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1. ARID1B-related disorder in 87 adults: Natural history and self-sustainability

Author

van der Sluijs, P.J., Gösgens, M., Dingemans, A.J.M., Striano, P., Riva, A., Mignot, C., Faudet, A., Vasileiou, G., Walther, M., Schrier Vergano, S.A., Alders, M., Alkuraya, F.S., Alorainy, I., Alsaif, H.S., Anderlid, B., Bache, I., van Beek, I., Blanluet, M., van Bon, B.W., Brunet, T., Brunner, H., Carriero, M.L., Charles, P., Chatron, N., Coccia, E., Dubourg, C., Earl, R.K., Eichler, E.E., Faivre, L., Foulds, N., Graziano, C., Guerrot, A.M., Hashem, M.O., Heide, S., Heron, D., Hickey, S.E., Hopman, S.M.J., Kattentidt-Mouravieva, A., Kerkhof, J., Klein Wassink-Ruiter, J.S., Kurtz-Nelson, E.C., Kušíková, K., Kvarnung, M., Lecoquierre, F., Leszinski, G.S., Loberti, L., Magoulas, P.L., Mari, F., Maystadt, I., Merla, G., Milunsky, J.M., Moortgat, S., Nicolas, G., Leary, M.O.’, Odent, S., Ozmore, J.R., Parbhoo, K., Pfundt, R., Piccione, M., Pinto, A.M., Popp, B., Putoux, A., Rehm, H.L., Reis, A., Renieri, A., Rosenfeld, J.A., Rossi, M., Salzano, E., Saugier-Veber, P., Seri, M., Severi, G., Sonmez, F.M., Strobl-Wildemann, G., Stuurman, K.E., Uctepe, E., Van Esch, H., Vitetta, G., de Vries, B.B.A., Wahl, D., Wang, T., Zacher, P., Heitink, K.R., Ropers, F.G., Steenbeek, D., Rybak, T., and Santen, G.W.E.

Published
2024
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4. 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

5. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

Author

Smol, T., Petit, F., Piton, A., Keren, B., Sanlaville, D., Afenjar, A., Baker, S., Bedoukian, E. C., Bhoj, E. J., Bonneau, D., Boudry-Labis, E., Bouquillon, S., Boute-Benejean, O., Caumes, R., Chatron, N., Colson, C., Coubes, C., Coutton, C., Devillard, F., Dieux-Coeslier, A., Doco-Fenzy, M., Ewans, L. J., Faivre, L., Fassi, E., Field, M., Fournier, C., Francannet, C., Genevieve, D., Giurgea, I., Goldenberg, A., Green, A. K., Guerrot, A. M., Heron, D., Isidor, B., Keena, B. A., Krock, B. L., Kuentz, P., Lapi, E., Le Meur, N., Lesca, G., Li, D., Marey, I., Mignot, C., Nava, C., Nesbitt, A., Nicolas, G., Roche-Lestienne, C., Roscioli, T., Satre, V., Santani, A., Stefanova, M., Steinwall Larsen, S., Saugier-Veber, P., Picker-Minh, S., Thuillier, C., Verloes, A., Vieville, G., Wenzel, M., Willems, M., Whalen, S., Zarate, Y. A., Ziegler, A., Manouvrier-Hanu, S., Kalscheuer, V. M., Gerard, B., and Ghoumid, Jamal

Published
2018
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6. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Author

Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., Stessman, H.A.F., Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C.J., Faundes, V., Duffourd, Y., Lee, P., Simon, M.C., Cruz, X. de la, Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., March, M., Diaz-Rosado, A., Peixoto de Barcelos, I., Choa, Z.X., Lim, C.Y., Dubourg, C., Journel, H., Demurger, F., Mulhern, M., Akman, C., Lippa, N., Andrews, M., Baldridge, D., Constantino, J., Haeringen, A. van, Snoeck-Streef, I., Chow, P., Hing, A., Graham Jr, J.M., Au, M., Faivre, L., Shen, W., Mao, R., Palumbos, J., Viskochil, D., Gahl, W., Tifft, C., Macnamara, E., Hauser, N., Miller, R., Maffeo, J., Afenjar, A., Doummar, D., Keren, B., Arn, P., Macklin-Mantia, S., Meerschaut, I., Callewaert, B., Reis, A., Zweier, C., Brewer, C., Saggar, A., Smeland, M.F., Kumar, Ajith, Elmslie, F., Deshpande, C., Nizon, M., Cogne, B., Ierland, Y. van, Wilke, M., Slegtenhorst, M. van, Koudijs, S., Chen, J.Y., Dredge, D., Pier, D., Wortmann, S.B., Kamsteeg, E.J., Koch, J., Haynes, D., Pollack, L., Titheradge, H., Ranguin, K., Denommé-Pichon, A.S., Weber, S., Perez de la Fuente, R., Sanchez Del Pozo, J., Lezana Rosales, J.M., Joset, P., Steindl, K., Rauch, A., Mei, D., Mari, F., Guerrini, R., Lespinasse, J., Tran Mau-Them, F., Philippe, C., Dauriat, B., Raymond, L., Moutton, S., Cueto-González, A.M., Tan, T.Y., Mignot, C., Grotto, S., Renaldo, F., Drivas, T.G., Hennessy, L., Raper, A., Parenti, I., Kaiser, F.J., Kuechler, A., Busk, Ø.L., Islam, L., Siedlik, J.A., Henderson, L.B., Juusola, J., Person, R., Schnur, R.E., Vitobello, A., Banka, S., Bhoj, E.J., and Stessman, H.A.F.

