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1. Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis Variant Curation Expert Panel

Author: Spier, I, Yin, X, Richardson, M, Pineda, M, Laner, A, Ritter, D, Boyle, J, Mur, P, Hansen, TVO, Shi, X, Mahmood, K, Plazzer, J-P, Ognedal, E, Nordling, M, Farrington, SM, Yamamoto, G, Baert-Desurmont, S, Martins, A, Borras, E, Tops, C, Webb, E, Beshay, V, Genuardi, M, Pesaran, T, Capella, G, Tavtigian, S, Latchford, A, Frayling, IM, Plon, SE, Greenblatt, M, Macrae, FA, Aretz, S, Spier, I, Yin, X, Richardson, M, Pineda, M, Laner, A, Ritter, D, Boyle, J, Mur, P, Hansen, TVO, Shi, X, Mahmood, K, Plazzer, J-P, Ognedal, E, Nordling, M, Farrington, SM, Yamamoto, G, Baert-Desurmont, S, Martins, A, Borras, E, Tops, C, Webb, E, Beshay, V, Genuardi, M, Pesaran, T, Capella, G, Tavtigian, S, Latchford, A, Frayling, IM, Plon, SE, Greenblatt, M, Macrae, FA, and Aretz, S
Abstract: PURPOSE: The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. METHODS: Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. RESULTS: The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). CONCLUSION: The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
Published: 2024

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. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

Author: Hendricks, L.A.J., Hoogerbrugge, N., Mensenkamp, A.R., Brunet, J., Lleuger-Pujol, R., Høberg-Vetti, H., Tveit Haavind, M., Innella, G., Turchetti, D., Aretz, S., Spier, I., Tischkowitz, M., Jahn, A., Links, T.P., Olderode-Berends, M.J., Blatnik, A., Leter, E.M., Evans, D.G., Woodward, E.R., Steinke-Lange, V., Anastasiadou, V.C., Colas, C., Villy, M.C., Benusiglio, P.R., Gerasimenko, A., Barili, V., Branchaud, M., Houdayer, C., Tesi, B., Yazicioglu, M.O., Post, R.S. van der, Schuurs-Hoeijmakers, J.H.M., Vos, J.R., Hendricks, L.A.J., Hoogerbrugge, N., Mensenkamp, A.R., Brunet, J., Lleuger-Pujol, R., Høberg-Vetti, H., Tveit Haavind, M., Innella, G., Turchetti, D., Aretz, S., Spier, I., Tischkowitz, M., Jahn, A., Links, T.P., Olderode-Berends, M.J., Blatnik, A., Leter, E.M., Evans, D.G., Woodward, E.R., Steinke-Lange, V., Anastasiadou, V.C., Colas, C., Villy, M.C., Benusiglio, P.R., Gerasimenko, A., Barili, V., Branchaud, M., Houdayer, C., Tesi, B., Yazicioglu, M.O., Post, R.S. van der, Schuurs-Hoeijmakers, J.H.M., and Vos, J.R.
Abstract: Item does not contain fulltext, BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.
Published: 2023

4. Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

Author: Soares de Lima, Y., Arnau-Collell, C., Muñoz, J., Herrera-Pariente, C., Moreira, L., Ocaña, T., Díaz-Gay, M., Franch-Expósito, S., Cuatrecasas, M., Carballal, S., Lopez-Novo, A., Moreno, L., Fernàndez, G., Diaz de Bustamante, A., Peters, Sophia, Sommer, A.K., Spier, I., Paske, I.B.A.W. te, Herwaarden, Y.J. van, Castells, A., Bujanda, L., Capellà, G., Steinke-Lange, V., Mahmood, K., Joo, J.E., Arnold, J., Parry, S., Macrae, F.A., Winship, I.M., Rosty, C., Cubiella, J., Rodríguez-Alcalde, D., Holinski-Feder, E., Voer, R.M. de, Buchanan, D.D., Aretz, S., Ruiz-Ponte, C., Valle, L., Balaguer, F., Bonjoch, L., Castellvi-Bel, S., Soares de Lima, Y., Arnau-Collell, C., Muñoz, J., Herrera-Pariente, C., Moreira, L., Ocaña, T., Díaz-Gay, M., Franch-Expósito, S., Cuatrecasas, M., Carballal, S., Lopez-Novo, A., Moreno, L., Fernàndez, G., Diaz de Bustamante, A., Peters, Sophia, Sommer, A.K., Spier, I., Paske, I.B.A.W. te, Herwaarden, Y.J. van, Castells, A., Bujanda, L., Capellà, G., Steinke-Lange, V., Mahmood, K., Joo, J.E., Arnold, J., Parry, S., Macrae, F.A., Winship, I.M., Rosty, C., Cubiella, J., Rodríguez-Alcalde, D., Holinski-Feder, E., Voer, R.M. de, Buchanan, D.D., Aretz, S., Ruiz-Ponte, C., Valle, L., Balaguer, F., Bonjoch, L., and Castellvi-Bel, S.
Abstract: 01 juni 2023, Item does not contain fulltext, BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.
Published: 2023

5. Germline mutations in WNK2 could be associated with serrated polyposis syndrome

Author: Soares de Lima, Y, Arnau-Collell, C, Munoz, J, Herrera-Pariente, C, Moreira, L, Ocana, T, Diaz-Gay, M, Franch-Exposito, S, Cuatrecasas, M, Carballal, S, Lopez-Novo, A, Moreno, L, Fernandez, G, Diaz de Bustamante, A, Peters, S, Sommer, AK, Spier, I, te Paske, IBAW, van Herwaarden, YJ, Castells, A, Bujanda, L, Capella, G, Steinke-Lange, V, Mahmood, K, Joo, JE, Arnold, J, Parry, S, Macrae, FA, Winship, IM, Rosty, C, Cubiella, J, Rodriguez-Alcalde, D, Holinski-Feder, E, de Voer, R, Buchanan, DD, Aretz, S, Ruiz-Ponte, C, Valle, L, Balaguer, F, Bonjoch, L, Castellvi-Bel, S, Soares de Lima, Y, Arnau-Collell, C, Munoz, J, Herrera-Pariente, C, Moreira, L, Ocana, T, Diaz-Gay, M, Franch-Exposito, S, Cuatrecasas, M, Carballal, S, Lopez-Novo, A, Moreno, L, Fernandez, G, Diaz de Bustamante, A, Peters, S, Sommer, AK, Spier, I, te Paske, IBAW, van Herwaarden, YJ, Castells, A, Bujanda, L, Capella, G, Steinke-Lange, V, Mahmood, K, Joo, JE, Arnold, J, Parry, S, Macrae, FA, Winship, IM, Rosty, C, Cubiella, J, Rodriguez-Alcalde, D, Holinski-Feder, E, de Voer, R, Buchanan, DD, Aretz, S, Ruiz-Ponte, C, Valle, L, Balaguer, F, Bonjoch, L, and Castellvi-Bel, S
Abstract: BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.
Published: 2023

