Blanluet, M., Willems, M., Spodenkiewicz, M., Doco-Fenzy, M., Rossi, M., Renaud, M., Fradin, M., Mathieu, M., Holder-Espinasse, M. H., Houcinat, N., Hanna, N., Leperrier, N., Chassaing, N., Philip, N., Boute, O., Van Kien, P. K., Parent, P., Bitoun, P., Sarda, P., Vabres, P., Jouk, P. -S., Touraine, R., El Chehadeh, S., Whalen, S., Marlin, S., Passemard, S., Grotto, S., Bellanger, S. A., Blesson, S., Nambot, S., Naudion, S., Lyonnet, S., Odent, S., Attie-Bitach, T., Busa, T., Drouin-Garraud, V., Layet, V., Bizaoui, V., Cusin, V., Capri, Y., Alembik, Y., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome reanalysis, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Developmental disorder, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology and Life Sciences, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ClinVar, Rare diseases, All institutes and research themes of the Radboud University Medical Center, Medicine and Health Sciences, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences], Exome reanalysi, Genetics (clinical)
Abstract

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí

Published
2023
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7. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Author

Dlamini, N., Voermans, N.C., Lillis, S., Stewart, K., Kamsteeg, E.-J., Drost, G., Quinlivan, R., Snoeck, M., Norwood, F., Radunovic, A., Straub, V., Roberts, M., Vrancken, A.F.J.E., van der Pol, W.L., de Coo, R.I.F.M., Manzur, A.Y., Yau, S., Abbs, S., King, A., Lammens, M., Hopkins, P.M., Mohammed, S., Treves, S., Muntoni, F., Wraige, E., Davis, M.R., van Engelen, B., and Jungbluth, H.

Published
2013
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8. The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4

Author

Parodi, L. Barbier, M. Jacoupy, M. Pujol, C. Lejeune, F.-X. Lallemant-Dudek, P. Esteves, T. Pennings, M. Kamsteeg, E.-J. Guillaud-Bataille, M. Banneau, G. Coarelli, G. Oumoussa, B.M. Fraidakis, M.J. Stevanin, G. Depienne, C. van de Warrenburg, B. Brice, A. Durr, A. and Parodi, L. Barbier, M. Jacoupy, M. Pujol, C. Lejeune, F.-X. Lallemant-Dudek, P. Esteves, T. Pennings, M. Kamsteeg, E.-J. Guillaud-Bataille, M. Banneau, G. Coarelli, G. Oumoussa, B.M. Fraidakis, M.J. Stevanin, G. Depienne, C. van de Warrenburg, B. Brice, A. Durr, A.

Abstract

Purpose: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset. Methods: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553). Results: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel–Cox test, P <.0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients. Conclusion: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy. © 2022 American College of Medical Genetics and Genomics

Published
2022

9. Correction: Solving unsolved rare neurological diseases—a Solve-RD viewpoint (European Journal of Human Genetics, (2021), 29, 9, (1332-1336), 10.1038/s41431-021-00901-1)