Abstract

Item does not contain fulltext, Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

7. Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

Author

Patterson, V., Ullah, F., Bryant, L., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, Xuyun, Mireguli, M., Luo, Y, Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R., Bhoj, E., Patterson, V., Ullah, F., Bryant, L., Griffin, J.N., Sidhu, A., Saliganan, S., Blaile, M., Saenz, M.S., Smith, R., Ellingwood, S., Grange, D.K., Hu, Xuyun, Mireguli, M., Luo, Y, Shen, Y., Mulhern, M., Zackai, E., Ritter, A., Izumi, K., Hoefele, J., Wagner, M., Riedhammer, K.M., Seitz, B., Robin, N.H., Goodloe, D., Mignot, C., Keren, B., Cox, H., Jarvis, J., Hempel, M., Gibson, C.F., Tran Mau-Them, F., Vitobello, A., Bruel, A.L., Sorlin, A., Mehta, S., Raymond, F.L., Gilmore, K., Powell, B.C., Weck, K., Li, C., Vulto-van Silfhout, A.T., Giacomini, T., Mancardi, M.M., Accogli, A., Salpietro, V., Zara, F., Vora, N.L., Davis, E.E., Burdine, R., and Bhoj, E.

Abstract

Item does not contain fulltext, We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.

Published
2023

8. Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

Author

Chérot, E., Keren, B., Dubourg, C., Carré, W., Fradin, M., Lavillaureix, A., Afenjar, A., Burglen, L., Whalen, S., Charles, P., Marey, I., Heide, S., Jacquette, A., Heron, D., Doummar, D., Rodriguez, D., Billette de Villemeur, T., Moutard, M.‐L., Guët, A., Xavier, J., Périsse, D., Cohen, D., Demurger, F., Quélin, C., Depienne, C., Odent, S., Nava, C., David, V., Pasquier, L., and Mignot, C.

Published
2018
Full Text
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9. 16p11.2 Locus modulates response to satiety before the onset of obesity

Author

Maillard, A M, Hippolyte, L, Rodriguez-Herreros, B, Chawner, S J R A, Dremmel, D, Agüera, Z, Fagundo, A B, Pain, A, Martin-Brevet, S, Hilbert, A, Kurz, S, Etienne, R, Draganski, B, Jimenez-Murcia, S, Männik, K, Metspalu, A, Reigo, A, Isidor, B, Le Caignec, C, David, A, Mignot, C, Keren, B, van den Bree, M B M, Munsch, S, Fernandez-Aranda, F, Beckmann, J S, Reymond, A, and Jacquemont, S

Published
2016
Full Text
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10. Effects of eight neuropsychiatric copy number variants on human brain structure

Author

Modenato, C., Kumar, K., Moreau, C., Martin-Brevet, S., Huguet, G., Schramm, C., Jean-Louis, M., Martin, C. -O., Younis, N., Tamer, P., Douard, E., Thebault-Dagher, F., Cote, V., Charlebois, A. -R., Deguire, F., Maillard, A. M., Rodriguez-Herreros, B., Pain, A., Richetin, S., Addor, M. -C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Bena, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J. -H., Campion, D., Colombert, V., Cordier, M. -P., David, A., Debray, F. -G., Delrue, M. -A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gerard, M., Giachino, D., Guichet, A., Guillin, O., Heron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaitre, M. -P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekaer Sorensen, K., Pinson, L., Plessis, G., Prieur, F., Raymond, A., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A. L., Benedetti, M., Berg, J., Berman, J., Berry, L. N., Bibb, A. L., Blaskey, L., Brennan, J., Brewton, C. M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A. G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J. E., Evans, Y. L., Findlay, A., Fischbach, G. D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S. E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F. I., Jenkins, J., Jeremy, R. J., Johnson, K., Kanne, S. M., Kessler, S., Khan, S. Y., Ku, M., Kuschner, E., Laakman, A. L., Lam, P., Lasala, M. W., Lee, H., Laguerre, K., Levy, S., Cavanagh, A. L., Llorens, A. V., Campe, K. L., Luks, T. L., Marco, E. J., Martin, S., Martin, A. J., Marzano, G., Masson, C., Mcgovern, K. E., Keehn, R. M. N., Miller, D. T., Miller, F. K., Moss, T. J., Murray, R., Nagarajan, S. S., Nowell, K. P., Owen, J., Paal, A. M., Packer, A., Page, P. Z., Paul, B. M., Peters, A., Peterson, D., Poduri, A., Pojman, N. J., Porche, K., Proud, M. B., Qasmieh, S., Ramocki, M. B., Reilly, B., Roberts, T. P. L., Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A. S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Melie-Garcia, L., Kushan, L., Silva, A. I., van den Bree, M. B. M., Linden, D. E. J., Owen, M. J., Hall, J., Lippe, S., Chakravarty, M., Bzdok, D., Bearden, C. E., Draganski, B., Jacquemont, S., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), 16p11.2 European Consortium, Simons Searchlight Consortium, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, RS: MHeNs - R3 - Neuroscience, Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Raymond, A., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., Keehn, R.M., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
0301 basic medicine, Simons Searchlight Consortium, Autism, 0302 clinical medicine, Gyrus, Gene duplication, 2.1 Biological and endogenous factors, Psychology, Copy-number variation, Aetiology, Genetics, Brain, Human brain, Magnetic Resonance Imaging, Psychiatry and Mental health, Mental Health, medicine.anatomical_structure, Schizophrenia, Neurological, Public Health and Health Services, RC321-571, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, 16p11.2 European Consortium, Neurosciences. Biological psychiatry. Neuropsychiatry, Neuroimaging, Biology, Basic Behavioral and Social Science, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Behavioral and Social Science, mental disorders, medicine, Humans, 22Q11.2 DELETION SYNDROME, Clinical genetics, AUTISM, COMMON, Biological Psychiatry, Prevention, Human Genome, Brain morphometry, Neurosciences, medicine.disease, DUPLICATION, Brain Disorders, 030104 developmental biology, 030217 neurology & neurosurgery, Neuroscience
Abstract