6. Wnt genes in colonic polyposis predisposition.

Author: Quintana, I., Terradas, M., Mur, P., Paske, I.B.A.W. te, Peters, Sophia, Spier, I., Steinke-Lange, V., Maestro, C., Torrents, D., Puiggròs, M., Royo, R., Tonda, R., Cerezo Parra, G., Piscia, D., Beltrán, S., Navarro, M., Piñol, V., Brunet, J., Gonzalez-Abuin, N., Aiza, G., Sommer, A., Herwaarden, Y.J. van, Astuti, G.D., Holinski-Feder, E., Hoogerbrugge, N., Voer, R.M. de, Aretz, S., Capellá, G., Valle, L., Quintana, I., Terradas, M., Mur, P., Paske, I.B.A.W. te, Peters, Sophia, Spier, I., Steinke-Lange, V., Maestro, C., Torrents, D., Puiggròs, M., Royo, R., Tonda, R., Cerezo Parra, G., Piscia, D., Beltrán, S., Navarro, M., Piñol, V., Brunet, J., Gonzalez-Abuin, N., Aiza, G., Sommer, A., Herwaarden, Y.J. van, Astuti, G.D., Holinski-Feder, E., Hoogerbrugge, N., Voer, R.M. de, Aretz, S., Capellá, G., and Valle, L.
Abstract: Contains fulltext : 294554.pdf (Publisher’s version ) (Open Access)
Published: 2023

7. JS04.4.A Beyond β-catenin: Genetic alterations ofTP53 andOTX2 and older age indicate increased risk of relapse in WNT medulloblastomas

Author: Goschzik, T, primary, Mynarek, M, additional, Doerner, E, additional, Spier, I, additional, Warmuth-Metz, M, additional, Bison, B, additional, Obrecht, D, additional, Struve, N, additional, Kortmann, R, additional, Hau, P, additional, Aretz, S, additional, Rutkowski, S, additional, and Pietsch, T, additional
Published: 2022
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8. Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review

Author: Hendricks, L.A.J., Schuurs-Hoeijmakers, J.H.M., Spier, I., Haadsma, M.L., Eijkelenboom, A., Cremer, K., Mensenkamp, A.R., Aretz, S., Vos, J.R., Hoogerbrugge, N., Hendricks, L.A.J., Schuurs-Hoeijmakers, J.H.M., Spier, I., Haadsma, M.L., Eijkelenboom, A., Cremer, K., Mensenkamp, A.R., Aretz, S., Vos, J.R., and Hoogerbrugge, N.
Abstract: Item does not contain fulltext, PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.
Published: 2022

9. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author: Hendricks, L.A.J., Hoogerbrugge, N., Venselaar, H., Aretz, Stefan, Spier, I., Legius, Eric, Schuurs-Hoeijmakers, J.H.M., Kleefstra, T., Mensenkamp, A.R., Vos, J.R., Hendricks, L.A.J., Hoogerbrugge, N., Venselaar, H., Aretz, Stefan, Spier, I., Legius, Eric, Schuurs-Hoeijmakers, J.H.M., Kleefstra, T., Mensenkamp, A.R., and Vos, J.R.
Abstract: Item does not contain fulltext
Published: 2022

10. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author: Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, Genuardi M (ORCID:0000-0002-7410-8351), Hendricks, Laj, Hoogerbrugge, N, Venselaar, H, Aretz, S, Spier, I, Legius, E, Brems, H, de Putter, R, Claes, Kbm, Evans, Dg, Woodward, Er, Genuardi, Maurizio, Brugnoletti, F, van Ierland, Y, Dijke, K, Tham, E, Tesi, B, Schuurs-Hoeijmakers, Jhm, Branchaud, M, Salvador, H, Jahn, A, Schnaiter, S, Anastasiadou, Vc, Brunet, J, Oliveira, C, Roht, L, Blatnik, A, Irmejs, A, Mensenkamp, Ar, Vos, Jr, and Genuardi M (ORCID:0000-0002-7410-8351)
Abstract: Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants. Keywords: Genetic association studies; Genetic variation; Human genetics; Medical oncology; Phenotype.
Published: 2022

11. GENOTYPE-PHENOTYPE ASSOCIATIONS PROVIDE A RATIONAL TO IDENTIFY POTENTIALLY ACTIONABLE VUS

Author: Pelaez J, Monteiro R, Lobo S, Sousa L, Pinheiro H, Castedo S, Garrido L, Teixeira M, Michils G, Bours V, de Putter R, Golmard L, Blanluet M, Colas C, Benusiglio P, Desseignes C, Florence C, Aretz S, Spier I, Huneburg R, Gieldon L, Schrock E, Holinski-Feder E, Steinke V, Calistri D, Tedaldi G, Ranzani G, Genuardi M, Silveira C, Silva I, Krajc M, Blatnik A, Novacovik S, Patino-Garcia A, Soto J, Lazaro C, Capella G, Brunet-Vidal J, Balmana J, Dominguez-Garrido E, Ligtenberg M, Fewings E, Fitzgerald R, Woodward E, Evans G, Hanson H, Lagerstedt-Robinson K, Bajalica-Lagercrantz S, Egas C, Tejada M, Dahan K, Feret D, Hoogerbrugge N, Tischkowitz M, and Oliveira C
Published: 2021

12. F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

Author: Maier, P, Heckmann, D, Spier, I, Laufs, S, Zucknick, M, Allgayer, H, Fruehauf, S, Zeller, W J, and Wenz, F
Published: 2012
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13. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

Author: Maier, P, Spier, I, Laufs, S, Veldwijk, M R, Fruehauf, S, Wenz, F, and Zeller, W J
Published: 2010
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14. Reply to Kratz et al.