Author

Schule R., Timmann D., Erasmus C. E., Reichbauer J., Wayand M., Baets J., Balicza P., Chinnery P., Durr A., Haack T., Hengel H., Horvath R., Houlden H., Kamsteeg E. -J., Kamsteeg C., Lohmann K., Macaya A., Marce-Grau A., Maver A., Molnar J., Munchau A., Peterlin B., Riess O., Schols L., Stevanin G., Synofzik M., Timmerman V., van de Warrenburg B., van Os N., Vandrovcova J., Wilke C., Bevot A., Zuchner S., Beltran S., Laurie S., Matalonga L., Graessner H., Zurek B., Ellwanger K., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., Hoischen A., 't Hoen P. A. C., Vissers L. E. L. M., Gilissen C., Steyaert W., Sablauskas K., de Voer R. M., Janssen E., de Boer E., Steehouwer M., Yaldiz B., Kleefstra T., Brookes A. J., Veal C., Gibson S., Wadsley M., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Topf A., Straub V., Bettolo C. M., Specht S., Clayton-Smith J., Banka S., Alexander E., Jackson A., Faivre L., Thauvin C., Vitobello A., Denomme-Pichon A. -S., Duffourd Y., Tisserant E., Bruel A. -L., Peyron C., Pelissier A., Gut I. G., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Garcia C., Fernandez-Callejo M., Hernandez C., Pico D., Paramonov I., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Olry A., Lagorce D., Havrylenko S., Izem K., Rigour F., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Nelson I., Yaou R. B., Metay C., Eymard B., Cohen E., Atalaia A., Stojkovic T., Macek M., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Havlovicova M., Kremlik V., Parkinson H., Keane T., Spalding D., Senf A., Robinson P., Danis D., Robert G., Costa A., Patch C., Hanna M., Reilly M., Muntoni F., Zaharieva I., Sarkozy A., de Jonghe P., Nigro V., Banfi S., Torella A., Musacchia F., Piluso G., Ferlini A., Selvatici R., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Velde J. K., van der Vries G., Neerincx P. B., Roelofs-Prins D., Kohler S., Metcalfe A., Verloes A., Drunat S., Rooryck C., Trimouille A., Castello R., Morleo M., Pinelli M., Varavallo A., De la Paz M. P., Sanchez E. B., Martin E. L., Delgado B. M., de la Rosa F. J. A. G., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Renieri A., Benetti E., Molnar M. J., Herzog R., Pauly M., Osorio A. N., de Benito D. N., Thompson R., Polavarapu K., Beeson D., Cossins J., Cruz P. M. R., Hackman P., Johari M., Savarese M., Udd B., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Schrock E., Rump A., Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., Baets, J., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, H., Horvath, R., Houlden, H., Kamsteeg, E. -J., Kamsteeg, C., Lohmann, K., Macaya, A., Marce-Grau, A., Maver, A., Molnar, J., Munchau, A., Peterlin, B., Riess, O., Schols, L., Stevanin, G., Synofzik, M., Timmerman, V., van de Warrenburg, B., van Os, N., Vandrovcova, J., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Zurek, B., Ellwanger, K., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., Hoischen, A., 't Hoen, P. A. C., Vissers, L. E. L. M., Gilissen, C., Steyaert, W., Sablauskas, K., de Voer, R. M., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Topf, A., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Vitobello, A., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., Zaharieva, I., Sarkozy, A., de Jonghe, P., Nigro, V., Banfi, S., Torella, A., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Verloes, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., and Rump, A.

Abstract

In the original publication of the article, consortium author lists were missing in the article. The details are given below

Published
2021

17. Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities

Author

Steel, D, Zech, M, Zhao, C, Barwick, KES, Burke, D, Demailly, D, Kumar, KR, Zorzi, G, Nardocci, N, Kaiyrzhanov, R, Wagner, M, Iuso, A, Berutti, R, Škorvánek, M, Necpál, J, Davis, R, Wiethoff, S, Mankad, K, Sudhakar, S, Ferrini, A, Sharma, S, Kamsteeg, E-J, Tijssen, MA, Verschuuren, C, van Egmond, ME, Flowers, JM, McEntagart, M, Tucci, A, Coubes, P, Bustos, BI, Gonzalez-Latapi, P, Tisch, S, Darveniza, P, Gorman, KM, Peall, KJ, Bötzel, K, Koch, JC, Kmieć, T, Plecko, B, Boesch, S, Haslinger, B, Jech, R, Garavaglia, B, Wood, N, Houlden, H, Gissen, P, Lubbe, SJ, Sue, CM, Cif, L, Mencacci, NE, Anderson, G, Kurian, MA, Winkelmann, J, and Genomics England Research Consortium

Abstract

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Published
2020

20. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

Author

Mencacci, NE, Kamsteeg, E-J, Nakashima, K, R'Bibo, L, Lynch, DS, Balint, B, Willemsen, MAAP, Adams, ME, Wiethoff, S, Suzuki, K, Davies, CH, Ng, J, Meyer, E, Veneziano, L, Giunti, P, Hughes, D, Raymond, FL, Carecchio, M, Zorzi, G, Nardocci, N, Barzaghi, C, Garavaglia, B, Salpietro, V, Hardy, J, Pittman, AM, Houlden, H, Kurian, MA, Kimura, H, Vissers, LELM, Wood, NW, and Bhatia, KP

Subjects
Male, Protein Conformation, Molecular Sequence Data, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Mice, Young Adult, PDE10A chorea, Chorea, Report, Cyclic AMP, Genetics, Animals, Humans, Genetics(clinical), Amino Acid Sequence, Child, Cyclic GMP, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Phosphoric Diester Hydrolases, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Magnetic Resonance Imaging, Corpus Striatum, Pedigree, Mutation, Female, Sequence Alignment, Signal Transduction
Abstract

Contains fulltext : 167700.pdf (Publisher’s version ) (Open Access) Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

Published
2016

21. The etiology of rhabdomyolysis: an interaction between genetic susceptibility and external triggers.

Author

Kruijt, N., Bersselaar, L. R., Kamsteeg, E. J., Verbeeck, W., Snoeck, M. M. J., Everaerd, D. S., Abdo, W. F., Jansen, D. R. M., Erasmus, C. E., Jungbluth, H., and Voermans, N. C.