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Published
2021

12. Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier

Author

Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., Wortmann, S.B., Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., and Wortmann, S.B.

Abstract

Contains fulltext : 283140.pdf (Publisher’s version ) (Open Access), The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Published
2022

13. HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein

Author

Kraatari-Tiri, M. (Minna), Soikkonen, L. (Leila), Myllykoski, M. (Matti), Jamshidi, Y. (Yalda), Karimiani, E. G. (Ehsan G.), Komulainen-Ebrahim, J. (Jonna), Kallankari, H. (Hanna), Mignot, C. (Cyril), Depienne, C. (Christel), Keren, B. (Boris), Nougues, M.-C. (Marie-Christine), Alsahlawi, Z. (Zahra), Romito, A. (Antonio), Martini, J. (Javier), Toosi, M. B. (Mehran B.), Carroll, C. J. (Christopher J.), Tripolszki, K. (Kornelia), Bauer, P. (Peter), Uusimaa, J. (Johanna), Bertoli-Avella, A. M. (Aida M.), Koivunen, P. (Peppi), Rahikkala, E. (Elisa), Kraatari-Tiri, M. (Minna), Soikkonen, L. (Leila), Myllykoski, M. (Matti), Jamshidi, Y. (Yalda), Karimiani, E. G. (Ehsan G.), Komulainen-Ebrahim, J. (Jonna), Kallankari, H. (Hanna), Mignot, C. (Cyril), Depienne, C. (Christel), Keren, B. (Boris), Nougues, M.-C. (Marie-Christine), Alsahlawi, Z. (Zahra), Romito, A. (Antonio), Martini, J. (Javier), Toosi, M. B. (Mehran B.), Carroll, C. J. (Christopher J.), Tripolszki, K. (Kornelia), Bauer, P. (Peter), Uusimaa, J. (Johanna), Bertoli-Avella, A. M. (Aida M.), Koivunen, P. (Peppi), and Rahikkala, E. (Elisa)

Abstract

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.

Published
2022

14. A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism.

Author

Parthasarathy, S, Ruggiero, SM, Gelot, A, Soardi, FC, Ribeiro, BFR, Pires, DEV, Ascher, DB, Schmitt, A, Rambaud, C, Represa, A, Xie, HM, Lusk, L, Wilmarth, O, McDonnell, PP, Juarez, OA, Grace, AN, Buratti, J, Mignot, C, Gras, D, Nava, C, Pierce, SR, Keren, B, Kennedy, BC, Pena, SDJ, Helbig, I, Cuddapah, VA, Parthasarathy, S, Ruggiero, SM, Gelot, A, Soardi, FC, Ribeiro, BFR, Pires, DEV, Ascher, DB, Schmitt, A, Rambaud, C, Represa, A, Xie, HM, Lusk, L, Wilmarth, O, McDonnell, PP, Juarez, OA, Grace, AN, Buratti, J, Mignot, C, Gras, D, Nava, C, Pierce, SR, Keren, B, Kennedy, BC, Pena, SDJ, Helbig, I, and Cuddapah, VA

Abstract

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied with a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in 39 pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A (GenBank: NM_001288739.1), which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of enlarged synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.Arg399Trp and p.Gly401Asp, had a similar DEE phenotype. In contrast, one individual with a missense variant affecting exon 10b, p.Pro405Leu, which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants as well as the possibility of splice site variants acting through a dominant-negative mechanism.