Author: Frebourg, T. (Thierry), Lagercrantz, S.B. (Svetlana Bajalica), Oliveira, C. (Carla), Magenheim, R. (Rita), Evans, D.G. (D. Gareth), Hoogerbrugge, N. (Nicoline), Ligtenberg, M.J. (Marjolijn), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Woodward, E.R. (Emma R.), Tischkowitz, M. (Marc), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Houdayer, C. (Claude), Colas, C. (Chrystelle), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Teixeira, M. (Manuel), Tham, E. (Emma), Jan, L. (Lubinski), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), Hietala, M. (Marja), Frebourg, T. (Thierry), Lagercrantz, S.B. (Svetlana Bajalica), Oliveira, C. (Carla), Magenheim, R. (Rita), Evans, D.G. (D. Gareth), Hoogerbrugge, N. (Nicoline), Ligtenberg, M.J. (Marjolijn), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Woodward, E.R. (Emma R.), Tischkowitz, M. (Marc), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Houdayer, C. (Claude), Colas, C. (Chrystelle), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Teixeira, M. (Manuel), Tham, E. (Emma), Jan, L. (Lubinski), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), and Hietala, M. (Marja)
Published: 2020
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15. Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes

Author: Frebourg, T. (Thierry), Bajalica Lagercrantz, S. (Svetlana), Oliveira, C. (Carla), Magenheim, R. (Rita), Evans, D.G. (D. Gareth), Hoogerbrugge, N. (Nicoline), Ligtenberg, M.J. (Marjolijn), Kets, C.M. (Marleen), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Evans, G. (Gareth), Woodward, E.R. (Emma R.), Tischkowitz, M. (Marc), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Houdayer, C. (Claude), Colas, C. (Chrystelle), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Teixeira, P.J., Tham, E. (Emma), Lubinski, J. (Jan), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), Hietala, M. (Marja), Frebourg, T. (Thierry), Bajalica Lagercrantz, S. (Svetlana), Oliveira, C. (Carla), Magenheim, R. (Rita), Evans, D.G. (D. Gareth), Hoogerbrugge, N. (Nicoline), Ligtenberg, M.J. (Marjolijn), Kets, C.M. (Marleen), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Evans, G. (Gareth), Woodward, E.R. (Emma R.), Tischkowitz, M. (Marc), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Houdayer, C. (Claude), Colas, C. (Chrystelle), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Teixeira, P.J., Tham, E. (Emma), Lubinski, J. (Jan), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), and Hietala, M. (Marja)
Abstract: Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher canc
Published: 2020
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16. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome

Author: Tischkowitz, M. (Marc), Colas, C. (Chrystelle), Pouwels, S. (Sjaak), Hoogerbrugge, N. (Nicoline), Bisseling, T. (Tanya), Bubien, V. (Virginie), Caux, F. (Frederic), Chabbert-Buffet, N. (Nathalie), Da Mota Gomes, S. (Sophie), Gotthardt, M. (Martin), Kets, C.M. (Marleen), Lachlan, K. (Katherine), Links, T.P. (Thera), Longy, M. (Michel), Mann, R. (Ritse), Kool, L.S. (Leo Schultze), Semple, R.K. (Robert K.), Stock, I. (Ian), Vos, J.R. (Janet), Ligtenberg, M.J. (Marjolijn), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Evans, G. (Gareth), Woodward, E.R. (Emma R.), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Frebourg, T. (Thierry), Houdayer, C. (Claude), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Oliveira, C. (Carla), Teixeira, P.J., Bajalica-Lagercrantz, S. (Svetlana), Tham, E. (Emma), Lubinski, J. (Jan), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), Hietala, M. (Marja), Tischkowitz, M. (Marc), Colas, C. (Chrystelle), Pouwels, S. (Sjaak), Hoogerbrugge, N. (Nicoline), Bisseling, T. (Tanya), Bubien, V. (Virginie), Caux, F. (Frederic), Chabbert-Buffet, N. (Nathalie), Da Mota Gomes, S. (Sophie), Gotthardt, M. (Martin), Kets, C.M. (Marleen), Lachlan, K. (Katherine), Links, T.P. (Thera), Longy, M. (Michel), Mann, R. (Ritse), Kool, L.S. (Leo Schultze), Semple, R.K. (Robert K.), Stock, I. (Ian), Vos, J.R. (Janet), Ligtenberg, M.J. (Marjolijn), Oostenbrink, R. (Rianne), Sijmons, R.H. (Rolf), Evans, G. (Gareth), Woodward, E.R. (Emma R.), Maher, E.R. (Eamonn), Ferner, R.E. (Rosalie E.), Aretz, S. (Stefan), Spier, I. (Isabel), Steinke-Lange, V. (Verena), Holinski-Feder, E. (Elke), Schröck, E. (Evelin), Frebourg, T. (Thierry), Houdayer, C. (Claude), Wolkenstein, P. (Pierre), Bours, V. (Vincent), Legius, E. (Eric), Poppe, B. (Bruce), Claes, K. (Kathleen), de Putter, R. (Robin), Guillermo, I.B. (Ignacio Blanco), Capellá, G. (Gabriel), Vidal, J.B. (Joan Brunet), Lázaro, C. (Conxi), Balmaña, J. (Judith), Hernandez, H.S. (Hector Salvador), Oliveira, C. (Carla), Teixeira, P.J., Bajalica-Lagercrantz, S. (Svetlana), Tham, E. (Emma), Lubinski, J. (Jan), Ertmanska, K. (Karolina), Melegh, B. (Bela), Krajc, M. (Mateja), Blatnik, A. (Ana), Peltonen, S. (Sirkku), and Hietala, M. (Marja)
Abstract: PTEN hamartoma tumour syndrome is a diverse multi-system disorder predisposing to the development of hamartomatous growths, increasing risk of breast, thyroid, renal cancer, and possibly increasing risk of endometrial cancer, colorectal cancer and melanoma. There is no international consensus on cancer surveillance in PHTS and all current guidelines are based on expert opinion. A comprehensive literature review was undertaken and guidelines were developed by clinicians with expertise from clinical genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and general surgery, together with affected individuals and their representatives. Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. The proposed cancer surveillance recommendations for PHTS require a coordinated multidisciplinary approach and significant patient commitment. The evidence base for cancer surveillance in this guideline are limited, emphasising the need for prospective evaluation of the effectiveness of surveillance in the PHTS population.
Published: 2020
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17. First family from Germany with early-onset chondrocalcinosis and osteoarthritis (CCAL1, OMIM %600668) caused by TNFRSF11B gene mutation

