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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. Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma

Author

Cuperus, E., Bygum, A., Boeckmann, L., Bodemer, C., Bolling, M. C., Caproni, M., Diociaiuti, A., Emmert, S., Fischer, J., Gostynski, A., Guez, S., van Gijn, M. E., Hannula-Jouppi, K., Has, C., Hernandez-Martin, A., Martinez, A. E., Mazereeuw-Hautier, J., Medvecz, M., Neri, I., Sigurdsson, V., Suessmuth, K., Traupe, H., Oji, V., Pasmans, S. G. M. A., Department of Dermatology, Allergology and Venereology, and HUS Inflammation Center

Subjects
GAUCHER-DISEASE, ICHTHYOSIFORM ERYTHRODERMA, NETHERTON-SYNDROME, 3121 General medicine, internal medicine and other clinical medicine, VERSUS-HOST-DISEASE, OMENN SYNDROME, AEC SYNDROME, PRIMARY IMMUNODEFICIENCY DISORDERS, CHANARIN-DORFMAN SYNDROME, HAIR SAMPLES, COLLODION BABY
Abstract

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis.

Published
2022

4. Curation and expansion of human phenotype ontology for defined groups of inborn errors of immunity

Author

Haimel, M., Pazmandi, J., Jiménez Heredia, R., Dmytrus, J., Köstel Bal, S., Zoghi, S., van Daele, P., Briggs, T. A., Wouters, C., Bader-Meunier, B., Aeschlimann, F. A., Caorsi, R., Eleftheriou , D., Hoppenreijs, E., Salzer, E., Bakhtiar, S., Derfalvi, B., Saettini , F., Kusters, M. A. A., Elfeky, R., Trück, J., Rivière, J. G., van der Burg, M., Gattorno, M., Seidel, M. G., Burns, S., Warnatz, K., Hauck, F., Brogan, P., Gilmour, K. C., Schuetz, C., Simon, A., Bock, C., Hambleton, S., de Vries, E., Robinson, P. N., van Gijn, M., Boztug, K., Haimel, M., Pazmandi, J., Jiménez Heredia, R., Dmytrus, J., Köstel Bal, S., Zoghi, S., van Daele, P., Briggs, T. A., Wouters, C., Bader-Meunier, B., Aeschlimann, F. A., Caorsi, R., Eleftheriou , D., Hoppenreijs, E., Salzer, E., Bakhtiar, S., Derfalvi, B., Saettini , F., Kusters, M. A. A., Elfeky, R., Trück, J., Rivière, J. G., van der Burg, M., Gattorno, M., Seidel, M. G., Burns, S., Warnatz, K., Hauck, F., Brogan, P., Gilmour, K. C., Schuetz, C., Simon, A., Bock, C., Hambleton, S., de Vries, E., Robinson, P. N., van Gijn, M., and Boztug, K.

Abstract

Background Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. Objectives We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. Methods We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. Results We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies–defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. Conclusions Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.

Published
2022

5. Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma

Author

MS Dermatologie/Allergologie, Other research (not in main researchprogram), Cuperus, E., Bygum, A., Boeckmann, L., Bodemer, C., Bolling, M. C., Caproni, M., Diociaiuti, A., Emmert, S., Fischer, J., Gostynski, A., Guez, S., van Gijn, M. E., Hannulla-Jouppi, K., Has, C., Hernández-Martín, A., Martinez, A. E., Mazereeuw-Hautier, J., Medvecz, M., Neri, I., Sigurdsson, V., Suessmuth, K., Traupe, H., Oji, V., Pasmans, S. G.M.A., MS Dermatologie/Allergologie, Other research (not in main researchprogram), Cuperus, E., Bygum, A., Boeckmann, L., Bodemer, C., Bolling, M. C., Caproni, M., Diociaiuti, A., Emmert, S., Fischer, J., Gostynski, A., Guez, S., van Gijn, M. E., Hannulla-Jouppi, K., Has, C., Hernández-Martín, A., Martinez, A. E., Mazereeuw-Hautier, J., Medvecz, M., Neri, I., Sigurdsson, V., Suessmuth, K., Traupe, H., Oji, V., and Pasmans, S. G.M.A.