Published
2022

15. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

Author

Cordovado, A., Schaettin, M., Jeanne, M., Panasenkava, V., Denomme-Pichon, A. -S., Keren, B., Mignot, C., Doco-Fenzy, M., Rodan, L., Ramsey, K., Narayanan, V., Jones, J. R., Prijoles, E. J., Mitchell, W. G., Ozmore, J. R., Juliette, K., Torti, E., Normand, E. A., Granger, L., Petersen, A. K., Au, M. G., Matheny, J. P., Phornphutkul, C., Chambers, M. -K., Fernandez-Ramos, J. -A., Lopez-Laso, E., Kruer, M. C., Bakhtiari, S., Zollino, Marcella, Morleo, M., Marangi, Giuseppe, Mei, D., Pisano, T., Guerrini, R., Louie, R. J., Childers, A., Everman, D. B., Isidor, B., Audebert-Bellanger, S., Odent, S., Bonneau, D., Gilbert-Dussardier, B., Redon, R., Bezieau, S., Laumonnier, F., Stoeckli, E. T., Toutain, A., Vuillaume, M. -L., Zollino M. (ORCID:0000-0003-4871-9519), Marangi G. (ORCID:0000-0002-6898-8882), Cordovado, A., Schaettin, M., Jeanne, M., Panasenkava, V., Denomme-Pichon, A. -S., Keren, B., Mignot, C., Doco-Fenzy, M., Rodan, L., Ramsey, K., Narayanan, V., Jones, J. R., Prijoles, E. J., Mitchell, W. G., Ozmore, J. R., Juliette, K., Torti, E., Normand, E. A., Granger, L., Petersen, A. K., Au, M. G., Matheny, J. P., Phornphutkul, C., Chambers, M. -K., Fernandez-Ramos, J. -A., Lopez-Laso, E., Kruer, M. C., Bakhtiari, S., Zollino, Marcella, Morleo, M., Marangi, Giuseppe, Mei, D., Pisano, T., Guerrini, R., Louie, R. J., Childers, A., Everman, D. B., Isidor, B., Audebert-Bellanger, S., Odent, S., Bonneau, D., Gilbert-Dussardier, B., Redon, R., Bezieau, S., Laumonnier, F., Stoeckli, E. T., Toutain, A., Vuillaume, M. -L., Zollino M. (ORCID:0000-0003-4871-9519), and Marangi G. (ORCID:0000-0002-6898-8882)

Abstract

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Published
2022

17. Additional file 2 of SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients

Author

Mouill��, M., Rio, M., Breton, S., Piketty, M. L., Afenjar, A., Amiel, J., Capri, Y., Goldenberg, A., Francannet, C., Michot, C., Mignot, C., Perrin, L., Quelin, C., Van Gils, J., Barcia, G., Pingault, V., Maruani, G., Koumakis, E., and Cormier-Daire, V.

Subjects
musculoskeletal diseases, musculoskeletal, neural, and ocular physiology, education, musculoskeletal system
Abstract

Additional file 2. Raw data and ULM values for P1NP and Osteocalcin in the 19 patients.

Published
2022
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18. Additional file 1 of SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients

Author

Mouill��, M., Rio, M., Breton, S., Piketty, M. L., Afenjar, A., Amiel, J., Capri, Y., Goldenberg, A., Francannet, C., Michot, C., Mignot, C., Perrin, L., Quelin, C., Van Gils, J., Barcia, G., Pingault, V., Maruani, G., Koumakis, E., and Cormier-Daire, V.

Abstract

Additional file 1. References for normal biological values for children and adults.

Published
2022
Full Text
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19. Phenotypic and genetic spectrum of ATP6V1A encephalopathy:a disorder of lysosomal homeostasis

Author

Guerrini, R. (Renzo), Mei, D. (Davide), Kerti-Szigeti, K. (Katalin), Pepe, S. (Sara), Koenig, M. K. (Mary Kay), Von Allmen, G. (Gretchen), Cho, M. T. (Megan T), McDonald, K. (Kimberly), Baker, J. (Janice), Bhambhani, V. (Vikas), Powis, Z. (Zöe), Rodan, L. (Lance), Nabbout, R. (Rima), Barcia, G. (Giulia), Rosenfeld, J. A. (Jill A), Bacino, C. A. (Carlos A), Mignot, C. (Cyril), Power, L. H. (Lillian H), Harris, C. J. (Catharine J), Marjanovic, D. (Dragan), Møller, R. S. (Rikke S), Hammer, T. B. (Trine B), T. D. (The DDD Study), Keski Filppula, R. (Riikka), Vieira, P. (Päivi), Hildebrandt, C. (Clara), Sacharow, S. (Stephanie), U. D. (Undiagnosed Diseases Network), Maragliano, L. (Luca), Benfenati, F. (Fabio), Lachlan, K. (Katherine), Benneche, A. (Andreas), Petit, F. (Florence), de Sainte Agathe, J. M. (Jean Madeleine), Hallinan, B. (Barbara), Si, Y. (Yue), Wentzensen, I. M. (Ingrid M), Zou, F. (Fanggeng), Narayanan, V. (Vinodh), Matsumoto, N. (Naomichi), Boncristiano, A. (Alessandra), la Marca, G. (Giancarlo), Kato, M. (Mitsuhiro), Anderson, K. (Kristin), Barba, C. (Carmen), Sturiale, L. (Luisa), Garozzo, D. (Domenico), Bei, R. (Roberto), A. c. (ATP6V1A collaborators), Masuelli, L. (Laura), Conti, V. (Valerio), Novarino, G. (Gaia), and Fassio, A. (Anna)

Subjects
developmental delay, epileptic encephalopathy, lysosomal disorder, ATP6V1A, progressive brain atrophy
Abstract

Vacuolar-type H⁺-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.