Author: Blumberg, A. C., Wingendorf, M., Spier, I., Riehmer, V., Bartsch, O., Blumberg, A. C., Wingendorf, M., Spier, I., Riehmer, V., and Bartsch, O.
Published: 2020

18. Dye chromoendoscopy leads to a higher adenoma detection in the duodenum and stomach in patients with familial adenomatous polyposis

Author: Strassburg, C. P., primary, Nattermann, J., primary, Hüneburg, R., additional, Heling, D., additional, Kaczmarek, D. J., additional, van Heteren, P., additional, Olthaus, M., additional, Fimmers, R., additional, Berger, M., additional, Coch, C., additional, Lau, J. F., additional, Kristiansen, G., additional, Weismüller, T. J., additional, Spier, I., additional, and Aretz, S., additional
Published: 2020
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19. Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes

Author: Vos, JR, Giepmans, L, Rohl, C, Geverink, N, Hoogerbrugge, N, Ligtenberg, M, Kets, M, Sijmons, R, Evans, G, Woodward, E, Tischkowitz, M, Maher, E, Steinke-Lange, V, Holinski-Feder, E, Frebourg, T, Houdayer, C, Ferner, RE, Lubinski, J, Ertmanska, K, Lagercrantz, SB, Tham, E, Guillermo, IB, Capella, G, Vidal, JB, Lazaro, C (Conxi), Balmana, J, Bours, V, Legius, E, Wolkenstein, P, Melegh, B, Oliveira, C, Teixeira, M, Poppe, B, Claes, K, Hernandez, HS, Aretz, AWM, Spier, I, Oostenbrink, Rianne, Krajc, M, Blatnik, A, Schrock, E, Peltonen, S, Hietala, M, Ern, G, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Erasmus School of Health Policy & Management, Pediatrics, and Legius, Eric
Subjects: 0301 basic medicine, Cancer Research, Pediatrics, Databases, Factual, Colorectal cancer, International Cooperation, 030105 genetics & heredity, Medical Oncology, GUIDELINES, COLORECTAL-CANCER, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 0302 clinical medicine, Epidemiology, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Registries, Genetics (clinical), Syndrome, Quality Improvement, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Rare diseases, Europe, Oncology, 030220 oncology & carcinogenesis, Clinical Competence, Hereditary diffuse gastric cancer, medicine.medical_specialty, Short Communication, European Reference Network, behavioral disciplines and activities, Time-to-Treatment, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Cross border health care, SDG 3 - Good Health and Well-being, Genetic, Neoplastic Syndromes, Hereditary, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Testing, Neurofibromatosis, Information Services, business.industry, Information Dissemination, Remote Consultation, Cancer, medicine.disease, PREVENTION, Hereditary cancer, Li–Fraumeni syndrome, business, Rare disease
Abstract: Approximately 27-36 million patients in Europe have one of the ~ 5.000-8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer. ispartof: Familial Cancer vol:18 issue:2 pages:281-284 ispartof: location:Netherlands status: published
Published: 2019
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20. Exome sequencing identified potential candidate genes for serrated polyposis syndrome

Author: Peters, S., Trueck, C., Altmueller, J., Kayser, K., Mangold, E., Holzapfel, S., Adam, R., Thiele, H., Spier, I., Aretz, S., Peters, S., Trueck, C., Altmueller, J., Kayser, K., Mangold, E., Holzapfel, S., Adam, R., Thiele, H., Spier, I., and Aretz, S.
Published: 2018

21. Neue Erkenntnisse in das phänotypische Spektrum von KIF11 assoziierten Retinopathien

Author: Birtel, J, Gliem, M, Mangold, E, Tebbe, L, Spier, I, Müller, PL, Holz, FG, Neuhaus, C, Wolfrum, U, Bolz, HJ, Charbel Issa, P, Birtel, J, Gliem, M, Mangold, E, Tebbe, L, Spier, I, Müller, PL, Holz, FG, Neuhaus, C, Wolfrum, U, Bolz, HJ, and Charbel Issa, P
Published: 2018

22. Distinct spectrum of apc germline mutations in familial adenomatous polyposis at the center-south of portugal: identification of a mutational hotspot and suggestion of a founder effect