Subjects
RHABDOMYOLYSIS, CREATINE kinase, ETIOLOGY of diseases, NUCLEOTIDE sequencing, GENETIC disorders
Abstract

Background and purpose: Rhabdomyolysis is a medical emergency characterized by acute skeletal muscle breakdown with a sudden rise and subsequent fall of serum creatine kinase (CK) levels. Rhabdomyolysis events are provoked by exposure to external triggers, possibly in combination with an increased genetic susceptibility. We aimed to describe comprehensively the external triggers and potentially pathogenic genetic variants possibly implicated in increased rhabdomyolysis susceptibility. Methods: We performed a retrospective single‐center study, including a total of 1302 patients with an acute CK level exceeding 2000 IU/l. Results: Anoxia was the most frequently reported trigger (40%). A subset of 193 patients were clinically suspected of an underlying genetic disorder (recurrent episodes, a positive family history, very high or persistently increased CK levels). In 72 of these patients, an unequivocal genetic defect was identified. A total of 22 genes with pathogenic variants were identified, including 52 different variants. Of those, 11 genes have been previously associated with rhabdomyolysis (ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, RYR1). Eleven genes are probably implicated in increased susceptibility (including AGL, CAPN3, CNBP, DMPK, MAGT1, ACADM, SCN4A, SGCA, SGCG, SMPD1, TANGO2). Conclusion: These findings suggest that the spectrum of genetic susceptibility for rhabdomyolysis has not yet been completely clarified. With the increasing availability of next‐generation sequencing in a diagnostic setting, we expect that in more cases a genetic defect will be identified. [ABSTRACT FROM AUTHOR]

Published
2021
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22. Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Author

Stunnenberg, B. C., Stunnenberg, B. C., Raaphorst, J., Deenen, J. C. W., Links, T. P., Wilde, A. A., Verbove, D. J., Kamsteeg, E. J., van den Wijngaard, A., Faber, C. G., van der Wilt, G. J., van Engelen, B. G. M., Drost, G., Ginjaar, H. B., Stunnenberg, B. C., Stunnenberg, B. C., Raaphorst, J., Deenen, J. C. W., Links, T. P., Wilde, A. A., Verbove, D. J., Kamsteeg, E. J., van den Wijngaard, A., Faber, C. G., van der Wilt, G. J., van Engelen, B. G. M., Drost, G., and Ginjaar, H. B.

Abstract

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCNJ, SCN4A, CACNAIS and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNAIS missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies. (C) 2018 Elsevier B.V. All rights reserved.