Published
2022

6. Collodion babies: a 15-year retrospective multicenter study in the Netherlands. Evaluation of severity scores to predict the underlying disease

Author

MS Dermatologie/Allergologie, Infection & Immunity, Genetica Klinische Genetica, Other research (not in main researchprogram), Cuperus, E, Bolling, M C, de Graaf, M, van den Akker, P C, van Gijn, M E, Simon, M E H, Sigurdsson, V, Pasmans, S G M A, MS Dermatologie/Allergologie, Infection & Immunity, Genetica Klinische Genetica, Other research (not in main researchprogram), Cuperus, E, Bolling, M C, de Graaf, M, van den Akker, P C, van Gijn, M E, Simon, M E H, Sigurdsson, V, and Pasmans, S G M A

Published
2021

10. A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease

Author

Smits, B. M., Lelieveld, P. H.C., Ververs, F. A., Turkenburg, M., de Koning, C., van Dijk, M., Leavis, H. L., Boelens, J. J., Lindemans, C. A., Bloem, A. C., van de Corput, L., van Montfrans, J., Nierkens, S., van Gijn, M. E., Geerke, D. P., Waterham, H. R., Koenderman, L., Boes, M., Smits, B. M., Lelieveld, P. H.C., Ververs, F. A., Turkenburg, M., de Koning, C., van Dijk, M., Leavis, H. L., Boelens, J. J., Lindemans, C. A., Bloem, A. C., van de Corput, L., van Montfrans, J., Nierkens, S., van Gijn, M. E., Geerke, D. P., Waterham, H. R., Koenderman, L., and Boes, M.

Published
2020
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11. A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease

Author

Infection & Immunity, Immuno/reuma onderzoek 1 (Vastert), Immuno/reuma onderzoek 7 (Montfrans), CTI Boes, CTI Nierkens, Cancer, CTI UDAIR, MS Reumatologie/Immunologie/Infectie, SCT patientenzorg, Regenerative Medicine and Stem Cells, Child Health, CDL Patiëntenzorg MI, Immuno/reuma patientenzorg, CTI Research, Genetica Sectie Genoomdiagnostiek, Experimentele Afdeling Longziekten, Immuno/reuma onderzoek 2 (Boes), Onderzoek, Smits, B. M., Lelieveld, P. H.C., Ververs, F. A., Turkenburg, M., de Koning, C., van Dijk, M., Leavis, H. L., Boelens, J. J., Lindemans, C. A., Bloem, A. C., van de Corput, L., van Montfrans, J., Nierkens, S., van Gijn, M. E., Geerke, D. P., Waterham, H. R., Koenderman, L., Boes, M., Infection & Immunity, Immuno/reuma onderzoek 1 (Vastert), Immuno/reuma onderzoek 7 (Montfrans), CTI Boes, CTI Nierkens, Cancer, CTI UDAIR, MS Reumatologie/Immunologie/Infectie, SCT patientenzorg, Regenerative Medicine and Stem Cells, Child Health, CDL Patiëntenzorg MI, Immuno/reuma patientenzorg, CTI Research, Genetica Sectie Genoomdiagnostiek, Experimentele Afdeling Longziekten, Immuno/reuma onderzoek 2 (Boes), Onderzoek, Smits, B. M., Lelieveld, P. H.C., Ververs, F. A., Turkenburg, M., de Koning, C., van Dijk, M., Leavis, H. L., Boelens, J. J., Lindemans, C. A., Bloem, A. C., van de Corput, L., van Montfrans, J., Nierkens, S., van Gijn, M. E., Geerke, D. P., Waterham, H. R., Koenderman, L., and Boes, M.