Author: Filipe, B., Claro, I., Lage, P., Ferreira, S., Rosa, I., Rodrigues, P., Spier, I., Theisen, Patrícia, Pereira-Caetano, Iris, Isidro, Glória, Gonçalves, João, Aretz, S., Dias Pereira, A., and Albuquerque, C.
Subjects: FAP, Polipose, Doenças Genéticas, APC
Abstract: Introduction: Familial adenomatous polyposis (FAP) is caused by APC germline mutations. These have been reported in classic and attenuated FAP (AFAP) but only two hotspots were described (codons 1309 and 1061-range:0-15%). We aimed to characterize the APC mutation spectrum in a FAP/AFAP population from the familial polyposis registry of the Portuguese Oncology Institute in Lisbon. Methods: We performed mutation analysis in 95 index patients from our FAP/AFAP cohort (61 FAP; 34 AFAP) using PTT, DGGE, sequencing and MLPA. Haplotype analysis was performed using 3 microsatellite markers flanking APC and 2 intragenic SNPs in 12 families with an intron 9 mutation (6 from our registry, 2 from INSA and 4 from IHG), occasionally detected in the literature, in order to evaluate a possible founder effect. All samples were anonymized. Statistics: Fisher’s exact and Χ2. Results: APC mutations were found in 47/61(77%) FAP and in 12/34(35%) AFAP families. The 1309del and 1061del contributed for 6/59(10%) and 2/59(4%) of the families, respectively. Exon 15 mutations were more frequent in FAP than in AFAP [30/47(64%) vs 1/12(8%),PG) was highly represented (6/59,10%), exclusively in AFAP (6/12;50%). Segregating with this mutation, we detected a common haplotype apparently shared by 6 families. For D5S346, the common allele segregating with this haplotype was more frequent in the index patients (11/20;46%) than in a control population (20/90;22%). Discussion: We identified a specific distribution of APC mutations and a mutational hotspot in our population. The higher frequency of the c.1312+3A>G mutation in Center-South Portugal suggest a non-uniform distribution which may be explained by a founder effect. Further studies using SNPs flanking intron 9 and the analysis of more families/relatives are needed.
Published: 2014

23. MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events

Author: Aretz, S, Tricarico, R, Papi, L, Spier, I, Pin, E, Horpaopan, S, Lucci Cordisco, Emanuela, Pedroni, M, Stienen, D, Gentile, A, Panza, A, Piepoli, A, De Leon, Mp, Friedl, W, Viel, A, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Aretz, S, Tricarico, R, Papi, L, Spier, I, Pin, E, Horpaopan, S, Lucci Cordisco, Emanuela, Pedroni, M, Stienen, D, Gentile, A, Panza, A, Piepoli, A, De Leon, Mp, Friedl, W, Viel, A, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)
Abstract: MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.Gly396Asp ranges between 50 and 82%, while these mutations have not been identified in Far Eastern Asian populations, supporting the hypothesis that a founder effect has occurred at some point in European history. To investigate the natural history of the two common European MUTYH alleles, we genotyped six gene-flanking microsatellite markers in 80 unrelated Italian and German MAP patients segregating one or both mutations and calculated their age in generations (g) by using DMLE+2.2 software. Three distinct common haplotypes, one for p.Tyr179Cys and two for p.Gly396Asp, were identified. Estimated mutation ages were 305 g (95% CS: 271-418) for p.Tyr179Cys and 350 g (95% CS: 313-435) for p.Gly396Asp. These results provide evidence for strong founder effects and suggest that the p.Tyr179Cys and p.Gly396Asp mutations derive from ancestors who lived between 5-8 thousand years and 6-9 thousand years B.C., respectively.European Journal of Human Genetics advance online publication, 30 January 2013; doi:10.1038/ejhg.2012.309.
Published: 2013

24. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K

Author: Maier, P, primary, Spier, I, additional, Laufs, S, additional, Veldwijk, M R, additional, Fruehauf, S, additional, Wenz, F, additional, and Zeller, W J, additional
Published: 2009
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25. F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells.

Author: Maier, P, Heckmann, D, Spier, I, Laufs, S, Zucknick, M, Allgayer, H, Fruehauf, S, Zeller, W J, and Wenz, F
Subjects: TUMOR treatment, CANCER chemotherapy, ANTIVIRAL agents, HEMATOPOIETIC stem cells, TUMOR suppressor genes, DRUG resistance in cancer cells, O6-Methylguanine-DNA Methyltransferase, DRUG efficacy
Abstract: Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMTP140K (an O6-benzylguanine-resistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMTP140K-F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMTP140K with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency. [ABSTRACT FROM AUTHOR]
Published: 2012
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26. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K.

Author: Maier, P., Spier, I., Laufs, S., Veldwijk, M. R., Fruehauf, S., Wenz, F., and Zeller, W. J.
Subjects: *HEMATOPOIETIC stem cells, *MULTIDRUG resistance, *METHYLTRANSFERASES, *CELL lines, *PACLITAXEL
Abstract: Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O6-benzylguanine (O6-BG)-resistant mutant MGMTP140K (O6-methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR′SIN–MDR1–IRES–MGMTP140K), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34+). Combination therapy with O6-BG/1-(2-chloroethyl)-3-(4-amino-2-methylpyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34+ cells, monotherapy with O6-BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR′SIN–MDR1–IRES–MGMTP140K (28.3%). For combination therapy with O6-BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMTP140K solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR′SIN–MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O6-BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drug-resistance genes, offering an opportunity to increase the cancer therapeutic index. [ABSTRACT FROM AUTHOR]
Published: 2010
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27. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O6-methylguanine-DNA methyltransferaseP140K.

Author: Maier, P., Spier, I., Laufs, S., Veldwijk, M. R., Fruehauf, S., Wenz, F., and Zeller, W. J.
Subjects: HEMATOPOIETIC stem cells, MULTIDRUG resistance, METHYLTRANSFERASES, CELL lines, PACLITAXEL
Abstract: Myelotoxicity is a dose-limiting effect of many chemotherapeutic regimens. Thus, there is great interest in protecting human hematopoietic stem cells by the transfer of drug resistance genes. The main focus of this study was the simultaneous overexpression of multidrug resistance 1 (MDR1) and the O6-benzylguanine (O6-BG)-resistant mutant MGMTP140K (O6-methylguanine-DNA methyltransferase) with a bicistronic lentiviral vector (HR′SIN–MDR1–IRES–MGMTP140K), with regard to the capability to convey chemoprotection in the leukemia cell line, HL60, and human hematopoietic stem cells (CD34+). Combination therapy with O6-BG/1-(2-chloroethyl)-3-(4-amino-2-methylpyrimidine-5-yl)methyl-1-nitrosourea) (ACNU) plus paclitaxel showed a significant survival advantage of HL60 cells transduced with this combination vector. In CD34+ cells, monotherapy with O6-BG/temozolomide (TMZ) resulted in an increased percentage of MGMT-positive cells (vs untreated cells) after transduction with HR′SIN–MDR1–IRES–MGMTP140K (28.3%). For combination therapy with O6-BG/temozolomide plus paclitaxel the increase was higher with the combination vector (52.8%) than with a vector expressing MGMTP140K solely (29.1%). With regard to MDR1-positive cells the protective effect of the combination vector (88.5%) was comparable to the single vector HR′SIN–MDR1 (90.0%) for monotherapy with paclitaxel and superior for combination therapy with O6-BG/temozolomide plus paclitaxel (84.6 vs 69.7%). In conclusion, the combination vector presents simultaneous protective effects of two drug-resistance genes, offering an opportunity to increase the cancer therapeutic index. [ABSTRACT FROM AUTHOR]
Published: 2010
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28. Manhattan transit with a path key

