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129 results on '"Steehouwer M"'

1. Clonal hematopoiesis has prognostic value in dilated cardiomyopathy independent of age and clone size

Author: Sikking, M, primary, Stroeks, S L V, additional, Henkens, M T H, additional, Raafs, A G, additional, Cossin, B, additional, Van Deuren, R, additional, Steehouwer, M, additional, Riksen, N P, additional, Van Den Wijngaard, A, additional, Brunner, H, additional, Hoischen, A, additional, Verdonschot, J A J, additional, and Heymans, S R B, additional
Published: 2023
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2. 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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3. Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity.

Author: Andersson-Assarsson, J.C., Deuren, R.C. van, Kristensson, F.M., Steehouwer, M., Sjöholm, K., Svensson, P.A., Pieterse, M., Gilissen, C., Taube, M., Jacobson, P., Perkins, R., Brunner, H.G., Netea, M.G., Peltonen, M., Carlsson, B., Hoischen, A., Carlsson, L.M.S., Andersson-Assarsson, J.C., Deuren, R.C. van, Kristensson, F.M., Steehouwer, M., Sjöholm, K., Svensson, P.A., Pieterse, M., Gilissen, C., Taube, M., Jacobson, P., Perkins, R., Brunner, H.G., Netea, M.G., Peltonen, M., Carlsson, B., Hoischen, A., and Carlsson, L.M.S.
Abstract: 01 juni 2023, Contains fulltext : 293878.pdf (Publisher’s version ) (Open Access), BACKGROUND: Haematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years. METHODS: Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care. FINDINGS: In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E(-04)). INTERPRETATION: Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care. FUNDING: The Swedish Research Council, The Swedish state under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, The Swedish Heart-Lung Foundation, The Novo Nordisk Foundation, The European Research Coun
Published: 2023

4. Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation

Author: Steyaert, W.A.R., Haer-Wigman, L., Pfundt, R.P., Hellebrekers, D., Steehouwer, M., Hampstead, J.E., Boer, E. de, Yntema, H.G., Kamsteeg, E.J., Brunner, H.G., Hoischen, A., Gilissen, C.F.H.A., Steyaert, W.A.R., Haer-Wigman, L., Pfundt, R.P., Hellebrekers, D., Steehouwer, M., Hampstead, J.E., Boer, E. de, Yntema, H.G., Kamsteeg, E.J., Brunner, H.G., Hoischen, A., and Gilissen, C.F.H.A.
Abstract: Contains fulltext : 298929.pdf (Publisher’s version ) (Open Access)
Published: 2023

5. Clonal Hematopoiesis Is Associated With Low CD4 Nadir and Increased Residual HIV Transcriptional Activity in Virally Suppressed Individuals With HIV

Author: Heijden, W.A. van der, Deuren, R.C. van, Wijer, L. van de, Munckhof, I.C.L. van den, Steehouwer, M., Riksen, N.P., Netea, M.G., Mast, Q. de, Vandekerckhove, L., Voer, R.M. de, Ven, A.J. van der, Hoischen, A., Heijden, W.A. van der, Deuren, R.C. van, Wijer, L. van de, Munckhof, I.C.L. van den, Steehouwer, M., Riksen, N.P., Netea, M.G., Mast, Q. de, Vandekerckhove, L., Voer, R.M. de, Ven, A.J. van der, and Hoischen, A.
Abstract: Contains fulltext : 251900.pdf (Publisher’s version ) (Open Access), Clonal hematopoiesis, a common age-related phenomenon marked by expansion of cells with clonal hematopoiesis driver mutations, has been associated with all-cause mortality, cancer, and cardiovascular disease. People with HIV (PWH) are at risk for non-AIDS-related comorbidities such as atherosclerotic cardiovascular disease and cancer. In a cross-sectional cohort study, we compared clonal hematopoiesis prevalence in PWH on stable antiretroviral therapy with prevalence in a cohort of overweight individuals and a cohort of age- and sex-matched population controls. The prevalence of clonal hematopoiesis adjusted for age was increased and clone size was larger in PWH compared to population controls. Clonal hematopoiesis is associated with low CD4 nadir, increased residual HIV-1 transcriptional activity, and coagulation factors in PWH. Future studies on the effect of clonal hematopoiesis on the HIV reservoir and non-AIDS-related comorbidities are warranted.
Published: 2022

6. Clinical Validation of Whole Genome Sequencing for Cancer Diagnostics

Author: Roepman, P., Bruijn, Ewart de, Lieshout, Stef van, Schoenmaker, L., Boelens, Mirjam C., Dubbink, Hendrikus J., Steehouwer, M., Hoischen, A., Hoeven, J.J.M van der, Cuppen, E., Roepman, P., Bruijn, Ewart de, Lieshout, Stef van, Schoenmaker, L., Boelens, Mirjam C., Dubbink, Hendrikus J., Steehouwer, M., Hoischen, A., Hoeven, J.J.M van der, and Cuppen, E.
Abstract: Item does not contain fulltext
Published: 2021

7. Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

Author: Deuren, R.C. van, Arts, P., Cavalli, G.C., Jaeger, M., Steehouwer, M., Vorst, M. van de, Gilissen, C., Joosten, L.A.B., Dinarello, C.A., Mhlanga, M.M.K., Kumar, V., Netea, M.G., Veerdonk, F.L. van de, Hoischen, A., Deuren, R.C. van, Arts, P., Cavalli, G.C., Jaeger, M., Steehouwer, M., Vorst, M. van de, Gilissen, C., Joosten, L.A.B., Dinarello, C.A., Mhlanga, M.M.K., Kumar, V., Netea, M.G., Veerdonk, F.L. van de, and Hoischen, A.
Abstract: Contains fulltext : 234188.pdf (Publisher’s version ) (Open Access)
Published: 2021

8. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype–phenotype study

Author: Makrythanasis, P, van Bon, B W, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, B M, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, E MHF, del Campo, M, Cordeiro, I, Cueto-González, A M, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, S M, Hoyer, J, Yntema, H G, Kets, C M, Koolen, D A, Marcelis, C L, Medeira, A, Micale, L, Mohammed, S, de Munnik, S A, Nordgren, A, Psoni, S, Reardon, W, Revencu, N, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, H G, Schoumans, J, Schuurs-Hoeijmakers, J HM, Silengo, M C, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, R C, Perez-Jurado, L, Dupont, J, de Vries, B BA, Brunner, H G, Veltman, J A, Merla, G, Antonarakis, S E, and Hoischen, A
Published: 2013
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9. Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Author: Kluck, V., Deuren, R.C. van, Cavalli, G., Shaukat, A., Arts, P., Cleophas, M.C.P., Crisan, T. O., Tausche, A.K., Riches, P., Dalbeth, N., Stamp, L.K., Hindmarsh, J.H., Jansen, T., Janssen, M., Steehouwer, M., Lelieveld, S.H., Vorst, M. van de, Gilissen, C., Dagna, L., Veerdonk, F.L. van de, Eisenmesser, E.Z., Kim, S., Merriman, T.R., Hoischen, A., Netea, M.G., Dinarello, C.A., Joosten, L.A.B., Kluck, V., Deuren, R.C. van, Cavalli, G., Shaukat, A., Arts, P., Cleophas, M.C.P., Crisan, T. O., Tausche, A.K., Riches, P., Dalbeth, N., Stamp, L.K., Hindmarsh, J.H., Jansen, T., Janssen, M., Steehouwer, M., Lelieveld, S.H., Vorst, M. van de, Gilissen, C., Dagna, L., Veerdonk, F.L. van de, Eisenmesser, E.Z., Kim, S., Merriman, T.R., Hoischen, A., Netea, M.G., Dinarello, C.A., and Joosten, L.A.B.
Abstract: Contains fulltext : 218310.pdf (Publisher’s version ) (Closed access), OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71x10(-5)). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.
Published: 2020

10. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Author: Khan, M., Cornelis, S.S., Pozo-Valero, M.D., Whelan, L., Runhart, E.H., Mishra, K., Bults, F., AlSwaiti, Y., AlTalbishi, A., Baere, E. De, Banfi, S., Banin, E., Bauwens, M., Ben-Yosef, T., Boon, C.J.F., Born, L.I. van den, Defoort, S., Devos, A., Dockery, A., Dudakova, L., Fakin, A., Farrar, G.J., Sallum, J.M.F., Fujinami, K., Gilissen, C., Glavač, D., Gorin, M.B., Greenberg, J., Hayashi, T., Hettinga, Y.M., Hoischen, A., Hoyng, C.B., Hufendiek, K., Jägle, H., Kamakari, S., Karali, M., Kellner, U., Klaver, C.C.W., Kousal, B., Lamey, T.M., MacDonald, I.M., Matynia, A., McLaren, T.L., Mena, M.D., Meunier, I., Miller, R., Newman, H., Ntozini, B., Oldak, M., Pieterse, M., Podhajcer, O.L., Puech, B., Ramesar, R., Rüther, K., Salameh, M., Salles, M.V., Sharon, D., Simonelli, F., Spital, G., Steehouwer, M., Szaflik, J.P., Thompson, J.A., Thuillier, C., Tracewska, A.M., Zweeden, M. van, Vincent, A.L., Zanlonghi, X., Liskova, P., Stöhr, H., Roach, J.N., Ayuso, C., Roberts, L., Weber, B.H.F., Dhaenens, C.M., Cremers, F.P.M., Khan, M., Cornelis, S.S., Pozo-Valero, M.D., Whelan, L., Runhart, E.H., Mishra, K., Bults, F., AlSwaiti, Y., AlTalbishi, A., Baere, E. De, Banfi, S., Banin, E., Bauwens, M., Ben-Yosef, T., Boon, C.J.F., Born, L.I. van den, Defoort, S., Devos, A., Dockery, A., Dudakova, L., Fakin, A., Farrar, G.J., Sallum, J.M.F., Fujinami, K., Gilissen, C., Glavač, D., Gorin, M.B., Greenberg, J., Hayashi, T., Hettinga, Y.M., Hoischen, A., Hoyng, C.B., Hufendiek, K., Jägle, H., Kamakari, S., Karali, M., Kellner, U., Klaver, C.C.W., Kousal, B., Lamey, T.M., MacDonald, I.M., Matynia, A., McLaren, T.L., Mena, M.D., Meunier, I., Miller, R., Newman, H., Ntozini, B., Oldak, M., Pieterse, M., Podhajcer, O.L., Puech, B., Ramesar, R., Rüther, K., Salameh, M., Salles, M.V., Sharon, D., Simonelli, F., Spital, G., Steehouwer, M., Szaflik, J.P., Thompson, J.A., Thuillier, C., Tracewska, A.M., Zweeden, M. van, Vincent, A.L., Zanlonghi, X., Liskova, P., Stöhr, H., Roach, J.N., Ayuso, C., Roberts, L., Weber, B.H.F., Dhaenens, C.M., and Cremers, F.P.M.
Abstract: Contains fulltext : 225504.pdf (Publisher’s version ) (Closed access), PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. METHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. RESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. CONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
Published: 2020

11. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Author: Putte, R. van de, Dworschak, Gabriel C., Brosens, E., Reutter, H., Marcelis, C.L.M., Acuna Hidalgo, R., Steehouwer, M., Blaauw, I. de, Roeleveld, N., Brunner, H.G., Rooij, I.A.L.M. van, Hoischen, A., Putte, R. van de, Dworschak, Gabriel C., Brosens, E., Reutter, H., Marcelis, C.L.M., Acuna Hidalgo, R., Steehouwer, M., Blaauw, I. de, Roeleveld, N., Brunner, H.G., Rooij, I.A.L.M. van, and Hoischen, A.
Abstract: Contains fulltext : 221455.pdf (publisher's version ) (Open Access)
Published: 2020

12. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Author: van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), Hoischen, A. (Alex), van de Putte, R. (Romy), Dworschak, G.C. (Gabriel C), Brosens, E. (Erwin), Reutter, H. (Heiko), Marcelis, C.L.M. (Carlo L. M.), Acuna-Hidalgo, R. (Rocio), Kurtas, N.E. (Nehir E.), Steehouwer, M. (Marloes), Dunwoodie, S.L. (Sally L.), Schmiedeke, E. (Eberhard), Märzheuser, S. (Stefanie), Schwarzer, S. (Stefan), Brooks, A.S. (Alice), Klein, A. (Annelies) de, Sloots, C.E.J. (Pim), Tibboel, D. (Dick), Brisighelli, G., Morandi, A. (Anna), Bedeschi, M.F. (Maria F.), Bates, M.D. (Michael D.), Levitt, M.A. (Marc), La Peña, A. (Amparo) de, Blaauw, I. (Ivo) de, Roeleveld, N. (Nel), Brunner, H.G. (Han), Rooij, I.A.L.M. (Iris), and Hoischen, A. (Alex)
Abstract: Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.
Published: 2020
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13. Presence of Genetic Variants Among Young Men With Severe COVID-19

Author: Made, C.I. van der, Simons, A., Schuurs-Hoeijmakers, J.H.M., Heuvel, Guus van den, Mantere, T., Kersten, S., Deuren, R.C. van, Steehouwer, M., Reijmersdal, S.V. van, Jaeger, M., Astuti, G.D., Corominas-Galbany, J., Hoeven, J.G. van der, Hagmolen of ten Have, W., Mast, Q. de, Bleeker-Rovers, C.P., Joosten, L.A.B., Yntema, H.G., Gilissen, C.F., Nelen, M.R., Meer, J.W.M. van der, Brunner, H.G., Netea, M.G., Veerdonk, F.L. van de, Hoischen, A., Made, C.I. van der, Simons, A., Schuurs-Hoeijmakers, J.H.M., Heuvel, Guus van den, Mantere, T., Kersten, S., Deuren, R.C. van, Steehouwer, M., Reijmersdal, S.V. van, Jaeger, M., Astuti, G.D., Corominas-Galbany, J., Hoeven, J.G. van der, Hagmolen of ten Have, W., Mast, Q. de, Bleeker-Rovers, C.P., Joosten, L.A.B., Yntema, H.G., Gilissen, C.F., Nelen, M.R., Meer, J.W.M. van der, Brunner, H.G., Netea, M.G., Veerdonk, F.L. van de, and Hoischen, A.
Abstract: Contains fulltext : 222168.pdf (Publisher’s version ) (Closed access)
Published: 2020

14. A Genetics-First Approach Revealed Monogenic Disorders in Patients With ARM and VACTERL Anomalies

Author: van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, Hoischen, A, van de Putte, R, Dworschak, GC, Brosens, Erwin, Reutter, HM, Marcelis, CL, Acuna-Hidalgo, R, Kurtas, NE, Steehouwer, M, Dunwoodie, SL, Schmiedeke, E, Marzheuser, S, Schwarzer, N, Brooks, Alice, de Klein, Annelies, Sloots, C.E.J., Tibboel, Dick, Brisighelli, G, Morandi, A, Bedeschi, MF, Bates, MD, Levitt, MA, de la Pena, A, de Blaauw, I, Roeleveld, N, Brunner, HG, de Rooij, I, and Hoischen, A
Published: 2020

15. Deletions and loss-of-function variants in TP63 associated with orofacial clefting

Author: Khandelwal, K., Boogaard, M. van den, Mehrem, S.L., Gebel, J., Fagerberg, C., Beusekom, E. van, Binsbergen, E. van, Topaloglu, O., Steehouwer, M., Gilissen, C., Ishorst, N., Rooij, I.A.L.M. van, Roeleveld, N., Christensen, K., Schoenaers, J., Berge, S.J., Murray, J.C., Hens, G., Devriendt, K., Ludwig, K.U., Mangold, E., Hoischen, A., Zhou, H., Dotsch, V., Carels, C.E.L., Bokhoven, H. van, Khandelwal, K., Boogaard, M. van den, Mehrem, S.L., Gebel, J., Fagerberg, C., Beusekom, E. van, Binsbergen, E. van, Topaloglu, O., Steehouwer, M., Gilissen, C., Ishorst, N., Rooij, I.A.L.M. van, Roeleveld, N., Christensen, K., Schoenaers, J., Berge, S.J., Murray, J.C., Hens, G., Devriendt, K., Ludwig, K.U., Mangold, E., Hoischen, A., Zhou, H., Dotsch, V., Carels, C.E.L., and Bokhoven, H. van
Abstract: Contains fulltext : 204872.pdf (publisher's version ) (Closed access), We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.
Published: 2019

16. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

Author: Putte, R. van de, Wijers, C.H.W., Reutter, H., Vermeulen, S.H., Marcelis, C.L.M., Brosens, E., Broens, P., Homberg, M., Ludwig, M., Jenetzky, E., Zwink, N., Sloots, C.E.J., Klein, A. de, Brooks, A.S., Hofstra, R.M.W., Holsink, S.A.C., Zanden, L.F.M. van der, Galesloot, T.E., Tam, P.K.H, Steehouwer, M., Acuna-Hidalgo, R., Vorst, J.M. van de, Kiemeney, L.A.L.M., Garcia- Barcelo, M.M., Blaauw, I. de, Brunner, H.G., Roeleveld, N., Rooij, I.A.L.M. van, Putte, R. van de, Wijers, C.H.W., Reutter, H., Vermeulen, S.H., Marcelis, C.L.M., Brosens, E., Broens, P., Homberg, M., Ludwig, M., Jenetzky, E., Zwink, N., Sloots, C.E.J., Klein, A. de, Brooks, A.S., Hofstra, R.M.W., Holsink, S.A.C., Zanden, L.F.M. van der, Galesloot, T.E., Tam, P.K.H, Steehouwer, M., Acuna-Hidalgo, R., Vorst, J.M. van de, Kiemeney, L.A.L.M., Garcia- Barcelo, M.M., Blaauw, I. de, Brunner, H.G., Roeleveld, N., and Rooij, I.A.L.M. van
Abstract: Contains fulltext : 205341.pdf (publisher's version ) (Open Access)
Published: 2019

17. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

Author: van de Putte, R., Wijers, C.H.W. (Charlotte), Reutter, H. (Heiko), Vermeulen, SH, Marcelis, CLM, Brosens, E. (Erwin), Broens, P.M.A. (Paul), Homberg, M., Ludwig, M. (Michael), Jenetzky, E. (Ekkehart), Zwink, N. (Nadine), Sloots, C.E.J. (Pim), Klein, J.E.M.M. (Annelies) de, Brooke, A.S., Hofstra, R.M.W. (Robert), Holsink, S.A.C., Zanden, L.F.M. (Loes) van der, Galesloot, TE, Tam, P.K.H. (Paul), Steehouwer, M., Acuna-Hidalgo, R., van de Vorst, M., Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, H.G., Roeleveld, N. (Nel), de Rooij, I, van de Putte, R., Wijers, C.H.W. (Charlotte), Reutter, H. (Heiko), Vermeulen, SH, Marcelis, CLM, Brosens, E. (Erwin), Broens, P.M.A. (Paul), Homberg, M., Ludwig, M. (Michael), Jenetzky, E. (Ekkehart), Zwink, N. (Nadine), Sloots, C.E.J. (Pim), Klein, J.E.M.M. (Annelies) de, Brooke, A.S., Hofstra, R.M.W. (Robert), Holsink, S.A.C., Zanden, L.F.M. (Loes) van der, Galesloot, TE, Tam, P.K.H. (Paul), Steehouwer, M., Acuna-Hidalgo, R., van de Vorst, M., Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, H.G., Roeleveld, N. (Nel), and de Rooij, I
Abstract: Introduction Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, as
Published: 2019
Full Text: View/download PDF

18. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

Author: van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, de Rooij, I, van de Putte, R, Wijers, CHW, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, Erwin, Broens, PMA, Homberg, M, Ludwig, M, Jenetzky, E, Zwink, N, Sloots, C.E.J., de Klein, Annelies, Brooks, Alice, Hofstra, Robert, Holsink, SAC, van der Zanden, LFM, Galesloot, TE, Tam, PKH, Steehouwer, M, Acuna-Hidalgo, R, van de Vorst, M, Kiemeney, LA, Garcia-Barcelo, MM, de Blaauw, I, Brunner, HG, Roeleveld, N, and de Rooij, I
Published: 2019

19. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

Author: Jansen, S, Hoischen, A., Coe, B.P., Carvill, G.L., Esch, H. Van, Bosch, D.G.M., Bon, B.W. van, Claahsen-van der Grinten, H.L., Gilissen, C.F., Kleefstra, T., Koolen, D.A., Marcelis, C.L., Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Steehouwer, M., Vries, P.F. de, Veltman, J.A., Brunner, H.G., Vissers, L.E.L.M., Eichler, E.E., Vries, B.B.A. de, Jansen, S, Hoischen, A., Coe, B.P., Carvill, G.L., Esch, H. Van, Bosch, D.G.M., Bon, B.W. van, Claahsen-van der Grinten, H.L., Gilissen, C.F., Kleefstra, T., Koolen, D.A., Marcelis, C.L., Schuurs-Hoeijmakers, J.H.M., Pfundt, R.P., Steehouwer, M., Vries, P.F. de, Veltman, J.A., Brunner, H.G., Vissers, L.E.L.M., Eichler, E.E., and Vries, B.B.A. de
Abstract: Item does not contain fulltext
Published: 2018

20. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

Author: Nicolas, Gael, Acuna Hidalgo, R., Keogh, Michael J., Quenez, Olivier, Steehouwer, M., Lelieveld, S.H., Oud, M.S., Gilissen, C., Veltman, J.A., Hoischen, A., Nicolas, Gael, Acuna Hidalgo, R., Keogh, Michael J., Quenez, Olivier, Steehouwer, M., Lelieveld, S.H., Oud, M.S., Gilissen, C., Veltman, J.A., and Hoischen, A.
Abstract: Item does not contain fulltext
Published: 2018

21. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author: Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., Bon, B.W.M. van, Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., and Bon, B.W.M. van
Abstract: Contains fulltext : 174787.pdf (publisher's version ) (Open Access), Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
Published: 2017

22. Novel irf6 mutations detected in orofacial cleft patients by targeted massively parallel sequencing

Author: Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, Carels, C.E.L., Khandelwal, K., Ishorst, N., Zhou, H., Ludwig, K.U., Venselaar, H., Gilissen, C.F., Thonissen, M., Rooij, I.A.L.M. van, Dreesen, K., Steehouwer, M., Vorst, J.M. van de, Bloemen, M., Beusekom, E. van, Roosenboom, J., Borstlap, W.A., Admiraal, R.J., Dormaar, T., Schoenaers, J., Poorten, V. Van der, Hens, G., Verdonck, A., Berge, S.J., Roeleveld, N., Vriend, G., Devriendt, K., Brunner, H.G., Mangold, E., Hoischen, A., Bokhoven, H. van, and Carels, C.E.L.
Abstract: Contains fulltext : 191986.pdf (publisher's version ) (Closed access)
Published: 2017

23. BRCA Testing by Single-Molecule Molecular Inversion Probes

Author: Neveling, K., Mensenkamp, A.R., Derks, R, Kwint, M.P., Ouchene, H., Steehouwer, M., Lier, L.A. van, Bosgoed, E.A.J., Rikken, A., Tychon, M.W.J., Zafeiropoulou, D., Castelein, S., Hehir-Kwa, J.Y., Thung, G.W., Hofste, T., Lelieveld, S.H., Bertens, S.M., Adan, I.B., Eijkelenboom, A., Tops, B.B.J., Yntema, H.G., Stokowy, T., Knappskog, P.M., Hoberg-Vetti, H., Steen, V.M., Boyle, E., Martin, B., Ligtenberg, M.J.L., Shendure, J., Nelen, M.R., Hoischen, A., Neveling, K., Mensenkamp, A.R., Derks, R, Kwint, M.P., Ouchene, H., Steehouwer, M., Lier, L.A. van, Bosgoed, E.A.J., Rikken, A., Tychon, M.W.J., Zafeiropoulou, D., Castelein, S., Hehir-Kwa, J.Y., Thung, G.W., Hofste, T., Lelieveld, S.H., Bertens, S.M., Adan, I.B., Eijkelenboom, A., Tops, B.B.J., Yntema, H.G., Stokowy, T., Knappskog, P.M., Hoberg-Vetti, H., Steen, V.M., Boyle, E., Martin, B., Ligtenberg, M.J.L., Shendure, J., Nelen, M.R., and Hoischen, A.
Abstract: Contains fulltext : 169902.pdf (publisher's version ) (Closed access), BACKGROUND: Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements in terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential in the area of clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested gene tests, those for the breast cancer genes BRCA1 and BRCA2, and developed an automated work flow based on smMIPs. METHODS: The BRCA1 and BRCA2 smMIPs were validated using 166 human genomic DNA samples with known variant status. A generic automated work flow was built to perform smMIP-based enrichment and sequencing for BRCA1, BRCA2, and the checkpoint kinase 2 (CHEK2) c.1100del variant. RESULTS: Pathogenic and benign variants were analyzed in a subset of 152 previously BRCA-genotyped samples, yielding an analytical sensitivity and specificity of 100%. Following automation, blind analysis of 65 in-house samples and 267 Norwegian samples correctly identified all true-positive variants (>3000), with no false positives. Consequent to process optimization, turnaround times were reduced by 60% to currently 10-15 days. Copy number variants were detected with an analytical sensitivity of 100% and an analytical specificity of 88%. CONCLUSIONS: smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable.
Published: 2017

24. Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life

Author: Acuna Hidalgo, R., Sengul, H., Steehouwer, M., Vorst, M. van de, Vermeulen, S.H., Kiemeney, B., Veltman, J.A., Gilissen, C.F., Hoischen, A., Acuna Hidalgo, R., Sengul, H., Steehouwer, M., Vorst, M. van de, Vermeulen, S.H., Kiemeney, B., Veltman, J.A., Gilissen, C.F., and Hoischen, A.
Abstract: Contains fulltext : 177281.pdf (publisher's version ) (Closed access), Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals >/=65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.
Published: 2017

25. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author: Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), Bon, B. (Bregje) van, Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), and Bon, B. (Bregje) van
Abstract: Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
Published: 2017
Full Text: View/download PDF

26. Quantification of differential gene expression by multiplexed targeted resequencing of cDNA

Author: Arts, P., Raadt, J. van der, Gestel, S.H.C. van, Steehouwer, M., Shendure, J., Hoischen, A., Albers, C.A., Arts, P., Raadt, J. van der, Gestel, S.H.C. van, Steehouwer, M., Shendure, J., Hoischen, A., and Albers, C.A.
Abstract: Contains fulltext : 174649.pdf (publisher's version ) (Open Access), Whole-transcriptome or RNA sequencing (RNA-Seq) is a powerful and versatile tool for functional analysis of different types of RNA molecules, but sample reagent and sequencing cost can be prohibitive for hypothesis-driven studies where the aim is to quantify differential expression of a limited number of genes. Here we present an approach for quantification of differential mRNA expression by targeted resequencing of complementary DNA using single-molecule molecular inversion probes (cDNA-smMIPs) that enable highly multiplexed resequencing of cDNA target regions of approximately 100 nucleotides and counting of individual molecules. We show that accurate estimates of differential expression can be obtained from molecule counts for hundreds of smMIPs per reaction and that smMIPs are also suitable for quantification of relative gene expression and allele-specific expression. Compared with low-coverage RNA-Seq and a hybridization-based targeted RNA-Seq method, cDNA-smMIPs are a cost-effective high-throughput tool for hypothesis-driven expression analysis in large numbers of genes (10 to 500) and samples (hundreds to thousands).
Published: 2017

27. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author: Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, van Bon, BW, Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, and van Bon, BW
Published: 2017

28. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Author: Ockeloen, C.W., Khandelwal, K.D., Dreesen, K., Ludwig, K.U., Sullivan, R., Rooij, I.A van, Thonissen, M., Swinnen, S., Phan, M., Conte, F, Ishorst, N., Gilissen, C., Roa Fuentes, L., van de Vorst, M., Henkes, A., Steehouwer, M., van Beusekom, E., Bloemen, M., Vankeirsbilck, B., Berge, S.J., Hens, G., Schoenaers, J., Vander Poorten, V., Roosenboom, J., Verdonck, A., Devriendt, K., Roeleveldt, N., Jhangiani, S.N., Vissers, L.E., Lupski, J.R., de Ligt, J., Von den Hoff, J.W., Pfundt, R., Brunner, H.G., Zhou, H., Dixon, J., Mangold, E., van Bokhoven, H., Dixon, M.J., Kleefstra, T., Hoischen, A., Carels, C.E., Ockeloen, C.W., Khandelwal, K.D., Dreesen, K., Ludwig, K.U., Sullivan, R., Rooij, I.A van, Thonissen, M., Swinnen, S., Phan, M., Conte, F, Ishorst, N., Gilissen, C., Roa Fuentes, L., van de Vorst, M., Henkes, A., Steehouwer, M., van Beusekom, E., Bloemen, M., Vankeirsbilck, B., Berge, S.J., Hens, G., Schoenaers, J., Vander Poorten, V., Roosenboom, J., Verdonck, A., Devriendt, K., Roeleveldt, N., Jhangiani, S.N., Vissers, L.E., Lupski, J.R., de Ligt, J., Von den Hoff, J.W., Pfundt, R., Brunner, H.G., Zhou, H., Dixon, J., Mangold, E., van Bokhoven, H., Dixon, M.J., Kleefstra, T., Hoischen, A., and Carels, C.E.
Abstract: Item does not contain fulltext
Published: 2016

29. DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome

Author: White, J.J., Mazzeu, J.F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., Kimonis, V., Steehouwer, M., Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Bon, B.W. van, Sutton, V.R., Lupski, J.R., Brunner, H.G., Carvalho, C.M., White, J.J., Mazzeu, J.F., Hoischen, A., Bayram, Y., Withers, M., Gezdirici, A., Kimonis, V., Steehouwer, M., Jhangiani, S.N., Muzny, D.M., Gibbs, R.A., Bon, B.W. van, Sutton, V.R., Lupski, J.R., Brunner, H.G., and Carvalho, C.M.
Abstract: Item does not contain fulltext, Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a -1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a -1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations.
Published: 2016

30. Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

Author: Wills, E.S., Cnossen, W.R., Veltman, J.A., Woestenenk, R.M., Steehouwer, M., Salomon, J., Morsche, R.H.M. te, Huch, M., Hehir-Kwa, J.Y., Banning, M.J., Pfundt, R.P., Roepman, R., Hoischen, A., Drenth, J.P.H., Wills, E.S., Cnossen, W.R., Veltman, J.A., Woestenenk, R.M., Steehouwer, M., Salomon, J., Morsche, R.H.M. te, Huch, M., Hehir-Kwa, J.Y., Banning, M.J., Pfundt, R.P., Roepman, R., Hoischen, A., and Drenth, J.P.H.
Abstract: Contains fulltext : 167652.pdf (publisher's version ) (Closed access), Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.
Published: 2016

31. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (THRA)

Author: Tylki-Szymanska, A., Acuna Hidalgo, R., Krajewska-Walasek, M., Lecka-Ambroziak, A., Steehouwer, M., Gilissen, C.F., Brunner, H.G., Jurecka, A., Rozdzynska-Swiatkowska, A., Hoischen, A., Chrzanowska, K.H., Tylki-Szymanska, A., Acuna Hidalgo, R., Krajewska-Walasek, M., Lecka-Ambroziak, A., Steehouwer, M., Gilissen, C.F., Brunner, H.G., Jurecka, A., Rozdzynska-Swiatkowska, A., Hoischen, A., and Chrzanowska, K.H.
Abstract: Item does not contain fulltext, BACKGROUND: Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor beta (TRbeta), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor alpha gene (THRA) defects. METHODS: We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families. FINDINGS: Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations. INTERPRETATION: THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.
Published: 2015

32. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome

Author: White, J., Mazzeu, J.F., Hoischen, A., Jhangiani, S.N., Gambin, T., Alcino, M.C., Penney, S., Saraiva, J.M., Hove, H., Skovby, F., Kayserili, H., Estrella, E., Silfhout, A.T. van, Steehouwer, M., Muzny, D.M., Sutton, V.R., Gibbs, R.A., Lupski, J.R., Brunner, H.G., Bon, B.W. van, Carvalho, C.M., White, J., Mazzeu, J.F., Hoischen, A., Jhangiani, S.N., Gambin, T., Alcino, M.C., Penney, S., Saraiva, J.M., Hove, H., Skovby, F., Kayserili, H., Estrella, E., Silfhout, A.T. van, Steehouwer, M., Muzny, D.M., Sutton, V.R., Gibbs, R.A., Lupski, J.R., Brunner, H.G., Bon, B.W. van, and Carvalho, C.M.
Abstract: Item does not contain fulltext, Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.
Published: 2015

33. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations

Author: Voigt, C., Megarbane, A., Neveling, K., Czeschik, J.C., Albrecht, B., Callewaert, B., Deimling, F. von, Hehr, A., Smeland, M. Falkenberg, Konig, R., Kuechler, A., Marcelis, C., Puiu, M., Reardon, W., Stensland, H.M. Riise, Schweiger, B., Steehouwer, M., Teller, C., Martin, M., Rahmann, S., Hehr, U., Brunner, H.G., Ludecke, H.J., Wieczorek, D., BMC, Ed., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Medizinische Genetik, Sozialpädiatrisches Zentrum Coburg, Zentrum für Humangenetik, Universitätsklinikum Regensburg, Department of Medical Genetics, Division of Child and Adolescent Health-University Hospital of North Norway [Tromsø] (UNN), Humangenetik, Universitätsklinikum Frankfurt, Genetica medicala, Victor Babeş University of Medicine and Pharmacy (UMFT), National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Institut für Humangenetik [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Bioinformatics, Computer Science XI, Technische Universität Dortmund [Dortmund] (TU), Abteilung Genominformatik, Universität Duisburg-Essen [Essen]-Institut für Humangenetik, This work was supported by the German Ministry of Education and Research for the CRANIRARE to DW and the FACE consortium to DW and H-JL (BMBF 01GM1211B and 01GM1109B). BC is a postdoctoral research fellow of the fund for scientific research-flanders., and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Institut für Humangenetik
Subjects: Adult, Male, Adolescent, Medizin, Oto-facial syndrome with midline malformation, [SDV.GEN] Life Sciences [q-bio]/Genetics, HAPLOINSUFFICIENCY, EFTUD2, Genomic disorders and inherited multi-system disorders [IGMD 3], Young Adult, Oto-facial syndrome with midline malformation, Acrofacial dysostosis type Guion-Almeida (AFDGA), SNRNP, Intellectual Disability, Humans, Genetics(clinical), Pharmacology (medical), Mandibulofacial dysostosis type Guion-Almeida (MFDGA), Child, Esophageal Atresia, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Medicine(all), Acrofacial dysostosis type Guion-Almeida (AFDGA), [SDV.GEN]Life Sciences [q-bio]/Genetics, COMPLEX, Esophageal atresia (EA), Research, Biology and Life Sciences, Sequence Analysis, DNA, NAGER SYNDROME, Peptide Elongation Factors, Phenotype, Child, Preschool, Mutation, Female, MANDIBULOFACIAL DYSOSTOSIS, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], MENTAL-RETARDATION, Mandibulofacial Dysostosis
Abstract: Contains fulltext : 185259.pdf (Publisher’s version ) (Open Access) BACKGROUND: Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). METHODS AND RESULTS: We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. CONCLUSIONS: The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Megarbane et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.
Published: 2013
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34. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Author: Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., Zenker, M., Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., and Zenker, M.
Abstract: Contains fulltext : 136372.pdf (Publisher’s version ) (Closed access), Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.
Published: 2014

35. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Author: UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, Hoischen, A, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Makrythanasis, P, van Bon, Bw, Steehouwer, M, Rodríguez-Santiago, B, Simpson, M, Dias, P, Anderlid, Bm, Arts, P, Bhat, M, Augello, B, Biamino, E, Bongers, Emhf, Del Campo, M, Cordeiro, I, Cueto-González, Am, Cuscó, I, Deshpande, C, Frysira, E, Izatt, L, Flores, R, Galán, E, Gener, B, Gilissen, C, Granneman, Sm, Hoyer, J, Yntema, Hg, Kets, Cm, Koolen, DA, Marcelis, Cl, Medeira, A, Micale, L, Mohammed, S, de Munnik, Sa, Nordgren, A, Psoni, S, Reardon, W, Revencu, Nicole, Roscioli, T, Ruiterkamp-Versteeg, M, Santos, Hg, Schoumans, J, Schuurs-Hoeijmakers, Jhm, Silengo, Mc, Toledo, L, Vendrell, T, van der Burgt, I, van Lier, B, Zweier, C, Reymond, A, Trembath, Rc, Perez-Jurado, L, Dupont, J, de Vries, Bba, Brunner, Hg, Veltman, Ja, Merla, G, Antonarakis, Se, and Hoischen, A
Abstract: Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Published: 2013

36. Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome

Author: Schuurs-Hoeijmakers, J.H.M., Oh, E.C., Peart-Vissers, L.E.L.M., Swinkels, M.E., Gilissen, C.F.H.A., Willemsen, M.A.A.P., Holvoet, M., Steehouwer, M., Veltman, J.A., Vries, L.B.A. de, Bokhoven, J.H.L.M. van, Brouwer, A.P.M. de, Katsanis, N., Devriendt, K., Brunner, H.G., Schuurs-Hoeijmakers, J.H.M., Oh, E.C., Peart-Vissers, L.E.L.M., Swinkels, M.E., Gilissen, C.F.H.A., Willemsen, M.A.A.P., Holvoet, M., Steehouwer, M., Veltman, J.A., Vries, L.B.A. de, Bokhoven, J.H.L.M. van, Brouwer, A.P.M. de, Katsanis, N., Devriendt, K., and Brunner, H.G.
Abstract: Item does not contain fulltext, We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.
Published: 2012

37. Cantu syndrome is caused by mutations in ABCC9

Author: van Bon, B.W., Gilissen, C.F.H.A., Grange, D.K., Hennekam, R.C., Kayserili, H., Engels, H., Reutter, H., Ostergaard, J.R., Morava, E., Tsiakas, K., Isidor, B., Le Merrer, M., Eser, M., Wieskamp, N., de Vries, P., Steehouwer, M., Veltman, J.A., Robertson, S.P., Brunner, H.G., Vries, L.B.A. de, Hoischen, A., van Bon, B.W., Gilissen, C.F.H.A., Grange, D.K., Hennekam, R.C., Kayserili, H., Engels, H., Reutter, H., Ostergaard, J.R., Morava, E., Tsiakas, K., Isidor, B., Le Merrer, M., Eser, M., Wieskamp, N., de Vries, P., Steehouwer, M., Veltman, J.A., Robertson, S.P., Brunner, H.G., Vries, L.B.A. de, and Hoischen, A.
Abstract: Item does not contain fulltext, Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantu syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantu syndrome and suggest that this is a new member of the potassium channelopathies.
Published: 2012

38. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome.