Published
2022

20. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood (vol 6, 92, 2021)

Author

Levy, M.A., Beck, D.B., Metcalfe, K., Douzgou, S., Sithambaram, S., Cottrell, T., Ansar, M., Kerkhof, J., Mignot, C., Nougues, M.C., Keren, B., Moore, H.W., Oegema, R., Giltay, J.C., Simon, M., Jaarsveld, R.H. van, Bos, J., Haelst, M. van, Motazacker, M.M., Boon, E.M.J., Santen, G.W.E., Ruivenkamp, C.A.L., Alders, M., Luperchio, T.R., Boukas, L., Ramsey, K., Narayanan, V., Schaefer, G.B., Bonasio, R., Doheny, K.F., Stevenson, R.E., Banka, S., Sadikovic, B., and Fahrner, J.A.

Published
2021

21. Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders (vol 108, pg 1692, 2021)

Author

Stolz, J.R., Foote, K.M., Veenstra-Knol, H.E., Pfundt, R., Broeke, S.W. ten, Leeuw, N. de, Roht, L., Pajusalu, S., Part, R., Rebane, I., Ounap, K., Stark, Z., Kirk, E.P., Lawson, J.A., Lunke, S., Christodoulou, J., Louie, R.J., Rogers, R.C., Davis, J.M., Innes, A.M., Wei, X.C., Keren, B., Mignot, C., Lebel, R.R., Sperber, S.M., Sakonju, A., Dosa, N., Barge-Schaapveld, D.Q.C.M., Peeters-Scholte, C.M.P.C.D., Ruivenkamp, C.A.L., Bon, B.W. van, Kennedy, J., Low, K.J., Ellard, S., Pang, L.W., Junewick, J.J., Mark, P.R., Carvill, G.L., and Swanson, G.T.

Published
2021

25. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Author

Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., Eichler, E.E., Gillentine, M.A., Wang, T., Hoekzema, K., Rosenfeld, J., Liu, P, Guo, H, Kim, C.N., Vries, B.B. de, Vissers, L.E.L.M., Nordenskjold, M., Kvarnung, M., Lindstrand, A., Nordgren, A., Gecz, J., Iascone, M., Cereda, A., Scatigno, A., Maitz, S., Zanni, G., Bertini, E., Zweier, C., Schuhmann, S., Wiesener, A., Pepper, M., Panjwani, H., Torti, E., Abid, F., Anselm, I., Srivastava, S., Atwal, P., Bacino, C.A., Bhat, G., Cobian, K., Bird, L.M., Friedman, J., Wright, M.S., Callewaert, B., Petit, F., Mathieu, S., Afenjar, A., Christensen, C.K., White, K.M., Elpeleg, O., Berger, I., Espineli, E.J., Fagerberg, C., Brasch-Andersen, C., Hansen, L.K., Feyma, T., Hughes, S., Thiffault, I., Sullivan, B., Yan, S., Keller, K., Keren, B., Mignot, C., Kooy, F., Meuwissen, M., Basinger, A., Kukolich, M., Philips, M., Ortega, L., Drummond-Borg, M., Lauridsen, M., Sorensen, K., Lehman, A., Lopez-Rangel, E., Levy, P., Lessel, D., Lotze, T., Madan-Khetarpal, S., Sebastian, J., Vento, J., Vats, D., Benman, L.M., McKee, S., Mirzaa, G.M., Muss, C., Pappas, J., Peeters, H, Romano, C, Elia, M., Galesi, O., Simon, M.E., Gassen, K.L.I. van, Simpson, K., Stratton, R., Syed, S., Thevenon, J., Palafoll, I.V., Vitobello, A., Bournez, M., Faivre, L., Xia, K., Earl, R.K., Nowakowski, T., Bernier, R.A., and Eichler, E.E.

Abstract

Contains fulltext : 245103.pdf (Publisher’s version ) (Open Access), BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare va

Published
2021

26. De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder

Author

Dias, C., Pfundt, R.P., Kleefstra, T., Schuurs-Hoeijmakers, J.H.M., Boon, E.M., Hagen, J.M. van, Zwijnenburg, P., Weiss, M.M., Keren, B., Mignot, C., Isapof, A., Weiss, K., Hershkovitz, T., Iascone, M., Maitz, S., Feichtinger, R.G., Kotzot, D., Mayr, J.A., Ben-Omran, T., Mahmoud, L., Pais, L.S., Walsh, C.A., Shashi, V., Sullivan, J.A., Stong, N., Lecoquierre, F., Guerrot, A.M., Charollais, A., Rodan, L.H., Dias, C., Pfundt, R.P., Kleefstra, T., Schuurs-Hoeijmakers, J.H.M., Boon, E.M., Hagen, J.M. van, Zwijnenburg, P., Weiss, M.M., Keren, B., Mignot, C., Isapof, A., Weiss, K., Hershkovitz, T., Iascone, M., Maitz, S., Feichtinger, R.G., Kotzot, D., Mayr, J.A., Ben-Omran, T., Mahmoud, L., Pais, L.S., Walsh, C.A., Shashi, V., Sullivan, J.A., Stong, N., Lecoquierre, F., Guerrot, A.M., Charollais, A., and Rodan, L.H.