Published
2020

13. Guidelines for the genetic diagnosis of hereditary recurrent fevers

Author

Shinar, Y, Obici, L, Aksentijevich, I, Bennetts, B, Austrup, F, Ceccherini, I, Costa, J M, De Leener, A, Gattorno, M, Kania, U, Kone-Paut, I, Lezer, S, Livneh, A, Moix, I, Nishikomori, R, Ozen, S, Phylactou, L, Risom, L, Rowczenio, D, Sarkisian, T, van Gijn, M E, Witsch-Baumgartner, M, Morris, M, Hoffman, H M, and Touitou, I

Published
2012
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18. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype

Author

Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., van Gijn, M. E., Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., and van Gijn, M. E.

Published
2017

19. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype

Author

Genetica Klinische Genetica, Child Health, Genetica Groep Koeleman, Translationele immunologie, Infection & Immunity, Immuno/reuma onderzoek 2 (Boes), CTI Boes, Arts-assistenten Kinderen, Genetica Sectie Genoomdiagnostiek, Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., van Gijn, M. E., Genetica Klinische Genetica, Child Health, Genetica Groep Koeleman, Translationele immunologie, Infection & Immunity, Immuno/reuma onderzoek 2 (Boes), CTI Boes, Arts-assistenten Kinderen, Genetica Sectie Genoomdiagnostiek, Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., and van Gijn, M. E.

Published
2017

20. Neonatale erythrodermie en collodionbaby

Author

Cuperus, E., Van Montfrans, J. M., Van Hasselt, P. M., Van Der Smagt, J. J., Sigurdsson, V., Van Dijk, M. R., Van Gijn, M. E., and Pasmans, S. G M A

Subjects
Infectious Diseases, Critical Care and Intensive Care Medicine
Abstract

Erythroderma in the newborn is rare and can be fatal. Ichthyosis, immunodeficiencies, infections and metabolic disorders are among the most common causes. An overview will be given of the most common causes of congenital (present at birth) and neonatal (developed within 4 weeks postpartum) erythroderma, including the collodion baby. Especially an immunodeficiency or metabolic disorder can be missed, as signs as lymphadenopathy, fever and 'failure to thrive' are absent. An erythrodermic newborn does not have to appear ill. It takes up to 11 months until a definitive diagnosis is made. To prevent complications and death,early and specific are needed. Unfortunately, history, physical examination and histological investigations are not always diagnostic and immunological and genetic research is needed. We have made a national protocol on how to approach the erythrodermic newborn. This is to be found using the following website: www.huidhuis.nl/afdeling/neonataleerythrodermie. The protocol is being tested in a prospective study at moment at the Erasmus MC. Doctors who are confronted by an erythrodermic neonate, are advised to follow this protocol.

Published
2015

23. Targeted NGS based hereditary autoinflammatory disorder screening in routine diagnostics, two year experience in the Netherlands

Author

Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Genoom 2, Brain, Arts-assistenten Kinderen, Reumatologie patientenzorg, Infection & Immunity, Elferink, M. G., van Zon, P., Frenkel, J., Harts, W., Simon, A., van Royen-Kerkhof, A., Swart, J., van Amstel, H. K Ploos, van Gijn, M., Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Genoom 2, Brain, Arts-assistenten Kinderen, Reumatologie patientenzorg, Infection & Immunity, Elferink, M. G., van Zon, P., Frenkel, J., Harts, W., Simon, A., van Royen-Kerkhof, A., Swart, J., van Amstel, H. K Ploos, and van Gijn, M.