Published
2018

23. Congenital Titinopathy: Comprehensive characterization and pathogenic insights

Author

Oates, EC, Jones, KJ, Donkervoort, S, Charlton, A, Brammah, S, Smith, JE, Ware, JS, Yau, KS, Swanson, LC, Whiffin, N, Peduto, AJ, Bournazos, A, Waddell, LB, Farrar, MA, Sampaio, HA, Teoh, HL, Lamont, PJ, Mowat, D, Fitzsimons, RB, Corbett, AJ, Ryan, MM, O'Grady, GL, Sandaradura, SA, Ghaoui, R, Joshi, H, Marshall, JL, Nolan, MA, Kaur, S, Punetha, J, Toepf, A, Harris, E, Bakshi, M, Genetti, CA, Marttila, M, Werlauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, JR, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, ME, Foley, AR, Bharucha-Goebel, D, Collins, J, Connolly, AM, Gilbreath, HR, Iannaccone, ST, Castro, D, Cummings, BB, Webster, RI, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H-M, Thomas, NH, Foulds, NC, Illingworth, MA, Ellard, S, McLean, CA, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Richard, I, Cooper, ST, Kamsteeg, E-J, Hoffman, EP, Bushby, K, Straub, V, Udd, B, Ferreiro, A, North, KN, Clarke, NF, Lek, M, Beggs, AH, Boennemann, CG, MacArthur, DG, Granzier, H, Davis, MR, Laing, NG, Oates, EC, Jones, KJ, Donkervoort, S, Charlton, A, Brammah, S, Smith, JE, Ware, JS, Yau, KS, Swanson, LC, Whiffin, N, Peduto, AJ, Bournazos, A, Waddell, LB, Farrar, MA, Sampaio, HA, Teoh, HL, Lamont, PJ, Mowat, D, Fitzsimons, RB, Corbett, AJ, Ryan, MM, O'Grady, GL, Sandaradura, SA, Ghaoui, R, Joshi, H, Marshall, JL, Nolan, MA, Kaur, S, Punetha, J, Toepf, A, Harris, E, Bakshi, M, Genetti, CA, Marttila, M, Werlauff, U, Streichenberger, N, Pestronk, A, Mazanti, I, Pinner, JR, Vuillerot, C, Grosmann, C, Camacho, A, Mohassel, P, Leach, ME, Foley, AR, Bharucha-Goebel, D, Collins, J, Connolly, AM, Gilbreath, HR, Iannaccone, ST, Castro, D, Cummings, BB, Webster, RI, Lazaro, L, Vissing, J, Coppens, S, Deconinck, N, Luk, H-M, Thomas, NH, Foulds, NC, Illingworth, MA, Ellard, S, McLean, CA, Phadke, R, Ravenscroft, G, Witting, N, Hackman, P, Richard, I, Cooper, ST, Kamsteeg, E-J, Hoffman, EP, Bushby, K, Straub, V, Udd, B, Ferreiro, A, North, KN, Clarke, NF, Lek, M, Beggs, AH, Boennemann, CG, MacArthur, DG, Granzier, H, Davis, MR, and Laing, NG

Abstract

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Published
2018

24. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Author

Chatron, N, Moller, RS, Champaigne, NL, Schneider, AL, Kuechler, A, Labalme, A, Simonet, T, Baggett, L, Bardel, C, Kamsteeg, E-J, Pfundt, R, Romano, C, Aronsson, J, Alberti, A, Vinci, M, Miranda, MJ, Lacroix, A, Marjanovic, D, des Portes, V, Edery, P, Wieczorek, D, Gardella, E, Scheffer, IE, Mefford, H, Sanlaville, D, Carvill, GL, Lesca, G, Chatron, N, Moller, RS, Champaigne, NL, Schneider, AL, Kuechler, A, Labalme, A, Simonet, T, Baggett, L, Bardel, C, Kamsteeg, E-J, Pfundt, R, Romano, C, Aronsson, J, Alberti, A, Vinci, M, Miranda, MJ, Lacroix, A, Marjanovic, D, des Portes, V, Edery, P, Wieczorek, D, Gardella, E, Scheffer, IE, Mefford, H, Sanlaville, D, Carvill, GL, and Lesca, G

Abstract

OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934.

Published
2018

25. Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Author

Witting, N, Laforêt, P, Voermans, N C, Roux-Buisson, N, Bompaire, F, Rendu, J, Duno, M, Feillet, F, Kamsteeg, E-J, Poulsen, N S, Dahlqvist, J R, Romero, N B, Fauré, J, Vissing, J, Behin, A, Witting, N, Laforêt, P, Voermans, N C, Roux-Buisson, N, Bompaire, F, Rendu, J, Duno, M, Feillet, F, Kamsteeg, E-J, Poulsen, N S, Dahlqvist, J R, Romero, N B, Fauré, J, Vissing, J, and Behin, A

Abstract

OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available.MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands.RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility.CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Published
2018

26. Freeman–Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa

Author

Ali, A. M., Mbwasi, R. M., Kinabo, G., Kamsteeg, E.-J., Hamel, B. C., and Dekker, M. C. J.

Subjects
Article Subject
Abstract

We report a case of a male baby who has characteristic signs of Freeman–Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman–Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman–Sheldon syndrome in sub-Saharan Africa.

Published
2017
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28. Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Author

Witting, N., primary, Laforêt, P., additional, Voermans, N. C., additional, Roux-Buisson, N., additional, Bompaire, F., additional, Rendu, J., additional, Duno, M., additional, Feillet, F., additional, Kamsteeg, E.-J., additional, Poulsen, N. S., additional, Dahlqvist, J. R., additional, Romero, N. B., additional, Fauré, J., additional, Vissing, J., additional, and Behin, A., additional

Published
2017
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31. Importance of aquaporin-2 expression levels in genotype -phenotype studies in nephrogenic diabetes insipidus

Author

KAMSTEEG, E. J. and DEEN, P. M. T.