Abstract

Item does not contain fulltext, TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.

Published
2021

27. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, H.K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C.S., Soucy, A., Genetti, C.A., Suslovitch, V., Rodan, L.H., Tiller, G.E., Lesca, G., Gripp, K.W., Asadollahi, R., Hamosh, A., Applegate, C.D., Turnpenny, P.D., Simon, M.E., Volker-Touw, C.M., Gassen, K. van, Binsbergen, E.V., Pfundt, R.P., Gardeitchik, T., Vries, B.B. de, Immken, L.L., Buchanan, C., Willing, M., Toler, T.L., Fassi, E., Baker, L., Vansenne, F., Wang, X, Ambrus, J.L., Jr., Fannemel, M., Posey, J.E., Agolini, E., Novelli, A., Rauch, A., Boonsawat, P., Fagerberg, C.R., Larsen, M.J., Kibaek, M., Labalme, A., Poisson, A., Payne, K.K., Walsh, L.E., Aldinger, K.A., Balciuniene, J., Skraban, C., Gray, C., Murrell, J., Bupp, C.P., Pascolini, G., Grammatico, P., Broly, M., Küry, S., Nizon, M., Rasool, I.G., Zahoor, M.Y., Kraus, C., Reis, A., Iqbal, M., Uguen, K., Audebert-Bellanger, S., Ferec, C., Redon, S., Baker, J., Wu, Y., Zampino, G., Syrbe, S., Brosse, I., Jamra, R.A., Dobyns, W.B., Cohen, L.L., Blomhoff, A., Mignot, C., Keren, B., Courtin, T., Agrawal, P.B., Beggs, A.H., Yu, T.W., Harris, H.K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C.S., Soucy, A., Genetti, C.A., Suslovitch, V., Rodan, L.H., Tiller, G.E., Lesca, G., Gripp, K.W., Asadollahi, R., Hamosh, A., Applegate, C.D., Turnpenny, P.D., Simon, M.E., Volker-Touw, C.M., Gassen, K. van, Binsbergen, E.V., Pfundt, R.P., Gardeitchik, T., Vries, B.B. de, Immken, L.L., Buchanan, C., Willing, M., Toler, T.L., Fassi, E., Baker, L., Vansenne, F., Wang, X, Ambrus, J.L., Jr., Fannemel, M., Posey, J.E., Agolini, E., Novelli, A., Rauch, A., Boonsawat, P., Fagerberg, C.R., Larsen, M.J., Kibaek, M., Labalme, A., Poisson, A., Payne, K.K., Walsh, L.E., Aldinger, K.A., Balciuniene, J., Skraban, C., Gray, C., Murrell, J., Bupp, C.P., Pascolini, G., Grammatico, P., Broly, M., Küry, S., Nizon, M., Rasool, I.G., Zahoor, M.Y., Kraus, C., Reis, A., Iqbal, M., Uguen, K., Audebert-Bellanger, S., Ferec, C., Redon, S., Baker, J., Wu, Y., Zampino, G., Syrbe, S., Brosse, I., Jamra, R.A., Dobyns, W.B., Cohen, L.L., Blomhoff, A., Mignot, C., Keren, B., Courtin, T., Agrawal, P.B., Beggs, A.H., and Yu, T.W.

Abstract

Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access), PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Published
2021

28. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2).

Author

Franken, G.A.C., Müller, D., Mignot, C., Keren, B., Lévy, J., Tabet, A.C., Germanaud, D., Tejada, M.I., Kroes, H.Y., Nievelstein, R.A., Brimble, E., Ruzhnikov, M., Claverie-Martin, F., Szczepańska, M., Ćuk, M., Latta, F., Konrad, M., Martínez-Cruz, L.A., Bindels, R.J.M., Hoenderop, J.G.J., Schlingmann, K.P., Baaij, J.H.F. de, Franken, G.A.C., Müller, D., Mignot, C., Keren, B., Lévy, J., Tabet, A.C., Germanaud, D., Tejada, M.I., Kroes, H.Y., Nievelstein, R.A., Brimble, E., Ruzhnikov, M., Claverie-Martin, F., Szczepańska, M., Ćuk, M., Latta, F., Konrad, M., Martínez-Cruz, L.A., Bindels, R.J.M., Hoenderop, J.G.J., Schlingmann, K.P., and Baaij, J.H.F. de

Abstract

01 april 2021, Contains fulltext : 238837.pdf (Publisher’s version ) (Open Access), Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. (25) Mg(2+) uptake assays demonstrated loss-of-function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44-0.72 mmol/L), which could not be fully corrected by Mg(2+) supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR.