Published
2015

24. Neonatale erythrodermie en collodionbaby

Author

Genetica Klinische Genetica, Circulatory Health, OK WKZ Bureau, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Metabole ziekten patientenzorg, UMC Utrecht, Afdeling Dermatologie/Allergologie, MS Dermatologie/Allergologie, Other research (not in main researchprogram), Project Ondersteuning, Genetica Sectie Genoomdiagnostiek, Cuperus, E., Van Montfrans, J. M., Van Hasselt, P. M., Van Der Smagt, J. J., Sigurdsson, V., Van Dijk, M. R., Van Gijn, M. E., Pasmans, S. G M A, Genetica Klinische Genetica, Circulatory Health, OK WKZ Bureau, Immuno/reuma patientenzorg, Infection & Immunity, Child Health, Metabole ziekten patientenzorg, UMC Utrecht, Afdeling Dermatologie/Allergologie, MS Dermatologie/Allergologie, Other research (not in main researchprogram), Project Ondersteuning, Genetica Sectie Genoomdiagnostiek, Cuperus, E., Van Montfrans, J. M., Van Hasselt, P. M., Van Der Smagt, J. J., Sigurdsson, V., Van Dijk, M. R., Van Gijn, M. E., and Pasmans, S. G M A

Published
2015

25. Mutation screening of the IL-1 receptor antagonist gene in chronic non-bacterial osteomyelitis of childhood and adolescence

Author

Beck, C., Girschick, H. J., Morbach, H., Schwarz, T., Yimam, T., Frenkel, J., van Gijn, M. E., and University of Groningen

Subjects
chronic non-bacterial osteomyelitis, DIAGNOSTIC-VALUE, AUTOINFLAMMATORY DISEASE, interleukin-1 receptor antagonist, CHILDREN, ASSOCIATION, RECURRENT MULTIFOCAL OSTEOMYELITIS, CROHNS-DISEASE, DIRA
Abstract

Objective Chronic non-bacterial osteomyelitis CNO is an inflammatory disorder of the musculoskeletal system with unknown etiology. In addition to bone inflammation, patients may present with inflammatory involvement of other tissues including, e.g.,skin. Recently, a novel syndrome due to deficiency of interleukin-1 receptor antagonist (IL1RN), DIRA has been identified. Clinically the syndrome is characterized by neonatal onset of pustular dermatosis, periostitis and chronic sterile multifocal osteomyelitis, strongly resembling CNO. Homozygous mutations of IL1RN have been identified and resulted in a truncated protein that is not secreted, hence leaving the action of interleukin-1 unopposed. Methods Because of similar clinical, radiological and histological features of CNO and DIRA, we hypothesized that both disorders might share a common autoinflammatory process. Thus, we searched for the presence of mutations in the interleukin-1 receptor antagonist gene in 60 patients diagnosed with CNO. Results In one patient with chronic multifocal osteomyelitis a heterozygous missense variant: c.281G>T (p.Cys94Phe) was detected. In the other patients only frequent polymorphisms were found. Conclusion Our findings were not able to confirm mutations in IL1RN being an important contributing factor to the pathogenesis of CNO.

Published
2011

29. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations

Author

Van Montfrans, J, primary, Hartman, E, additional, Braun, K, additional, Hennekam, F, additional, Hak, A, additional, Nederkoorn, P, additional, Westendorp, W, additional, Bredius, R, additional, Kollen, W, additional, Scholvinck, E, additional, Legger, G, additional, Meyts, I, additional, Liston, A, additional, Lichtenbelt, K, additional, Giltay, J, additional, Van Haaften, G, additional, De Vries Simons, G, additional, Leavis, H, additional, Nierkens, S, additional, Sanders, C, additional, and Van Gijn, M, additional

Published
2015
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31. OR7-002 – Pyrin 577 mutations in dominant autoinflammation

Author

Stoffels, M, primary, Szperl, A, additional, Simon, A, additional, Netea, MG, additional, Plantinga, TS, additional, van Deuren, M, additional, Kamphuis, S, additional, Lachmann, H, additional, Cuppen, E, additional, Kloosterman, WP, additional, Frenkel, J, additional, van Diemen, CC, additional, Wijmenga, C, additional, van Gijn, M, additional, and van der Meer, JW, additional

Published
2013
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37. Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report.

Author

Korppi, M., van Gijn, M. E., and Antila, K.