Author: Gilissen, C.F.H.A., Arts, H.H., Hoischen, A., Spruijt, L., Mans, D.A., Arts, P.J.W., Lier, B. van, Steehouwer, M., Reeuwijk, J. van, Kant, S.G., Roepman, R., Knoers, N.V.A.M., Veltman, J.A., Brunner, H.G., Gilissen, C.F.H.A., Arts, H.H., Hoischen, A., Spruijt, L., Mans, D.A., Arts, P.J.W., Lier, B. van, Steehouwer, M., Reeuwijk, J. van, Kant, S.G., Roepman, R., Knoers, N.V.A.M., Veltman, J.A., and Brunner, H.G.
Abstract: Contains fulltext : 88664.pdf (publisher's version ) (Closed access), Sensenbrenner syndrome/cranioectodermal dysplasia (CED) is an autosomal-recessive disease that is characterized by craniosynostosis and ectodermal and skeletal abnormalities. We sequenced the exomes of two unrelated CED patients and identified compound heterozygous mutations in WDR35 as the cause of the disease in each of the two patients independently, showing that it is possible to find the causative gene by sequencing the exome of a single sporadic patient. With RT-PCR, we demonstrate that a splice-site mutation in exon 2 of WDR35 alters splicing of RNA on the affected allele, introducing a premature stop codon. WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder.
Published: 2010

39. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome.

Author: Hoischen, A., Bon, B.W.M. van, Gilissen, C.F.H.A., Arts, P.J.W., Lier, B. van, Steehouwer, M., Vries, P.F. de, Reuver, R. de, Wieskamp, N.A.W., Mortier, G., Devriendt, K., Amorim, M.Z., Revencu, N., Kidd, A., Barbosa, M., Turner, A., Smith, J., Oley, C., Henderson, A., Hayes, I.M., Thompson, E.M., Brunner, H.G., Vries, L.B.A. de, Veltman, J.A., Hoischen, A., Bon, B.W.M. van, Gilissen, C.F.H.A., Arts, P.J.W., Lier, B. van, Steehouwer, M., Vries, P.F. de, Reuver, R. de, Wieskamp, N.A.W., Mortier, G., Devriendt, K., Amorim, M.Z., Revencu, N., Kidd, A., Barbosa, M., Turner, A., Smith, J., Oley, C., Henderson, A., Hayes, I.M., Thompson, E.M., Brunner, H.G., Vries, L.B.A. de, and Veltman, J.A.
Abstract: 01 juni 2010, Contains fulltext : 88081.pdf (publisher's version ) (Closed access), Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.
Published: 2010

40. A de novo paradigm for mental retardation.

Author: Vissers, L.E.L.M., Ligt, J. de, Gilissen, C.F.H.A., Janssen, I.M., Steehouwer, M., Vries, P.F. de, Lier, B. van, Arts, P.J.W., Wieskamp, N.A.W., Rosario, M. del, Bon, B.W.M. van, Hoischen, A., Vries, L.B.A. de, Brunner, H.G., Veltman, J.A., Vissers, L.E.L.M., Ligt, J. de, Gilissen, C.F.H.A., Janssen, I.M., Steehouwer, M., Vries, P.F. de, Lier, B. van, Arts, P.J.W., Wieskamp, N.A.W., Rosario, M. del, Bon, B.W.M. van, Hoischen, A., Vries, L.B.A. de, Brunner, H.G., and Veltman, J.A.
Abstract: 01 december 2010, Contains fulltext : 89284.pdf (publisher's version ) (Closed access), The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.
Published: 2010

41. Massively parallel sequencing of ataxia genes after array-based enrichment.

Author: Hoischen, A., Gilissen, C.F.H.A., Arts, P.J.W., Wieskamp, N.A.W., Vliet, W. van der, Vermeer, S., Steehouwer, M., Vries, P.F. de, Meijer, R., Seiqueros, J., Knoers, N.V.A.M., Buckley, M.F., Scheffer, H., Veltman, J.A., Hoischen, A., Gilissen, C.F.H.A., Arts, P.J.W., Wieskamp, N.A.W., Vliet, W. van der, Vermeer, S., Steehouwer, M., Vries, P.F. de, Meijer, R., Seiqueros, J., Knoers, N.V.A.M., Buckley, M.F., Scheffer, H., and Veltman, J.A.
Abstract: 01 april 2010, Contains fulltext : 87530.pdf (publisher's version ) (Closed access), Massively parallel sequencing has tremendous diagnostic potential but requires enriched templates for sequencing. Here we report the validation of an array-based sequence capture method in genetically heterogeneous disorders. The model disorder selected was AR ataxia, using five subjects with known mutations and two unaffected controls. The genomic sequences of seven disease genes, together with two control loci were targeted on a 2-Mb sequence-capture array. After enrichment, the patients' DNA samples were analyzed using one-quarter Roche GS FLX Titanium sequencing run, resulting in an average of 65 Mb of sequence data per patient. This was sufficient for an average 25-fold coverage/base in all targeted regions. Enrichment showed high specificity; on average, 80% of uniquely mapped reads were on target. Importantly, this approach enabled automated detection of deletions and hetero- and homozygous point mutations for 6/7 mutant alleles, and greater than 99% accuracy for known SNP variants. Our results also clearly show reduced coverage for sequences in repeat-rich regions, which significantly impacts the reliable detection of genomic variants. Based on these findings we recommend a minimal coverage of 15-fold for diagnostic implementation of this technology. We conclude that massive parallel sequencing of enriched samples enables personalized diagnosis of heterogeneous genetic disorders and qualifies for rapid diagnostic implementation.
Published: 2010

42. Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: a multicenter study.

Author: McMullan, D.J., Bonin, M., Hehir-Kwa, J.Y., Vries, L.B.A. de, Dufke, A., Rattenberry, E., Steehouwer, M., Moruz, L.M., Pfundt, R.P., Leeuw, N. de, Riess, A., Altug-Teber, O., Enders, H., Singer, S., Grasshoff, U., Walter, M., Walker, J.M., Lamb, C.V., Davison, E.V., Brueton, L., Riess, O., Veltman, J.A., McMullan, D.J., Bonin, M., Hehir-Kwa, J.Y., Vries, L.B.A. de, Dufke, A., Rattenberry, E., Steehouwer, M., Moruz, L.M., Pfundt, R.P., Leeuw, N. de, Riess, A., Altug-Teber, O., Enders, H., Singer, S., Grasshoff, U., Walter, M., Walker, J.M., Lamb, C.V., Davison, E.V., Brueton, L., Riess, O., and Veltman, J.A.
Abstract: Contains fulltext : 79652.pdf (publisher's version ) (Closed access), Genomic microarrays have been implemented in the diagnosis of patients with unexplained mental retardation. This method, although revolutionizing cytogenetics, is still limited to the detection of rare de novo copy number variants (CNVs). Genome-wide single nucleotide polymorphism (SNP) microarrays provide high-resolution genotype as well as CNV information in a single experiment. We hypothesize that the widespread use of these microarray platforms can be exploited to greatly improve our understanding of the genetic causes of mental retardation and many other common disorders, while already providing a robust platform for routine diagnostics. Here we report a detailed validation of Affymetrix 500k SNP microarrays for the detection of CNVs associated to mental retardation. After this validation we applied the same platform in a multicenter study to test a total of 120 patients with unexplained mental retardation and their parents. Rare de novo CNVs were identified in 15% of cases, showing the importance of this approach in daily clinical practice. In addition, much more genomic variation was observed in these patients as well as their parents. We provide all of these data for the scientific community to jointly enhance our understanding of these genomic variants and their potential role in this common disorder.
Published: 2009

43. MLL2mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Author: Makrythanasis, P, primary, van Bon, BW, additional, Steehouwer, M, additional, Rodríguez-Santiago, B, additional, Simpson, M, additional, Dias, P, additional, Anderlid, BM, additional, Arts, P, additional, Bhat, M, additional, Augello, B, additional, Biamino, E, additional, Bongers, EMHF, additional, del Campo, M, additional, Cordeiro, I, additional, Cueto-González, AM, additional, Cuscó, I, additional, Deshpande, C, additional, Frysira, E, additional, Izatt, L, additional, Flores, R, additional, Galán, E, additional, Gener, B, additional, Gilissen, C, additional, Granneman, SM, additional, Hoyer, J, additional, Yntema, HG, additional, Kets, CM, additional, Koolen, DA, additional, Marcelis, CL, additional, Medeira, A, additional, Micale, L, additional, Mohammed, S, additional, de Munnik, SA, additional, Nordgren, A, additional, Psoni, S, additional, Reardon, W, additional, Revencu, N, additional, Roscioli, T, additional, Ruiterkamp-Versteeg, M, additional, Santos, HG, additional, Schoumans, J, additional, Schuurs-Hoeijmakers, JHM, additional, Silengo, MC, additional, Toledo, L, additional, Vendrell, T, additional, van der Burgt, I, additional, van Lier, B, additional, Zweier, C, additional, Reymond, A, additional, Trembath, RC, additional, Perez-Jurado, L, additional, Dupont, J, additional, de Vries, BBA, additional, Brunner, HG, additional, Veltman, JA, additional, Merla, G, additional, Antonarakis, SE, additional, and Hoischen, A, additional
Published: 2013
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44. Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related Autosomal Recessive Ectodermal Dysplasia 14