Author: Spier, I. Martin
Subjects: New York. Metropolitan Transportation Authority -- Planning, Subways -- New York
Published: 1981

29. The Martin Mizzen

Author: Spier, I. Martin
Subjects: Sails -- Innovations
Published: 1979

30. 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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31. 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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32. 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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33. Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS.

Author: Yin X, Richardson M, Laner A, Shi X, Ognedal E, Vasta V, Hansen TVO, Pineda M, Ritter D, de Dunnen J, Hassanin E, Lin WL, Borras E, Krahn K, Nordling M, Martins A, Mahmood K, Nadeau E, Beshay V, Tops C, Genuardi M, Pesaran T, Frayling IM, Capellá G, Latchford A, Tavtigian SV, Maj C, Plon SE, Greenblatt MS, Macrae FA, Spier I, and Aretz S
Subjects: Humans, Genomics methods, Algorithms, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli Protein genetics, Databases, Genetic, Genetic Variation
Abstract: Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign. The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC-specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use., Competing Interests: Declaration of interests S.E.P. is a member of the scientific advisory panel of Baylor Genetics Laboratories., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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34. MTHFR C677T and A1298C polymorphism's effect on risk of colorectal cancer in Lynch syndrome.

Author: Wiik MU, Negline M, Beisvåg V, Clapham M, Holliday E, Dueñas N, Brunet J, Pineda M, Bonifaci N, Aretz S, Klinkhammer H, Spier I, Perne C, Mayr A, Valle L, Lubinski J, Sjursen W, Scott RJ, and Talseth-Palmer BA
Subjects: Humans, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Genotype, Polymorphism, Single Nucleotide, DNA, Genetic Predisposition to Disease, Case-Control Studies, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms epidemiology, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology
Abstract: Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals., (© 2023. Crown.)
Published: 2023
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35. Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome.

Author: Dueñas N, Klinkhammer H, Bonifaci N, Spier I, Mayr A, Hassanin E, Diez-Villanueva A, Moreno V, Pineda M, Maj C, Capellà G, Aretz S, and Brunet J
Abstract: Background: Polygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary CRC, is still conflicting. We aimed to assess the ability of PRS to refine CRC risk prediction in European-descendant individuals with LS., Methods: 1465 individuals with LS (557 MLH1 , 517 MSH2/EPCAM , 299 MSH6 and 92 PMS2 ) and 5656 CRC-free population-based controls from two independent cohorts were included. A 91-SNP PRS was applied. A Cox proportional hazard regression model with 'family' as a random effect and a logistic regression analysis, followed by a meta-analysis combining both cohorts were conducted., Results: Overall, we did not observe a statistically significant association between PRS and CRC risk in the entire cohort. Nevertheless, PRS was significantly associated with a slightly increased risk of CRC or advanced adenoma (AA), in those with CRC diagnosed <50 years and in individuals with multiple CRCs or AAs diagnosed <60 years., Conclusion: The PRS may slightly influence CRC risk in individuals with LS in particular in more extreme phenotypes such as early-onset disease. However, the study design and recruitment strategy strongly influence the results of PRS studies. A separate analysis by genes and its combination with other genetic and non-genetic risk factors will help refine its role as a risk modifier in LS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2023
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36. Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

Author: Soares de Lima Y, Arnau-Collell C, Muñoz J, Herrera-Pariente C, Moreira L, Ocaña T, Díaz-Gay M, Franch-Expósito S, Cuatrecasas M, Carballal S, Lopez-Novo A, Moreno L, Fernàndez G, Díaz de Bustamante A, Peters S, Sommer AK, Spier I, Te Paske IBAW, van Herwaarden YJ, Castells A, Bujanda L, Capellà G, Steinke-Lange V, Mahmood K, Joo JE, Arnold J, Parry S, Macrae FA, Winship IM, Rosty C, Cubiella J, Rodríguez-Alcalde D, Holinski-Feder E, de Voer R, Buchanan DD, Aretz S, Ruiz-Ponte C, Valle L, Balaguer F, Bonjoch L, and Castellvi-Bel S
Subjects: Humans, Germ-Line Mutation genetics, Genotype, Protein Serine-Threonine Kinases genetics, Adenomatous Polyposis Coli genetics, Colonic Polyps genetics, Colorectal Neoplasms genetics
Abstract: Background: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts., Methods: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion., Results: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2., Conclusion: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
Published: 2023
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37. Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.

Author: Gallon R, Phelps R, Hayes C, Brugieres L, Guerrini-Rousseau L, Colas C, Muleris M, Ryan NAJ, Evans DG, Grice H, Jessop E, Kunzemann-Martinez A, Marshall L, Schamschula E, Oberhuber K, Azizi AA, Baris Feldman H, Beilken A, Brauer N, Brozou T, Dahan K, Demirsoy U, Florkin B, Foulkes W, Januszkiewicz-Lewandowska D, Jones KJ, Kratz CP, Lobitz S, Meade J, Nathrath M, Pander HJ, Perne C, Ragab I, Ripperger T, Rosenbaum T, Rueda D, Sarosiek T, Sehested A, Spier I, Suerink M, Zimmermann SY, Zschocke J, Borthwick GM, Wimmer K, Burn J, Jackson MS, and Santibanez-Koref M
Subjects: Humans, Microsatellite Instability, Genotype, DNA Mismatch Repair genetics, Mismatch Repair Endonuclease PMS2 genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms diagnosis, Brain Neoplasms diagnosis
Abstract: Background & Aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood., Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls., Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor., Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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38. Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence.