Subjects
*EXANTHEMA, *IMMUNOGLOBULIN D, *SUMMER diseases, *LEUCOCYTES, *ABDOMINAL pain
Abstract

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3-7 days and recurring every 4-6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C-reactive protein are elevated during the episode, and in addition, high levels of interleukine-1 (IL-1), IL-6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF-alpha inhibitor, and three children with anakinra, IL-1 receptor antagonist. This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5-year-old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented. [ABSTRACT FROM AUTHOR]

Published
2011
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40. Two pathogenic CIAS1 mutations and plasma cytokine profile in a Finnish patient with familial cold autoinflammatory syndrome responsive to anakinra.

Author

Kaipiainen‐Seppänen, O., Punnonen, K., van Gijn, M. E., and Mononen, T.

Subjects
LETTERS to the editor, INFLAMMATION
Abstract

A letter to the editor is presented concerning CIAS1 mutations and plasma cytokine profile in a patient with familial cold autoinflammatory syndrome responsive to anakinra theraphy.

Published
2008
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41. A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

Author

van Riel Els, Ausems Margreet GEM, Hogervorst Frans BL, Kluijt Irma, van Gijn Marielle E, van Echtelt Jeanne, Scheidel-Jacobse Karen, Hennekam Eric FAM, Stulp Rein P, Vos Yvonne J, Offerhaus G Johan A, Menko Fred H, and Gille Johan JP

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Abstract

Abstract Background An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. Methods We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. Results The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. Conclusions We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.

Published
2010
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42. Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases

Author

Joost Frenkel, Valda Stanevica, Michael Hofer, Francesco Licciardi, Antonella Insalaco, Rolando Cimaz, Riccardo Papa, Alma Nunzia Olivieri, Nienke M. ter Haar, Nicolino Ruperto, Susan Nielsen, Paul A. Brogan, Consuelo Modesto, Nicolae Iagaru, Marco Gattorno, Sarka Fingerhutova, Charlotte Eijkelboom, Antonio Vitale, Marielle E. van Gijn, Luca Cantarini, Marija Jelušić, Yosef Uziel, Gordana Susic, Efimia Papadopoulou-Alataki, Isabelle Koné-Paut, Irina Nikishina, Ter Haar, Nm, Eijkelboom, C, Cantarini, L, Papa, R, Brogan, Pa, Kone-Paut, I, Modesto, C, Hofer, M, Iagaru, N, Fingerhutová, S, Insalaco, A, Licciardi, F, Uziel, Y, Jelusic, M, Nikishina, I, Nielsen, S, Papadopoulou-Alataki, E, Olivieri, An, Cimaz, R, Susic, G, Stanevica, V, van Gijn, M, Vitale, A, Ruperto, N, Frenkel, J, and Gattorno, M

Subjects
Male, myalgia, Abdominal pain, Biochemistry, 0302 clinical medicine, eurofever, Adrenal Cortex Hormones, autoinflammatory diseases, inflammation, recurrent fever, Immunology and Allergy, Registries, Age of Onset, Child, 0303 health sciences, Pedigree, 3. Good health, Europe, Child, Preschool, Antirheumatic Agents, Adolescent, Adult, Chronic Disease, Colchicine, Female, Genetic Variation, Hereditary Autoinflammatory Diseases, Humans, Interleukin 1 Receptor Antagonist Protein, Retrospective Studies, Young Adult, medicine.symptom, medicine.drug, medicine.medical_specialty, Immunology, Mucocutaneous zone, General Biochemistry, Genetics and Molecular Biology, Malaise, 03 medical and health sciences, Pericarditis, Rheumatology, Internal medicine, Journal Article, medicine, Recurrent disease, Preschool, 030304 developmental biology, 030203 arthritis & rheumatology, Anakinra, Biochemistry, Genetics and Molecular Biology(all), business.industry, medicine.disease, business, Genetics and Molecular Biology(all)
Abstract

ObjectivesTo describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).MethodsClinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.ResultsThis study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).ConclusionThis study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.