Subjects
Physiology -- Research, Diabetes -- Physiological aspects, Endoplasmic reticulum -- Research, Diabetes insipidus -- Research, Oocytes -- Research, Biological sciences
Abstract

Kamsteeg, E. J., and P. M. T. Deen. Importance of aquaporin-2 expression levels in genotype-phenotype studies in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 279: F778-F784, 2000.--Aquaporin-2 (AQP2) water channel mutations cause autosomal recessive and dominant nephrogenic diabetes insipidus. Expressed in oocytes, a mutant in dominant (AQP2-E258K), but not in recessive (AQP2-R187C), NDI conferred a specific dominant-negative effect (DNE) on wild-type (WT) AQP2 water permeability ([P.sub.f]) but only at low expression levels. Here, we determined the cell biological basis for this requirement. Injection of different amounts of WT-AQP2 cRNAs revealed that a correlation between AQP2 protein levels and [P.sub.f] is only obtained with low expression levels. In coexpression studies of WT- and mutant AQP2 proteins, higher expression levels of AQP2-R187C also exerted a DNE on the [P.sub.f] of WT-AQP2. Immunoblot and immunoprecipitation analysis revealed that this DNE was caused by competitive inhibition of WT-AQP2 expression and escape of AQP2-R187C from the endoplasmic reticulum, resulting in oligomerization with WT-AQP2. Because many disease-related mutants of multimeric renal membrane transporters and channels are likely to be identified, our data provide important information for studying the effects of such mutants on the activity of WT transporters and channels in oocytes. recessive nephrogenic diabetes insipidus; overexpression; water channel; endoplasmic reticulum; oocytes

Published
2000

32. Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis‐myalgia syndrome.

Author

Witting, N., Laforêt, P., Voermans, N. C., Roux‐Buisson, N., Bompaire, F., Rendu, J., Duno, M., Feillet, F., Kamsteeg, E.‐J., Poulsen, N. S., Dahlqvist, J. R., Romero, N. B., Fauré, J., Vissing, J., and Behin, A.

Subjects
HYPOTHERMIA, MYALGIA, RHABDOMYOLYSIS, RYANODINE receptors, GENOTYPES
Abstract

Objectives: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next‐generation sequencing technology and limited phenotypic descriptions are therefore available. Material & Methods: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. Results: Twenty‐two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. Conclusion: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy. [ABSTRACT FROM AUTHOR]

Published
2018
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34. A Feingold syndrome case with previously undescribed features and a new mutation

Author

Koçak, H., Özaydin, E., Köse, G., Marcelis, C. L. M., Kamsteeg, E. -J, and Serdar Ceylaner

Subjects
Genomic disorders and inherited multi-system disorders [IGMD 3]
Abstract

Item does not contain fulltext Feingold syndrome (FS) is a dominantly inherited combination of microcephaly with or without learning disabilities, hand and foot abnormalities, short palpebral fissures and esophageal/duodenal atresia. The syndrome has autosomal dominant inheritance with full penetrance, and variable expressivity. Digital anomalies are almost always present. The gene for FS is localized to a 2.2 cM region in 2p23-p24. We report on the first Turkish family with Feingold syndrome. The propositus is a male infant with microcephaly, frontal balding, brachymesophalangy of the second and fifth fingers, bilateral syndactyly of toes 2-3, facial anomalies, choanal atresia and focal epilepsy. His father has microcephaly, and more severe hands and feet abnormalities. One of his brothers died because of eosofageal atresia. Clinical presentation of the family was suggestive of Feingold syndrome, and genetic testing of the MYCN gene confirmed the diagnosis. The missense mutation we report here has not been described previously. FS is an autosomal dominant condition, and therefore, the diagnosis has important implications for genetic counseling.

Published
2009

36. ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes

Author

Bot, S.T., Veldink, J.H., Vermeer, S., Mensenkamp, A.R., Brugman, F., Scheffer, H., van den Berg, L.H., Kremer, H., Kamsteeg, E-J., Warrenburg, B.P.C., Bot, S.T., Veldink, J.H., Vermeer, S., Mensenkamp, A.R., Brugman, F., Scheffer, H., van den Berg, L.H., Kremer, H., Kamsteeg, E-J., and Warrenburg, B.P.C.