Author: Hassanin E, Spier I, Bobbili DR, Aldisi R, Klinkhammer H, David F, Dueñas N, Hüneburg R, Perne C, Brunet J, Capella G, Nöthen MM, Forstner AJ, Mayr A, Krawitz P, May P, Aretz S, and Maj C
Subjects: Humans, Incidence, Risk Factors, Germ Cells, Germ-Line Mutation, Colorectal Neoplasms
Abstract: Background and Aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification., Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (< 20%), intermediate (20-80%), or high PRS (> 80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively., Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704)., Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups., (© 2023. The Author(s).)
Published: 2023
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39. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

Author: Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, Brunet J, Lleuger-Pujol R, Høberg-Vetti H, Tveit Haavind M, Innella G, Turchetti D, Aretz S, Spier I, Tischkowitz M, Jahn A, Links TP, Olderode-Berends MJW, Blatnik A, Leter EM, Evans DG, Woodward ER, Steinke-Lange V, Anastasiadou VC, Colas C, Villy MC, Benusiglio PR, Gerasimenko A, Barili V, Branchaud M, Houdayer C, Tesi B, Yazicioglu MO, van der Post RS, Schuurs-Hoeijmakers JHM, and Vos JR
Subjects: Adult, Male, Humans, Female, Middle Aged, Cohort Studies, Prospective Studies, PTEN Phosphohydrolase genetics, Germ-Line Mutation, Hamartoma Syndrome, Multiple epidemiology, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Thyroid Neoplasms, Kidney Neoplasms epidemiology
Abstract: Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks., Methods: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses., Results: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%., Conclusions: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management., (© The Author(s) 2022. Published by Oxford University Press.)
Published: 2023
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40. Wnt genes in colonic polyposis predisposition.

Author: Quintana I, Terradas M, Mur P, Te Paske IBAW, Peters S, Spier I, Steinke-Lange V, Maestro C, Torrents D, Puiggròs M, Royo R, Tonda R, Parra G, Piscia D, Beltrán S, Navarro M, Piñol V, Brunet J, Gonzalez-Abuin N, Aiza G, Sommer A, van Herwaarden Y, Astuti G, Holinski-Feder E, Hoogerbrugge N, de Voer RM, Aretz S, Capellá G, and Valle L
Published: 2022
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41. First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants.

Author: Coudert M, Drouet Y, Delhomelle H, Svrcek M, Benusiglio PR, Coulet F, Clark DF, Katona BW, van Hest LP, van der Kolk LE, Cats A, van Dieren JM, Nehoray B, Slavin T, Spier I, Hüneburg R, Lobo S, Oliveira C, Boussemart L, Masson L, Chiesa J, Schwartz M, Buecher B, Golmard L, Bouvier AM, Bonadona V, Stoppa-Lyonnet D, Lasset C, and Colas C
Subjects: Humans, Cadherins genetics, Genetic Predisposition to Disease, Heterozygote, Germ Cells pathology, Germ-Line Mutation genetics, alpha Catenin genetics, Stomach Neoplasms epidemiology, Stomach Neoplasms genetics, Stomach Neoplasms pathology
Abstract: Background: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV., Methods: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty., Results: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL., Conclusion: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2022
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42. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort.

Author: Hendricks LAJ, Hoogerbrugge N, Venselaar H, Aretz S, Spier I, Legius E, Brems H, de Putter R, Claes KBM, Evans DG, Woodward ER, Genuardi M, Brugnoletti F, van Ierland Y, Dijke K, Tham E, Tesi B, Schuurs-Hoeijmakers JHM, Branchaud M, Salvador H, Jahn A, Schnaiter S, Anastasiadou VC, Brunet J, Oliveira C, Roht L, Blatnik A, Irmejs A, Mensenkamp AR, and Vos JR
Subjects: Humans, Cohort Studies, Genetic Association Studies, PTEN Phosphohydrolase genetics, Phenotype, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Megalencephaly genetics
Abstract: Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study., Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age., Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2., Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2022
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43. Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review.

Author: Hendricks LAJ, Schuurs-Hoeijmakers J, Spier I, Haadsma ML, Eijkelenboom A, Cremer K, Mensenkamp AR, Aretz S, Vos JR, and Hoogerbrugge N
Subjects: Adolescent, Adult, Child, Developmental Disabilities, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Mosaicism, PTEN Phosphohydrolase genetics, Young Adult, Hamartoma Syndrome, Multiple diagnosis, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Megalencephaly
Abstract: PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2022
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44. Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD.

Author: Sommer AK, Te Paske IBAW, Garcia-Pelaez J, Laner A, Holinski-Feder E, Steinke-Lange V, Peters S, Valle L, Spier I, Huntsman D, Oliveira C, de Voer RM, Hoogerbrugge N, and Aretz S
Subjects: Genetic Predisposition to Disease, Genomics, Humans, Exome Sequencing, Colorectal Neoplasms genetics, Neoplastic Syndromes, Hereditary genetics
Abstract: Background: Patients and families with suspected, but genetically unexplained (unsolved) genetic tumour risk syndromes lack appropriate treatment and prevention, leading to preventable morbidity and mortality. To tackle this problem, patients from the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) are analysed in the European Commission's research project "Solving the unsolved rare diseases" (Solve-RD). The aim is to uncover known and novel cancer predisposing genes by reanalysing available whole-exome sequencing (WES) data of large cohorts in a combined manner, and applying a multidimensional omics approach., Approach: Around 500 genetically unsolved cases with suspected hereditary gastrointestinal tumour syndromes (polyposis, early-onset/familial colorectal cancer and gastric cancer) from multiple European centres are aimed to be included. Currently, clinical and germline WES data from 294 cases have been analysed. In addition, an extensive molecular profiling of gastrointestinal tumours from these patients is planned and deep learning techniques will be applied. The ambitious, multidisciplinary project is accompanied by a number of methodical, technical, and logistic challenges, which require the development and implementation of new analysis tools, the standardisation of bioinformatics pipelines, and strategies to exchange data and knowledge., Results: and Outlook. The first re-analysis of 229 known and proposed cancer predisposition genes allowed solving 2-3% of previously unsolved GENTURIS cases. The integration of expert knowledge and new technologies will help to identify the genetic basis of additional unsolved cases within the ongoing project. The ERN GENTURIS approach might serve as a model for other genomic initiatives., (Copyright © 2022. Published by Elsevier Masson SAS.)
Published: 2022
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45. Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history.