Published
2019

43. AI-Inclusivity in Healthcare: Motivating an Institutional Epistemic Trust Perspective.

Author

Maheshwari K, Jedan C, Christiaans I, van Gijn M, Maeckelberghe E, and Plantinga M

Abstract

This paper motivates institutional epistemic trust as an important ethical consideration informing the responsible development and implementation of artificial intelligence (AI) technologies (or AI-inclusivity) in healthcare. Drawing on recent literature on epistemic trust and public trust in science, we start by examining the conditions under which we can have institutional epistemic trust in AI-inclusive healthcare systems and their members as providers of medical information and advice. In particular, we discuss that institutional epistemic trust in AI-inclusive healthcare depends, in part, on the reliability of AI-inclusive medical practices and programs, its knowledge and understanding among different stakeholders involved, its effect on epistemic and communicative duties and burdens on medical professionals and, finally, its interaction and alignment with the public's ethical values and interests as well as background sociopolitical conditions against which AI-inclusive healthcare systems are embedded. To assess the applicability of these conditions, we explore a recent proposal for AI-inclusivity within the Dutch Newborn Screening Program. In doing so, we illustrate the importance, scope, and potential challenges of fostering and maintaining institutional epistemic trust in a context where generating, assessing, and providing reliable and timely screening results for genetic risk is of high priority. Finally, to motivate the general relevance of our discussion and case study, we end with suggestions for strategies, interventions, and measures for AI-inclusivity in healthcare more widely.

Published
2024
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44. Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.

Author

Maassen W, Legger G, Kul Cinar O, van Daele P, Gattorno M, Bader-Meunier B, Wouters C, Briggs T, Johansson L, van der Velde J, Swertz M, Omoyinmi E, Hoppenreijs E, Belot A, Eleftheriou D, Caorsi R, Aeschlimann F, Boursier G, Brogan P, Haimel M, and van Gijn M

Subjects
Humans, Animals, Pilot Projects, Databases, Genetic, Phenotype, Simian Acquired Immunodeficiency Syndrome, Hereditary Autoinflammatory Diseases diagnosis, Hereditary Autoinflammatory Diseases genetics
Abstract

Introduction: Accurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs., Methods: We collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient., Results: Our results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2., Discussion: This study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs., Competing Interests: MH is currently employed by Boehringer Ingelheim RCV GmbH & Co KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Maassen, Legger, Kul Cinar, van Daele, Gattorno, Bader-Meunier, Wouters, Briggs, Johansson, van der Velde, Swertz, Omoyinmi, Hoppenreijs, Belot, Eleftheriou, Caorsi, Aeschlimann, Boursier, Brogan, Haimel and van Gijn.)

Published
2023
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45. Recommendations for whole genome sequencing in diagnostics for rare diseases.

Author

Souche E, Beltran S, Brosens E, Belmont JW, Fossum M, Riess O, Gilissen C, Ardeshirdavani A, Houge G, van Gijn M, Clayton-Smith J, Synofzik M, de Leeuw N, Deans ZC, Dincer Y, Eck SH, van der Crabben S, Balasubramanian M, Graessner H, Sturm M, Firth H, Ferlini A, Nabbout R, De Baere E, Liehr T, Macek M, Matthijs G, Scheffer H, Bauer P, Yntema HG, and Weiss MM

Subjects
High-Throughput Nucleotide Sequencing methods, Humans, Polymorphism, Single Nucleotide, Rare Diseases diagnosis, Rare Diseases genetics, Whole Genome Sequencing, Exome, Genome, Human
Abstract

In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation and update of previously published guidelines. This work was jointly initiated by EuroGentest and the Horizon2020 project Solve-RD. Statements from the 2016 guidelines have been reviewed in the context of WGS and updated where necessary. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results., (© 2022. The Author(s).)

Published
2022
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46. Proposal for a 6-step approach for differential diagnosis of neonatal erythroderma.