Published
2013

37. 'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation

Author

Lomax, LB, Bayly, MA, Hjalgrim, H, Moller, RS, Vlaar, AM, Aaberg, KM, Marquardt, I, Gandolfo, LC, Willemsen, M, Kamsteeg, E-J, O'Sullivan, JD, Korenke, GC, Bloem, BR, de Coo, IF, Verhagen, JMA, Said, I, Prescott, T, Stray-Pedersen, A, Rasmussen, M, Vears, DF, Lehesjoki, A-E, Corbett, MA, Bahlo, M, Gecz, J, Dibbens, LM, Berkovic, SF, Lomax, LB, Bayly, MA, Hjalgrim, H, Moller, RS, Vlaar, AM, Aaberg, KM, Marquardt, I, Gandolfo, LC, Willemsen, M, Kamsteeg, E-J, O'Sullivan, JD, Korenke, GC, Bloem, BR, de Coo, IF, Verhagen, JMA, Said, I, Prescott, T, Stray-Pedersen, A, Rasmussen, M, Vears, DF, Lehesjoki, A-E, Corbett, MA, Bahlo, M, Gecz, J, Dibbens, LM, and Berkovic, SF

Abstract

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

Published
2013

38. ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes

Author

Brain, Neurologie, Bot, S.T., Veldink, J.H., Vermeer, S., Mensenkamp, A.R., Brugman, F., Scheffer, H., van den Berg, L.H., Kremer, H., Kamsteeg, E-J., Warrenburg, B.P.C., Brain, Neurologie, Bot, S.T., Veldink, J.H., Vermeer, S., Mensenkamp, A.R., Brugman, F., Scheffer, H., van den Berg, L.H., Kremer, H., Kamsteeg, E-J., and Warrenburg, B.P.C.

Published
2013

39. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Author

Willemsen, M A, Verbeek, M M, Kamsteeg, E J, de Rijk-van Andel, J F, Aeby, A, Blau, N, Burlina, A, Donati, M A, Geurtz, B, Grattan-Smith, P J, Haeussler, M, Hoffmann, G F, Jung, H, de Klerk, J B, van der Knaap, M S, Kok, F, Leuzzi, V, de Lonlay, P, Megarbane, A, Monaghan, H, Renier, W O, Rondot, P, Ryan, M M, Seeger, J, Smeitink, J A, Steenbergen-Spanjers, G C, Wassmer, E, Weschke, B, Wijburg, F A, Wilcken, B, Zafeiriou, D I, Wevers, R A, Willemsen, M A, Verbeek, M M, Kamsteeg, E J, de Rijk-van Andel, J F, Aeby, A, Blau, N, Burlina, A, Donati, M A, Geurtz, B, Grattan-Smith, P J, Haeussler, M, Hoffmann, G F, Jung, H, de Klerk, J B, van der Knaap, M S, Kok, F, Leuzzi, V, de Lonlay, P, Megarbane, A, Monaghan, H, Renier, W O, Rondot, P, Ryan, M M, Seeger, J, Smeitink, J A, Steenbergen-Spanjers, G C, Wassmer, E, Weschke, B, Wijburg, F A, Wilcken, B, Zafeiriou, D I, and Wevers, R A

Abstract

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Published
2010

43. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Author

Willemsen, M. A., primary, Verbeek, M. M., additional, Kamsteeg, E.-J., additional, de Rijk-van Andel, J. F., additional, Aeby, A., additional, Blau, N., additional, Burlina, A., additional, Donati, M. A., additional, Geurtz, B., additional, Grattan-Smith, P. J., additional, Haeussler, M., additional, Hoffmann, G. F., additional, Jung, H., additional, de Klerk, J. B., additional, van der Knaap, M. S., additional, Kok, F., additional, Leuzzi, V., additional, de Lonlay, P., additional, Megarbane, A., additional, Monaghan, H., additional, Renier, W. O., additional, Rondot, P., additional, Ryan, M. M., additional, Seeger, J., additional, Smeitink, J. A., additional, Steenbergen-Spanjers, G. C., additional, Wassmer, E., additional, Weschke, B., additional, Wijburg, F. A., additional, Wilcken, B., additional, Zafeiriou, D. I., additional, and Wevers, R. A., additional

Published
2010
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44. P18 Variant triplet repeats in the CTG expansion of DMPK affect stability of the expanded region and may contribute to unusual symptoms observed in some myotonic dystrophy type 1 cases

Author

Braida, C., primary, Stapleton, G., additional, Neil, F., additional, Rhadvanyi, H., additional, Philippe, C., additional, Finsterer, J., additional, Schraen-Maschke, S., additional, Gallano, P., additional, Warner, J., additional, Longman, C., additional, Hilton-Jones, D., additional, Brunner, H., additional, Kamsteeg, E.-J., additional, Berland, S., additional, Catalli, C., additional, Botta, A., additional, and Monckton, D.G., additional

Published
2010
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47. Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases.