Published
2021

29. CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Author

Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, Aggarwal, V, Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, and Aggarwal, V

Abstract

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Published
2021

30. The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy

Author

Datta, AN, Bahi-Buisson, N, Bienvenu, T, Buerki, SE, Gardiner, F, Cross, JH, Heron, B, Kaminska, A, Korff, CM, Lepine, A, Lesca, G, McTague, A, Mefford, HC, Mignot, C, Milh, M, Piton, A, Pressler, RM, Ruf, S, Sadleir, LG, de Saint Martin, A, Van Gassen, K, Verbeek, NE, Ville, D, Villeneuve, N, Zacher, P, Scheffer, IE, Lemke, JR, Datta, AN, Bahi-Buisson, N, Bienvenu, T, Buerki, SE, Gardiner, F, Cross, JH, Heron, B, Kaminska, A, Korff, CM, Lepine, A, Lesca, G, McTague, A, Mefford, HC, Mignot, C, Milh, M, Piton, A, Pressler, RM, Ruf, S, Sadleir, LG, de Saint Martin, A, Van Gassen, K, Verbeek, NE, Ville, D, Villeneuve, N, Zacher, P, Scheffer, IE, and Lemke, JR

Abstract

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

Published
2021

33. Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56

Author

Legrand, A., primary, Pujol, C., additional, Durand, C. M., additional, Mesnil, A., additional, Rubera, I., additional, Duranton, C., additional, Zuily, S., additional, Sousa, A. B., additional, Renaud, M., additional, Boucher, J. L., additional, Pietrancosta, N., additional, Adham, S., additional, Orssaud, C., additional, Marelli, C., additional, Casali, C., additional, Ziccardi, L., additional, Villain, N., additional, Ewenczyk, C., additional, Durr, A., additional, Mignot, C., additional, Stevanin, G., additional, Billon, C., additional, Hureaux, M., additional, Jeunemaitre, X., additional, Goizet, C., additional, and Albuisson, J., additional

Published
2021
Full Text
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36. Integrated genome and transcriptome analyses solves about one third of the patients with rare developmental disorders and negative first-line molecular investigations

Author

Vitobello, A., Mau-Them, F. Tran, Bruel, A. L., Duffourd, Y., Tisserant, E., Callier, P., Moutton, S., Nambot, S., Lehalle, D., Jean-Marcais, N., Delanne, J., Racine, C., Thevenon, J., Poe, C., Jouan, T., Chevarin, M., Willems, M., Coubes, C., Genevieve, D., Houcinat, N., Masurel-Paulet, Alice, Mosca-Boidron, A.-L., Sorlin, A., Isidor, B., Heide, S., Afenjar, A., Rodriguez, D., Mignot, C., Heron, D., Vincent, M., Charles, P., Odent, S., Dubourg, C., Faudet, A., Keren, B., Cogne, B., Boland, A., Olaso, R., Philippe, C., Deleuze, J. F., Faivre, L., Thauvin-Robinet, C., Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lapeyronie [Montpellier] (CHU), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Université Paris 1 Panthéon-Sorbonne (UP1), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Paris-Saclay, 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, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

37. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Aref-Eshghi, E., Kerkhof, J., Pedro, V.P., Barat-Houari, M., Ruiz-Pallares, N., Andrau, J.C., Lacombe, D., Van-Gils, J., Fergelot, P., Dubourg, C., Cormier-Daire, V., Rondeau, S., Lecoquierre, F., Saugier-Veber, P., Nicolas, G., Lesca, G., Chatron, N., Sanlaville, D., Vitobello, A., Faivre, L., Thauvin-Robinet, C., Laumonnier, F., Raynaud, M., Alders, M., Mannens, M., Henneman, P., Hennekam, R.C., Velasco, G., Francastel, C., Ulveling, D., Ciolfi, A., Pizzi, S., Tartaglia, M., Heide, S. van der, Heron, D., Mignot, C., Keren, B., Whalen, S., Afenjar, A., Bienvenu, T., Campeau, P.M., Rousseau, J., Levy, M.A., Brick, L., Kozenko, M., Balci, T.B., Siu, V.M., Stuart, A., Kadour, M., Masters, J., Takano, K., Kleefstra, T., Leeuw, N. de, Field, M., Shaw, M., Gecz, J., Ainsworth, P.J., Lin, H., Rodenhiser, D.I., Friez, M.J., Tedder, M., Lee, Jae Lyun, DuPont, B.R., Stevenson, R.E., Skinner, S.A., Schwartz, C.E., Genevieve, D., Sadikovic, B., Aref-Eshghi, E., Kerkhof, J., Pedro, V.P., Barat-Houari, M., Ruiz-Pallares, N., Andrau, J.C., Lacombe, D., Van-Gils, J., Fergelot, P., Dubourg, C., Cormier-Daire, V., Rondeau, S., Lecoquierre, F., Saugier-Veber, P., Nicolas, G., Lesca, G., Chatron, N., Sanlaville, D., Vitobello, A., Faivre, L., Thauvin-Robinet, C., Laumonnier, F., Raynaud, M., Alders, M., Mannens, M., Henneman, P., Hennekam, R.C., Velasco, G., Francastel, C., Ulveling, D., Ciolfi, A., Pizzi, S., Tartaglia, M., Heide, S. van der, Heron, D., Mignot, C., Keren, B., Whalen, S., Afenjar, A., Bienvenu, T., Campeau, P.M., Rousseau, J., Levy, M.A., Brick, L., Kozenko, M., Balci, T.B., Siu, V.M., Stuart, A., Kadour, M., Masters, J., Takano, K., Kleefstra, T., Leeuw, N. de, Field, M., Shaw, M., Gecz, J., Ainsworth, P.J., Lin, H., Rodenhiser, D.I., Friez, M.J., Tedder, M., Lee, Jae Lyun, DuPont, B.R., Stevenson, R.E., Skinner, S.A., Schwartz, C.E., Genevieve, D., and Sadikovic, B.