Author

Cuperus E, Bygum A, Boeckmann L, Bodemer C, Bolling MC, Caproni M, Diociaiuti A, Emmert S, Fischer J, Gostynski A, Guez S, van Gijn ME, Hannulla-Jouppi K, Has C, Hernández-Martín A, Martinez AE, Mazereeuw-Hautier J, Medvecz M, Neri I, Sigurdsson V, Suessmuth K, Traupe H, Oji V, and Pasmans SGMA

Subjects
Diagnosis, Differential, Humans, Infant, Newborn, Dermatitis, Exfoliative etiology, Ichthyosis genetics, Ichthyosis, Lamellar, Netherton Syndrome complications, Severe Combined Immunodeficiency complications
Abstract

The broad differential diagnosis of neonatal erythroderma often poses a diagnostic challenge. Mortality of neonatal erythroderma is high due to complications of the erythroderma itself and the occasionally severe and life-threatening underlying disease. Early correct recognition of the underlying cause leads to better treatment and prognosis. Currently, neonatal erythroderma is approached on a case-by-case basis. The purpose of this scoping review was to develop a diagnostic approach in neonatal erythroderma. After a systematic literature search in Embase (January 1990 - May 2020, 74 cases of neonatal erythroderma were identified, and 50+ diagnoses could be extracted. Main causes were the ichthyoses (40%) and primary immunodeficiencies (35%). Congenital erythroderma was present in 64% (47/74) of the cases, predominantly with congenital ichthyosis (11/11; 100%), Netherton syndrome (12/14, 86%) and Omenn syndrome (11/23, 48%). Time until diagnosis ranged from 102 days to 116 days for cases of non-congenital erythroderma and congenital erythroderma respectively. Among the 74 identified cases a total of 17 patients (23%) died within a mean of 158 days and were related to Omenn syndrome (35%), graft-versus-host disease (67%) and Netherton syndrome (18%). Disease history and physical examination are summarized in this paper. Age of onset and a collodion membrane can help to narrow the differential diagnoses. Investigations of blood, histology, hair analysis, genetic analysis and clinical imaging are summarized and discussed. A standard blood investigation is proposed, and the need for skin biopsies with lympho-epithelial Kazal-type related Inhibitor staining is highlighted. Overall, this review shows that diagnostic procedures narrow the differential diagnosis in neonatal erythroderma. A 6-step flowchart for the diagnostic approach for neonatal erythroderma during the first month of life is proposed. The approach was made with the support of expert leaders from international multidisciplinary collaborations in the European Reference Network Skin-subthematic group Ichthyosis., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Published
2022
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47. Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

Author

Haimel M, Pazmandi J, Heredia RJ, Dmytrus J, Bal SK, Zoghi S, van Daele P, Briggs TA, Wouters C, Bader-Meunier B, Aeschlimann FA, Caorsi R, Eleftheriou D, Hoppenreijs E, Salzer E, Bakhtiar S, Derfalvi B, Saettini F, Kusters MAA, Elfeky R, Trück J, Rivière JG, van der Burg M, Gattorno M, Seidel MG, Burns S, Warnatz K, Hauck F, Brogan P, Gilmour KC, Schuetz C, Simon A, Bock C, Hambleton S, de Vries E, Robinson PN, van Gijn M, and Boztug K

Subjects
Biological Ontologies, Humans, Phenotype, Genetic Diseases, Inborn classification, Immune System Diseases classification, Rare Diseases classification
Abstract

Background: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms., Objectives: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions., Methods: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs., Results: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification., Conclusions: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2022
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48. A Minimal Parameter Set Facilitating Early Decision-making in the Diagnosis of Hemophagocytic Lymphohistiocytosis.

Author

Smits BM, van Montfrans J, Merrill SA, van de Corput L, van Gijn M, de Vries A, van den Bos C, Abbink F, van der Molen RG, Dors N, Lindemans C, Boelens JJ, and Nierkens S