Author

Hofstra, R M, primary, Stelwagen, T, additional, Stulp, R P, additional, de Jong, D, additional, Hulsbeek, M, additional, Kamsteeg, E J, additional, van den Berg, A, additional, Landsvater, R M, additional, Vermey, A, additional, Molenaar, W M, additional, Lips, C J, additional, and Buys, C H, additional

Published
1996
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48. Autosomal Recessive Inheritance of GLUT1 Deficiency Syndrome.

Author

Kiepper, J., Scheffer, H., Elsaid, M. F., Kamsteeg, E.-J., Leferink, M., and Ben-Omran, T.

Subjects
BRAIN disease research, GENETIC mutation, CEREBROSPINAL fluid, DISEASES in girls, ARABS, DEVELOPMENTAL disabilities, KETOGENIC diet, DISEASES
Abstract

GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36mg/dL; CSF lactate 1.09 mmol/L; CSF/blood glucose ratio 0.44). Molecular analysis of the SLC2A1 gene identified a novel hornozygous c1402C>T (p. Arg468Trp) mutation in exon lOin the index patient and her asymptomatic younger sister. The mutation was absent in 120 control alleles of healthy individuals as well as in 400 alleles of other GLUT1DS patients. Arg468 represents a highly conserved, functionally important amino acid residue in the GWT1 carboxy-terminus essential for substrate recognition and transport. Both unaffected parents were heterozygous for the mutation. A younger brother and two family members were healthy and carried the GLUTI wild type. A ketogenic diet effectively controlled seizures in the index patient. We conclude that GLUT1DS can be transmitted as an autosomal recessive disease and provide new insights into genetic counselling for this treatable disorder. [ABSTRACT FROM AUTHOR]

Published
2009

49. Functionality of aquaporin-2 missense mutants in recessive nephrogenic diabetes insipidus.

Author

Marr, N., Kamsteeg, E. J., van Raak, M., van Os, C. H, and Deen, P. M. T.

Subjects
AQUAPORINS, MEMBRANE proteins, GLYCOPROTEINS, DIABETES, CARBOHYDRATE intolerance, ENDOCRINE diseases, NUTRITION disorders
Abstract

Aquaporin-2 (AQP2) missense mutants in recessive nephrogenic diabetes insipidus (NDI) are all retained in the endoplasmic reticulum (ER), but some could function as water channels. No conclusions could be drawn about the water permeability (Pf) of others, because there was no method for quantifying AQP2 expression in the plasma membrane. We recently developed such a method, which has allowed us to study the functionality of these AQP2 mutants. Immunoblot analysis of membranes of injected oocytes revealed that all mutants (AQP2-G64R, AQP2-N68S, AQP2-T126M, AQP2-A147T, AQP2-R187C, AQP2-S216P) are expressed as unglycosylated and high-mannose glycosylated AQP2. The level of the high-mannose form of AQP2-A147T in the plasma membranes was low, indicating that this mutation has a less severe effect on proper folding. Analysis of Pf values and plasma membrane expression levels reveals that AQP2-N68S, AQP2-R187C and AQP2-S216P are non-functional, AQP2-A147T is as functional as wt-AQP2, while AQP2-T126M and AQP2-G64R retain 20% of the permeability of wt-AQP2. Since G64 is highly conserved between AQPs and expected to form essential interactions with other amino acids within AQP1, the residual functionality of AQP2-G64R is surprising. Our data furthermore indicate that an eventual therapy with chemical chaperones that restores the routing of AQP2 mutants to the apical membrane of collecting ducts cells might relieve NDI in patients encoding AQP2-A147T, and to a lesser extent AQP2-T126M and AQP2-G64R, but not in patients encoding AQP2-N68S, AQP2-R187C or AQP2-S216P. [ABSTRACT FROM AUTHOR]

Published
2001
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