Author: Adam Jackson, Sheng-Jia Lin, Elizabeth A. Jones, Kate E. Chandler, David Orr, Celia Moss, Zahra Haider, Gavin Ryan, Simon Holden, Mike Harrison, Nigel Burrows, Wendy D. Jones, Mary Loveless, Cassidy Petree, Helen Stewart, Karen Low, Deirdre Donnelly, Simon Lovell, Konstantina Drosou, Gaurav K. Varshney, Siddharth Banka, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.A. Brown, M.J. Caulfield, G.C. Chan, A. Giess, J.N. Griffin, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, A. Lakey, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, J. Mitchell, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Olaf Riess, Tobias B. Haack, Holm Graessner, Birte Zurek, Kornelia Ellwanger, Stephan Ossowski, German Demidov, Marc Sturm, Julia M. Schulze-Hentrich, Rebecca Schüle, Christoph Kessler, Melanie Wayand, Matthis Synofzik, Carlo Wilke, Andreas Traschütz, Ludger Schöls, Holger Hengel, Peter Heutink, Han Brunner, Hans Scheffer, Nicoline Hoogerbrugge, Alexander Hoischen, Peter A.C. ’t Hoen, Lisenka E.L.M. Vissers, Christian Gilissen, Wouter Steyaert, Karolis Sablauskas, Richarda M. de Voer, Erik-Jan Kamsteeg, Bart van de Warrenburg, Nienke van Os, Iris te Paske, Erik Janssen, Elke de Boer, Marloes Steehouwer, Burcu Yaldiz, Tjitske Kleefstra, Anthony J. Brookes, Colin Veal, Spencer Gibson, Marc Wadsley, Mehdi Mehtarizadeh, Umar Riaz, Greg Warren, Farid Yavari Dizjikan, Thomas Shorter, Ana Töpf, Volker Straub, Chiara Marini Bettolo, Sabine Specht, Jill Clayton-Smith, Elizabeth Alexander, Laurence Faivre, Christel Thauvin, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Emilie Tisserant, Ange-Line Bruel, Christine Peyron, Aurore Pélissier, Sergi Beltran, Ivo Glynne Gut, Steven Laurie, Davide Piscia, Leslie Matalonga, Anastasios Papakonstantinou, Gemma Bullich, Alberto Corvo, Carles Garcia, Marcos Fernandez-Callejo, Carles Hernández, Daniel Picó, Ida Paramonov, Hanns Lochmüller, Gulcin Gumus, Virginie Bros-Facer, Ana Rath, Marc Hanauer, Annie Olry, David Lagorce, Svitlana Havrylenko, Katia Izem, Fanny Rigour, Giovanni Stevanin, Alexandra Durr, Claire-Sophie Davoine, Léna Guillot-Noel, Anna Heinzmann, Giulia Coarelli, Gisèle Bonne, Teresinha Evangelista, Valérie Allamand, Isabelle Nelson, Rabah Ben Yaou, Corinne Metay, Bruno Eymard, Enzo Cohen, Antonio Atalaia, Tanya Stojkovic, Milan Macek, Marek Turnovec, Dana Thomasová, Radka Pourová Kremliková, Vera Franková, Markéta Havlovicová, Vlastimil Kremlik, Helen Parkinson, Thomas Keane, Dylan Spalding, Alexander Senf, Peter Robinson, Daniel Danis, Glenn Robert, Alessia Costa, Christine Patch, Mike Hanna, Henry Houlden, Mary Reilly, Jana Vandrovcova, Francesco Muntoni, Irina Zaharieva, Anna Sarkozy, Vincent Timmerman, Jonathan Baets, Liedewei Van de Vondel, Danique Beijer, Peter de Jonghe, Vincenzo Nigro, Sandro Banfi, Annalaura Torella, Francesco Musacchia, Giulio Piluso, Alessandra Ferlini, Rita Selvatici, Rachele Rossi, Marcella Neri, Stefan Aretz, Isabel Spier, Anna Katharina Sommer, Sophia Peters, Carla Oliveira, Jose Garcia Pelaez, Ana Rita Matos, Celina São José, Marta Ferreira, Irene Gullo, Susana Fernandes, Luzia Garrido, Pedro Ferreira, Fátima Carneiro, Morris A. Swertz, Lennart Johansson, Joeri K. van der Velde, Gerben van der Vries, Pieter B. Neerincx, Dieuwke Roelofs-Prins, Sebastian Köhler, Alison Metcalfe, Alain Verloes, Séverine Drunat, Caroline Rooryck, Aurelien Trimouille, Raffaele Castello, Manuela Morleo, Michele Pinelli, Alessandra Varavallo, Manuel Posada De la Paz, Eva Bermejo Sánchez, Estrella López Martín, Beatriz Martínez Delgado, F. Javier Alonso García de la Rosa, Andrea Ciolfi, Bruno Dallapiccola, Simone Pizzi, Francesca Clementina Radio, Marco Tartaglia, Alessandra Renieri, Elisa Benetti, Peter Balicza, Maria Judit Molnar, Ales Maver, Borut Peterlin, Alexander Münchau, Katja Lohmann, Rebecca Herzog, Martje Pauly, Alfons Macaya, Anna Marcé-Grau, Andres Nascimiento Osorio, Daniel Natera de Benito, Rachel Thompson, Kiran Polavarapu, David Beeson, Judith Cossins, Pedro M. Rodriguez Cruz, Peter Hackman, Mridul Johari, Marco Savarese, Bjarne Udd, Rita Horvath, Gabriel Capella, Laura Valle, Elke Holinski-Feder, Andreas Laner, Verena Steinke-Lange, Evelin Schröck, Andreas Rump, Jackson, A., Lin, S. -J., Jones, E. A., Chandler, K. E., Orr, D., Moss, C., Haider, Z., Ryan, G., Holden, S., Harrison, M., Burrows, N., Jones, W. D., Loveless, M., Petree, C., Stewart, H., Low, K., Donnelly, D., Lovell, S., Drosou, K., Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Giess, A., Griffin, J. N., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Lakey, A., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., Mcentagart, M., Minneci, F., Mitchell, J., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O'Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Riess, O., Haack, T. B., Graessner, H., Zurek, B., Ellwanger, K., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., 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., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., 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., Faivre, L., Thauvin, C., Vitobello, A., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Matalonga, L., 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., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Nelson, I., Ben Yaou, R., 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., Hanna, M., Houlden, H., Reilly, M., Vandrovcova, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., Van de Vondel, L., Beijer, D., de Jonghe, P., 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., Alonso Garcia de la Rosa, F. J., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Balicza, P., Molnar, M. J., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., Macaya, A., Marce-Grau, A., Osorio, A. N., Natera de Benito, D., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Rodriguez Cruz, P. M., Hackman, P., Johari, M., Savarese, M., Udd, B., Horvath, R., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., Rump, A., and Varshney, G. K.
Subjects: Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Hypodontia, Closca, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Ectodermal dysplasia, TSPEAR, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Conical teeth, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, Enamel knot, Autosomal recessive ectodermal dysplasia type 14, WNT10A, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Extracellular matrix dependant signalling, Molecular Medicine, zebrafish fin regeneration, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Genetics (clinical)
Abstract: Item does not contain fulltext TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara (-/-);tspearb (-/-) double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.
Published: 2023
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45. Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout

Author: Viola Klück, Leo A. B. Joosten, Alexander Hoischen, Charles A. Dinarello, Nicola Dalbeth, Rosanne C. van Deuren, Tony R. Merriman, T.L.Th.A. Jansen, Matthijs Janssen, Amara Shaukat, Christian Gilissen, Lorenzo Dagna, Peer Arts, Marloes Steehouwer, Lisa K. Stamp, Soohyun Kim, Stefan H. Lelieveld, Maartje C. P. Cleophas, Frank L. van de Veerdonk, Philip Riches, Elan Z. Eisenmesser, Tania O Crișan, Jennie Harré Hindmarsh, Mihai G. Netea, Maartje van de Vorst, Giulio Cavalli, Anne-Kathrin Tausche, Kluck, V., Van Deuren, R. C., Cavalli, G., Shaukat, A., Arts, P., Cleophas, M. C., Cri an, T. O., Tausche, A. -K., Riches, P., Dalbeth, N., Stamp, L. K., Hindmarsh, J. H., Jansen, T. L. T. A., Janssen, M., Steehouwer, M., Lelieveld, S., Van De Vorst, M., Gilissen, C., Dagna, L., Van De Veerdonk, F. L., Eisenmesser, E. Z., Kim, S., Merriman, T. R., Hoischen, A., Netea, M. G., Dinarello, C. A., Joosten, L. A. B., Klück, Viola, Van Deuren, Rosanne C, Cavalli, Giulio, Shaukat, Amara, Arts, Peer, and Joosten, Leo AB
Subjects: Male, 0301 basic medicine, Native Hawaiian or Other Pacific Islander, Gout, Neutrophils, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Interleukin-1beta, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Pathogenesis, Mice, chemistry.chemical_compound, 0302 clinical medicine, cytokine, Immunology and Allergy, Aged, 80 and over, treatment, biology, Interleukin, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Middle Aged, Recombinant Proteins, Female, Adult, gene polymorphism, Immunology, In Vitro Techniques, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, gout, Rheumatology, medicine, Animals, Humans, Genetic Predisposition to Disease, Interleukin 6, Genotyping, Aged, 030203 arthritis & rheumatology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Polymorphism, Genetic, Interleukin-6, business.industry, Interleukin-8, Case-control study, medicine.disease, cytokines, Uric Acid, 030104 developmental biology, chemistry, inflammation, Case-Control Studies, Leukocytes, Mononuclear, biology.protein, Uric acid, Gene polymorphism, business, Interleukin-1
Abstract: ObjectiveGout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.MethodsVariant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.ResultsWe identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher’s exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10−5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.ConclusionHere, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.
Published: 2020
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46. Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Author: Matalonga, Leslie, Hernández-Ferrer, Carles, DITF-ITHACA, Solve-RD, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cohen, Enzo, DITF-euroNMD, Solve-RD, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G, Horvath, Rita, Houlden, Henry, Johari, Mridul, Lau, Jarred, Lochmüller, Hanns, DITF-RND, Solve-RD, Macken, William L, Musacchia, Francesco, Nascimento, Andres, Natera-de Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D S, Polavarapu, Kiran, Cruz, Pedro M Rodriguez, Tonda, Raul, Sarkozy, Anna, Savarese, Marco, Selvatici, Rita, Thompson, Rachel, Udd, Bjarne, Van de Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Balicza, Peter, Laurie, Steven, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Fernandez-Callejo, Marcos, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Schüle-Freyer, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, Picó, Daniel, van de Warrenburg, Bart, van Os, Nienke, Wayand, Melanie, Wilke, Carlo, Haack, Tobias B, Graessner, Holm, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Garcia-Linares, Carles, Sturm, Marc, Schulze-Hentrich, Julia M, Kessler, Christoph, Heutink, Peter, Brunner, Han, Scheffer, Hans, Papakonstantinou, Anastasios, Hoogerbrugge, Nicoline, 't Hoen, Peter A C, Steyaert, Wouter, Sablauskas, Karolis, Te Paske, Iris, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Corvó, Alberto, Brookes, Anthony J, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Piscia, Davide, Joshi, Ricky, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Duffourd, Yannis, Tisserant, Emilie, Diez, Hector, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Bullich, Gemma, Gut, Ivo, Corvo, Alberto, Garcia, Carles, Hernández, Carles, Paramonov, Ida, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hoischen, Alexander, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Consortia, Solve-RD, Spalding, Dylan, Senf, Alexander, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, de Jonghe, Peter, Banfi, Sandro, Torella, Annalaura, Cuesta, Isabel, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A, Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B, group, Solve-RD SNV-indel working, Denommé-Pichon, Anne-Sophie, Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F Javier Alonso García, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Gilissen, Christian, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Beeson, David, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Li, Shuang, Prasanth, Sivakumar, Robinson, Peter, van der Velde, Joeri K, de Voer, Richarda M, Evans, Gareth, Sommer, Anna Katharina, Töpf, Ana, Paske, Iris Te, Tischkowitz, Marc, Casari, Giorgio, Ciolfi, Andrea, Dallapiccola, Bruno, de Boer, Elke, Vissers, Lisenka E L M, Hammarsjö, Anna, Havlovicova, Marketa, Hugon, Anne, de Voer, Richarda, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, DITF-GENTURIS, Solve-RD, Posada, Manuel, Ryba, Lukas, Schwarz, Martin, Trimouille, Aurélien, Solve RD SNV Indel Working Grp, Solve RD DITF GENTURIS, Solve RD DITF ITHACA, Solve RD DITF-euroNMD, Solve RD DITF RND, Solve RD Consortia, Matalonga, L., Hernandez-Ferrer, C., Piscia, D., Cohen, E., Cuesta, I., Danis, D., Denomme-Pichon, A. -S., Duffourd, Y., Gilissen, C., Johari, M., Laurie, S., Li, S., Nelson, I., Peters, S., Paramonov, I., Prasanth, S., Robinson, P., Sablauskas, K., Savarese, M., Steyaert, W., van der Velde, J. K., Vitobello, A., Schule, R., Synofzik, M., Topf, A., Vissers, L. E. L. M., de Voer, R., Aretz, S., Capella, G., de Voer, R. M., Evans, G., Pelaez, J. G., Holinski-Feder, E., Hoogerbrugge, N., Laner, A., Oliveira, C., Rump, A., Schrock, E., Sommer, A. K., Steinke-Lange, V., Paske, I., Tischkowitz, M., Valle, L., Banka, S., Benetti, E., Casari, G., Ciolfi, A., Clayton-Smith, J., Dallapiccola, B., de Boer, E., Ellwanger, K., Faivre, L., Graessner, H., Haack, T. B., Hammarsjo, A., Havlovicova, M., Hoischen, A., Hugon, A., Jackson, A., Kleefstra, T., Lindstrand, A., Lopez-Martin, E., Macek, M., Morleo, M., Nigro, V., Nordgren, A., Pettersson, M., Pinelli, M., Pizzi, S., Posada, M., Radio, F. C., Renieri, A., Rooryck, C., Ryba, L., Schwarz, M., Tartaglia, M., Thauvin, C., Torella, A., Trimouille, A., Verloes, A., Vissers, L., Votypka, P., Vyshka, K., Zurek, B., Baets, J., Beijer, D., Bonne, G., Cossins, J., Evangelista, T., Ferlini, A., Hackman, P., Hanna, M. G., Horvath, R., Houlden, H., Lau, J., Lochmuller, H., Macken, W. L., Musacchia, F., Nascimento, A., Natera-de Benito, D., Piluso, G., Pini, V., Pitceathly, R. D. S., Polavarapu, K., Cruz, P. M. R., Sarkozy, A., Selvatici, R., Thompson, R., Udd, B., Van de Vondel, L., Vandrovcova, J., Zaharieva, I., Balicza, P., Chinnery, P., Durr, A., Haack, T., Hengel, 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., Schule-Freyer, R., Stevanin, G., Timmerman, V., van de Warrenburg, B., van Os, N., Wayand, M., Wilke, C., Tonda, R., Fernandez-Callejo, M., Pico, D., Garcia-Linares, C., Papakonstantinou, A., Corvo, A., Joshi, R., Diez, H., Gut, I., Beltran, S., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Kessler, C., Heutink, P., Brunner, H., Scheffer, H., 't Hoen, P. A. C., te Paske, I., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Alexander, E., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Bullich, G., Garcia, C., Hernandez, C., 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., Allamand, V., Yaou, R. B., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Kremlik, V., Parkinson, H., Keane, T., Spalding, D., Senf, A., Robert, G., Costa, A., Patch, C., Hanna, M., Reilly, M., Muntoni, F., de Jonghe, P., Banfi, S., Rossi, R., Neri, M., Spier, I., 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., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Castello, R., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Molnar, M. J., Herzog, R., Pauly, M., Osorio, A. N., de Benito, D. N., Beeson, D., Unión Europea. Comisión Europea. H2020, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Government of Catalonia (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto Nacional de Bioinformatica (España), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Instituto de Salud Carlos III [Madrid] (ISC), Radboud University Medical Center [Nijmegen], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Barcelona Institute of Science and Technology (BIST), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Genetic testing, Computer science, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], EXOME, MEDICAL GENETICS, Diseases, Disease, VARIANTS, Genome informatics, Genomic analysis, Diseases, Genetic testing, Genome informatics, Genomic analysis, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Genetics (clinical), Exome sequencing, 0303 health sciences, Application programming interface, methods [Genomics], 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Pedigree, diagnosis [Rare Diseases], Chemistry, Medical genetics, medicine.medical_specialty, methods [Genetic Testing], MEDLINE, Socio-culturale, Phenome, AMERICAN-COLLEGE, INHERITANCE, Sensitivity and Specificity, Article, standards [Genetic Testing], 03 medical and health sciences, Rare Diseases, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetics, medicine, Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Data science, Workflow, 3111 Biomedicine, standards [Genomics], Human medicine, Software
Abstract: Correction to: Solving patients with rare diseases through programmatic reanalysis of genome-phenome data. Eur J Hum Genet. 2021 Sep;29(9):1466-1469. doi: 10.1038/s41431-021-00934-6. PMID: 34393220 Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya. We also acknowledge the support of the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. Sí
Published: 2021
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47. Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