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, K562 Cells, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Sensitivity and Specificity, Young Adult, Lymphohistiocytosis, Hemophagocytic diagnosis
Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation syndrome characterized by uncontrolled immune cell activation. Timely diagnosis is important, since early treatment can improve survival rates. However, completing all assessments needed to reach ≥5 positive criteria out of the 8 HLH-2004 criteria can be time consuming and may delay timely initiation of treatment. Hence, we applied a data-driven approach to identify a minimal parameter set for early decision-making towards the initiation of HLH-specific treatment. We retrospectively evaluated 165 patients from five Dutch tertiary hospitals with suspected HLH. Sixteen pHLH (median age 0.5 years) and 70 sHLH patients (median age 8.7 years) were identified using the HLH-2004 criteria. Clustering analysis and multi-receiver operator characteristics were used to identify parameters distinctive of HLH. The presence of either increased ferritin, cytopenia in ≥2 lineages, or splenomegaly distinguished HLH from non-HLH cases with a negative predictive value of 100%. A minimal parameter set consisting of 2 major criteria (phagocytosis and splenomegaly) and 3 minor criteria (cytopenia, increased ferritin, and increased triglycerides/low fibrinogen) predicted HLH with 95% (88-99) sensitivity and 94% (86-98) specificity. This finding was replicated in an independent retrospective validation cohort of 109 US patients (n = 109). By dividing a subset of the HLH-2004 criteria into major and minor criteria, this strategy uses the evaluation of less than 5 criteria to quickly identify patients with HLH. When confirmed in a prospective setting, this approach could be of value for timely diagnosis and treatment of HLH., (© 2021. The Author(s).)

Published
2021
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49. A dominant activating RAC2 variant associated with immunodeficiency and pulmonary disease.

Author

Smits BM, Lelieveld PHC, Ververs FA, Turkenburg M, de Koning C, van Dijk M, Leavis HL, Boelens JJ, Lindemans CA, Bloem AC, van de Corput L, van Montfrans J, Nierkens S, van Gijn ME, Geerke DP, Waterham HR, Koenderman L, and Boes M

Subjects
Adult, B-Lymphocytes immunology, Disease Progression, GTPase-Activating Proteins metabolism, Gain of Function Mutation, Graft vs Host Disease drug therapy, Guanosine Triphosphate metabolism, Hematopoietic Stem Cell Transplantation, Heterozygote, Humans, Immunologic Memory immunology, Immunosuppressive Agents therapeutic use, Infant, Lung Diseases immunology, Lung Diseases physiopathology, Lung Diseases surgery, Lung Transplantation, Lymphopenia immunology, Male, Molecular Docking Simulation, Neutrophils, Primary Immunodeficiency Diseases immunology, Primary Immunodeficiency Diseases therapy, Recurrence, Respiratory Tract Infections immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes immunology, rac GTP-Binding Proteins immunology, rac GTP-Binding Proteins metabolism, rac GTP-Binding Proteins ultrastructure, RAC2 GTP-Binding Protein, Lung Diseases genetics, Lymphopenia genetics, Primary Immunodeficiency Diseases genetics, rac GTP-Binding Proteins genetics
Abstract

Competing Interests: Declaration of Competing Interest None to disclose.

Published
2020
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50. Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases.

Author

Ter Haar NM, Eijkelboom C, Cantarini L, Papa R, Brogan PA, Kone-Paut I, Modesto C, Hofer M, Iagaru N, Fingerhutová S, Insalaco A, Licciardi F, Uziel Y, Jelusic M, Nikishina I, Nielsen S, Papadopoulou-Alataki E, Olivieri AN, Cimaz R, Susic G, Stanevica V, van Gijn M, Vitale A, Ruperto N, Frenkel J, and Gattorno M

Subjects
Adolescent, Adrenal Cortex Hormones therapeutic use, Adult, Age of Onset, Antirheumatic Agents therapeutic use, Child, Child, Preschool, Chronic Disease, Colchicine therapeutic use, Europe, Female, Hereditary Autoinflammatory Diseases drug therapy, Hereditary Autoinflammatory Diseases pathology, Humans, Interleukin 1 Receptor Antagonist Protein therapeutic use, Male, Pedigree, Registries, Retrospective Studies, Young Adult, Genetic Variation genetics, Hereditary Autoinflammatory Diseases genetics
Abstract

Objectives: To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs)., Methods: Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases., Results: This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%)., Conclusion: This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2019
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