Author: Hassanin E, May P, Aldisi R, Spier I, Forstner AJ, Nöthen MM, Aretz S, Krawitz P, Bobbili DR, and Maj C
Subjects: Aged, Genetic Predisposition to Disease, Germ Cells, Humans, Male, Multifactorial Inheritance genetics, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics
Abstract: Purpose: We aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk., Methods: A total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life., Results: Cumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio., Conclusion: PRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2022
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46. Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis.

Author: Perne C, Peters S, Cartolano M, Horpaopan S, Grimm C, Altmüller J, Sommer AK, Hillmer AM, Thiele H, Odenthal M, Möslein G, Adam R, Sivalingam S, Kirfel J, Schweiger MR, Peifer M, Spier I, and Aretz S
Subjects: Activin Receptors, Type II genetics, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli Protein genetics, Colorectal Neoplasms genetics, Humans, INDEL Mutation, Polymorphism, Single Nucleotide, Adenomatous Polyposis Coli pathology, Colorectal Neoplasms pathology, MutS Homolog 3 Protein genetics
Abstract: The spectrum of somatic genetic variation in colorectal adenomas caused by biallelic pathogenic germline variants in the MSH3 gene, was comprehensively analysed to characterise mutational signatures and identify potential driver genes and pathways of MSH3-related tumourigenesis. Three patients from two families with MSH3-associated polyposis were included. Whole exome sequencing of nine adenomas and matched normal tissue was performed. The amount of somatic variants in the MSH3-deficient adenomas and the pattern of single nucleotide variants (SNVs) was similar to sporadic adenomas, whereas the fraction of small insertions/deletions (indels) (21-42% of all small variants) was significantly higher. Interestingly, pathogenic somatic APC variants were found in all but one adenoma. The vast majority (12/13) of these were di-, tetra-, or penta-base pair (bp) deletions. The fraction of APC indels was significantly higher than that reported in patients with familial adenomatous polyposis (FAP) (p < 0.01) or in sporadic adenomas (p < 0.0001). In MSH3-deficient adenomas, the occurrence of APC indels in a repetitive sequence context was significantly higher than in FAP patients (p < 0.01). In addition, the MSH3-deficient adenomas harboured one to five (recurrent) somatic variants in 13 established or candidate driver genes for early colorectal carcinogenesis, including ACVR2A and ARID genes. Our data suggest that MSH3-related colorectal carcinogenesis seems to follow the classical APC-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic APC mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis., Competing Interests: The authors have declared that no competing interests exist.
Published: 2021
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47. Overview of the Clinical Features of Li-Fraumeni Syndrome and the Current European ERN GENTURIS Guideline.

Author: Kratz CP, Steinke-Lange V, Spier I, Aretz S, Schröck E, and Holinski-Feder E
Abstract: Patients with a tumour-risk syndrome have a significantly increased risk of developing cancer during their lifetime. A positive family history of tumour disease or an unusually early age of onset may be indicative of a tumour risk syndrome. With the diagnosis of a tumour risk syndrome it is possible to recommend a risk-adapted tumour surveillance programme for the patient and (asymptomatic) family members at risk. This facilitates early detection of possible tumours and thus often prevents advanced tumour stages. Li-Fraumeni syndrome is associated with a significantly increased risk of sarcoma and breast cancer in particular, but it is often not diagnosed clinically in those affected. This article reviews the clinical picture, genetic cause and special aspects in the diagnosis and care of patients with Li-Fraumeni syndrome. The initiative resulted from the European reference network GENTURIS, which has set itself the task of improving the identification and care of patients with tumour risk syndromes. A first step is the recent publication of a European guideline for Li-Fraumeni syndrome, which is summarised here and discussed in the context of existing recommendations., Competing Interests: Conflict of Interest/Interessenkonflikt The authors declare that they have no conflict of interest./Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)
Published: 2021
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48. Cancer predisposition and germline CTNNA1 variants.

Author: Lobo S, Benusiglio PR, Coulet F, Boussemart L, Golmard L, Spier I, Hüneburg R, Aretz S, Colas C, and Oliveira C
Subjects: Antigens, CD genetics, Cadherins genetics, Gene Frequency, Heterozygote, Humans, Pedigree, Phenotype, Stomach Neoplasms pathology, Genetic Predisposition to Disease, Germ-Line Mutation, Stomach Neoplasms genetics, alpha Catenin genetics
Abstract: Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Published: 2021
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49. mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Author: Taylor H, Yerlioglu D, Phen C, Ballauff A, Nedelkopoulou N, Spier I, Loverdos I, Busoni VB, Heise J, Dale P, de Meij T, Sweet K, Cohen MC, Fox VL, Mas E, Aretz S, Eng C, Buderus S, Thomson M, Rojas I, and Uhlig HH
Subjects: Bone Morphogenetic Protein Receptors, Type I, Colectomy, Gastrointestinal Hemorrhage, Humans, Intestinal Polyposis congenital, PTEN Phosphohydrolase genetics, TOR Serine-Threonine Kinases genetics, MTOR Inhibitors, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary pathology, Neoplastic Syndromes, Hereditary surgery
Abstract: Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2021
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50. Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status.

Author: Marwitz T, Hüneburg R, Spier I, Lau JF, Kristiansen G, Lingohr P, Kalff JC, Aretz S, Nattermann J, and Strassburg CP
Abstract: Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent ( n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% ( n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
Published: 2020
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