Author: Zurek, Birte, Ellwanger, Kornelia, Vissers, Lisenka E. L. M., Schüle, Rebecca, Synofzik, Matthis, Töpf, Ana, de Voer, Richarda M., Laurie, Steven, Matalonga, Leslie, Gilissen, Christian, Ossowski, Stephan, ’t Hoen, Peter A. C., Vitobello, Antonio, Schulze-Hentrich, Julia M., Riess, Olaf, Brunner, Han G., Brookes, Anthony J., Rath, Ana, Bonne, Gisèle, Gumus, Gulcin, Verloes, Alain, Hoogerbrugge, Nicoline, Evangelista, Teresinha, Harmuth, Tina, Swertz, Morris, Spalding, Dylan, Hoischen, Alexander, Beltran, Sergi, Graessner, Holm, Haack, Tobias B., Demidov, German, Sturm, Marc, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, Brunner, Han, Scheffer, Hans, Steyaert, Wouter, Sablauskas, Karolis, Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Bros-Facer, Virginie, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, Van de Vondel, Liedewei, Beijer, Danique, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Marcé-Grau, Anna, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), Zurek, Birte [0000-0002-8200-7542], Ellwanger, Kornelia [0000-0003-4845-5795], Vissers, Lisenka ELM [0000-0001-6470-5497], Synofzik, Matthis [0000-0002-2280-7273], de Voer, Richarda M [0000-0002-8222-0343], Laurie, Steven [0000-0003-3913-5829], Gilissen, Christian [0000-0003-1693-9699], 't Hoen, Peter AC [0000-0003-4450-3112], Vitobello, Antonio [0000-0003-3717-8374], Brookes, Anthony J [0000-0001-8686-0017], Rath, Ana [0000-0003-4308-6337], Bonne, Gisèle [0000-0002-2516-3258], Verloes, Alain [0000-0003-4819-0264], Hoogerbrugge, Nicoline [0000-0003-2393-8141], Harmuth, Tina [0000-0002-4833-8057], Spalding, Dylan [0000-0002-4285-2493], Beltran, Sergi [0000-0002-2810-3445], Graessner, Holm [0000-0001-9803-7183], Apollo - University of Cambridge Repository, Zurek, B., Ellwanger, K., Vissers, L. E. L. M., Schule, R., Synofzik, M., Topf, A., de Voer, R. M., Laurie, S., Matalonga, L., Gilissen, C., Ossowski, S., 't Hoen, P. A. C., Vitobello, A., Schulze-Hentrich, J. M., Riess, O., Brunner, H. G., Brookes, A. J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Beltran, S., Graessner, H., Nigro, V., Banfi, S., Torella, A., Piluso, G., Dürr, Alexandra, Lohmann, Katja, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschuetz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, University of Tübingen, Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Leicester, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), EURORDIS-Rare Diseases Europe (Bureau de Paris), EURORDIS - Plateforme Maladies Rares [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center Groningen [Groningen] (UMCG), European Molecular Biology Laboratory [Hinxton], Universitat de Barcelona (UB), SOLVE-RD Consortium, Projekt DEAL, Unión Europea. Comisión Europea. H2020, European Reference Network for Rare Neurological Diseases (ERN-RND), Haack, T. B., Demidov, G., Sturm, M., Kessler, C., Wayand, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Heutink, P., Brunner, H., Scheffer, H., Steyaert, W., Sablauskas, K., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., te Paske, I., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Bros-Facer, V., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Vandrovcova, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., Van de Vondel, L., Beijer, D., de Jonghe, P., Musacchia, F., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Balicza, P., Molnar, M. J., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., Macaya, A., Marce-Grau, A., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Horvath, R., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., Rump, A., Gestionnaire, HAL Sorbonne Université 5, Centre de Recherche en Myologie, Medicum, University of Helsinki, and Department of Medical and Clinical Genetics
Subjects: Computer science, Consensus Development Conferences as Topic, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Diseases, Pan european, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Intersectoral Collaboration, Genetics (clinical), Exome sequencing, 0303 health sciences, 030305 genetics & heredity, Medical genetics, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, diagnosis [Rare Diseases], Europe, GENOME, Chemistry, New disease, Patient representatives, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], methods [Genetic Testing], MEDLINE, Socio-culturale, 03 medical and health sciences, Viewpoint, Rare Diseases, Exome Sequencing, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, genetics [Genetic Diseases, Inborn], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Information Dissemination, Genetic Diseases, Inborn, Correction, Data science, diagnosis [Genetic Diseases, Inborn], Data sharing, methods [Exome Sequencing], 3111 Biomedicine, Human medicine, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Rare disease
Abstract: For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. This research is supported (not financially) by four ERNs: (1) The ERN for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA)-Project ID No 869189; (2) The ERN on Rare Neurological Diseases (ERN-RND)-Project ID No 739510; (3) The ERN for Neuromuscular Diseases (ERN Euro-NMD)-Project ID No 870177; (4) The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS)-Project ID No 739547. The ERNs are co-funded by the European Union within the framework of the Third Health Programme. Open Access funding enabled and organized by Projekt DEAL. Sí
Published: 2021
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48. Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

Author: Vinod Kumar, Mihai G. Netea, Maartje van de Vorst, Charles A. Dinarello, Frank L. van de Veerdonk, Christian Gilissen, Martin Jaeger, Marloes Steehouwer, Musa M. Mhlanga, Rosanne C. van Deuren, Peer Arts, Leo A. B. Joosten, Alexander Hoischen, Giulio Cavalli, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), van Deuren, R. C., Arts, P., Cavalli, Giulio., Jaeger, M., Steehouwer, M., van de Vorst, M., Gilissen, C., Joosten, L. A. B., Dinarello, C. A., Mhlanga, M. M., Kumar, V., Netea, M. G., van de Veerdonk, F. L., Hoischen, A., van Deuren, Rosanne C, Arts, Peer, Cavalli, Giulio, Jaeger, Martin, Steehouwer, Marloes, van de Vorst, Maartje, Gilissen, Christian, Joosten, Leo AB, Dinarello, Charles A, Mhlanga, Musa M, Kumar, Vinod, Netea, Mihai G, van de Veerdonk, Frank L, and Hoischen, Alexander
Subjects: BLOCKADE, medicine.medical_treatment, Interleukin-1beta, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], QH426-470, SUSCEPTIBILITY, Molecular Inversion Probe, DISEASE, 0302 clinical medicine, Genetics (clinical), Genetics, 0303 health sciences, IMMUNE-RESPONSES, Systems Biology, High-Throughput Nucleotide Sequencing, Interleukin, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Phenotype, Healthy Volunteers, Corpus albicans, FAMILY, Cytokine, 030220 oncology & carcinogenesis, MOLECULAR INVERSION PROBES, Medicine, Cytokines, Interleukin-1 pathway, Molecular Medicine, AUTOPHAGY, Disease Susceptibility, Systems biology, Functional genomics, Signal Transduction, Biology, Immunophenotyping, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Immune system, Region-based analysis, INFLAMMATION, Genetic variation, medicine, Humans, Molecular Biology, Gene, 030304 developmental biology, Inflammation, RECEPTOR, Research, Gene Expression Profiling, Common variants, Genetic Variation, Rare variants, Cell Biology, SKAT, Immunity, Innate, In vitro, Human genetics, Gene Expression Regulation, Immunological mechanisms, VARIANT ASSOCIATION, Biomarkers, 030217 neurology & neurosurgery, Interleukin-1
Abstract: BackgroundInterleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in related genes have been linked to various inflammation-mediated diseases and stimulation-induced cytokine responses, but the role of rare variants remains to be elucidated.MethodsIn this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. Using a systems biology approach, we examined the inter-individual variability of in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test.ResultsWe identified strong associations for rare genetic variants in NCF4 (adjP=7.2E−05) and CASP1 (adjP=3.0E−05) with IL-6 production in response to PHA and LPS stimulation, respectively. In addition, common variants in IL36A and IL38 were associated to both C. albicans-induced IL-1β (IL36AadjP=0.0442; IL38adjP=0.0092) and IL-6 production (IL36AadjP=0.0037; IL38adjP=0.0082), an effect that was stronger at the subpathway level both for IL-1β (adjP=0.0017) and IL-6 (adjP=1.8E−04). The common variant signature for the IL-1β and IL-6 response to C. albicans was confirmed by an association with all anti-inflammatory genes (adjP=1.87E−03 and adjP=5.75E−04), and we validated this finding for non-coding common variants. Lastly, we identified a burden of rare variants in pro-inflammatory genes and LPS-induced IL-6 production (adjP=2.42E−04), and a new role for anti-inflammatory rare variants on S. aureus-stimulated IL-6 production (adjP=6.71E−03).ConclusionsIn conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore accentuates potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.
Published: 2021

49. Systematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation.

Author: Steyaert W, Haer-Wigman L, Pfundt R, Hellebrekers D, Steehouwer M, Hampstead J, de Boer E, Stegmann A, Yntema H, Kamsteeg EJ, Brunner H, Hoischen A, and Gilissen C
Subjects: Humans, INDEL Mutation, DNA Copy Number Variations, Systems Analysis, High-Throughput Nucleotide Sequencing methods, Exome genetics, Polymorphism, Single Nucleotide
Abstract: The short lengths of short-read sequencing reads challenge the analysis of paralogous genomic regions in exome and genome sequencing data. Most genetic variants within these homologous regions therefore remain unidentified in standard analyses. Here, we present a method (Chameleolyser) that accurately identifies single nucleotide variants and small insertions/deletions (SNVs/Indels), copy number variants and ectopic gene conversion events in duplicated genomic regions using whole-exome sequencing data. Application to a cohort of 41,755 exome samples yields 20,432 rare homozygous deletions and 2,529,791 rare SNVs/Indels, of which we show that 338,084 are due to gene conversion events. None of the SNVs/Indels are detectable using regular analysis techniques. Validation by high-fidelity long-read sequencing in 20 samples confirms >88% of called variants. Focusing on variation in known disease genes leads to a direct molecular diagnosis in 25 previously undiagnosed patients. Our method can readily be applied to existing exome data., (© 2023. The Author(s).)
Published: 2023
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50. Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity.

Author: Andersson-Assarsson JC, van Deuren RC, Kristensson FM, Steehouwer M, Sjöholm K, Svensson PA, Pieterse M, Gilissen C, Taube M, Jacobson P, Perkins R, Brunner HG, Netea MG, Peltonen M, Carlsson B, Hoischen A, and Carlsson LMS
Subjects: Humans, Young Adult, Adult, Clonal Hematopoiesis genetics, Obesity genetics, Obesity complications, Mutation, Bariatric Surgery adverse effects, Cardiovascular Diseases etiology, Cardiovascular Diseases genetics
Abstract: Background: Haematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years., Methods: Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n = 40) of the individuals treated by usual care., Findings: In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P = 0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range -4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R = -0.68, 1.74 E -04 )., Interpretation: Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care., Funding: The Swedish Research Council, The Swedish state under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, The Swedish Heart-Lung Foundation, The Novo Nordisk Foundation, The European Research Council, The Netherlands Organisation for Scientific Research., Competing Interests: Declaration of interests Dr F.M. Kristensson is supported by a grant from the Swedish State under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, grant ALFGBG-970993 and has received a travel grant from the Gothenburg Society of Medicine. Ms. M. Steehouwer, Dr C Gilissen, Dr H.G. Brunner, and Dr A. Hoischen are supported by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 779257. Dr C. Gilissen is a member of the board of the European Society of Human Genetics (ESHG) and a member of the scientific programme committee of ESHG. Dr H.G. Brunner is a co-coordinator of the Solve-RD project. Dr M.G. Netea is a scientific founder of and owns stock in Trained Therapeuticx Discovery, has received an unrestricted grant from ViiV HealthCare, and a Spinoza Grant from The Netherlands Organisation for Scientific Research. Dr B. Carlsson is employed by and owns stock in AstraZeneca. Dr L.M.S. Carlsson has received consulting fees from Johnson & Johnson. All other authors declare they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2023
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