Abstract

Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access), Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Published
2020

38. Mutations in the KIF21B Kinesin Gene Cause Neurodevelopmental Disorders Through Imbalanced Canonical Motor Activity

Author

Asselin, L., Alvarez, J., Heide, S. van der, Bonnet, C.S., Tilly, P., Vitet, H., Weber, C., Bacino, C.A., Baranaño, K., Chassevent, A., Dameron, A., Faivre, L., Hanchard, N.A., Mahida, S., K., M., Mignot, C., Nava, C., Rastetter, A., Streff, H., Thauvin-Robinet, C., Weiss, M.M., Zapata, G., Zwijnenburg, P.J., F., S., Depienne, C., Golzio, C., Héron, D., Godin, J.D., Asselin, L., Alvarez, J., Heide, S. van der, Bonnet, C.S., Tilly, P., Vitet, H., Weber, C., Bacino, C.A., Baranaño, K., Chassevent, A., Dameron, A., Faivre, L., Hanchard, N.A., Mahida, S., K., M., Mignot, C., Nava, C., Rastetter, A., Streff, H., Thauvin-Robinet, C., Weiss, M.M., Zapata, G., Zwijnenburg, P.J., F., S., Depienne, C., Golzio, C., Héron, D., and Godin, J.D.

Abstract

Contains fulltext : 220453.pdf (publisher's version ) (Open Access)

Published
2020

39. Developmental and epilepsy spectrum ofKCNB1encephalopathy with long-term outcome

Author

Bar, C, Kuchenbuch, M, Barcia, G, Schneider, A, Jennesson, M, Le Guyader, G, Lesca, G, Mignot, C, Montomoli, M, Parrini, E, Isnard, H, Rolland, A, Keren, B, Afenjar, A, Dorison, N, Sadleir, LG, Breuillard, D, Levy, R, Rio, M, Dupont, S, Negrin, S, Danieli, A, Scalais, E, De Saint Martin, A, El Chehadeh, S, Chelly, J, Poisson, A, Lebre, A-S, Nica, A, Odent, S, Sekhara, T, Brankovic, V, Goldenberg, A, Vrielynck, P, Lederer, D, Maurey, H, Terrone, G, Besmond, C, Hubert, L, Berquin, P, Billette de Villemeur, T, Isidor, B, Freeman, JL, Mefford, HC, Myers, CT, Howell, KB, Rodriguez-Sacristan Cascajo, A, Meyer, P, Genevieve, D, Guet, A, Doummar, D, Durigneux, J, van Dooren, MF, de Wit, MCY, Gerard, M, Marey, I, Munnich, A, Guerrini, R, Scheffer, IE, Kabashi, E, Nabbout, R, Bar, C, Kuchenbuch, M, Barcia, G, Schneider, A, Jennesson, M, Le Guyader, G, Lesca, G, Mignot, C, Montomoli, M, Parrini, E, Isnard, H, Rolland, A, Keren, B, Afenjar, A, Dorison, N, Sadleir, LG, Breuillard, D, Levy, R, Rio, M, Dupont, S, Negrin, S, Danieli, A, Scalais, E, De Saint Martin, A, El Chehadeh, S, Chelly, J, Poisson, A, Lebre, A-S, Nica, A, Odent, S, Sekhara, T, Brankovic, V, Goldenberg, A, Vrielynck, P, Lederer, D, Maurey, H, Terrone, G, Besmond, C, Hubert, L, Berquin, P, Billette de Villemeur, T, Isidor, B, Freeman, JL, Mefford, HC, Myers, CT, Howell, KB, Rodriguez-Sacristan Cascajo, A, Meyer, P, Genevieve, D, Guet, A, Doummar, D, Durigneux, J, van Dooren, MF, de Wit, MCY, Gerard, M, Marey, I, Munnich, A, Guerrini, R, Scheffer, IE, Kabashi, E, and Nabbout, R

Abstract

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechani

Published
2020

40. Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations

Author

Spencer-Smith, M, Knight, JL, Lacaze, E, Depienne, C, Lockhart, PJ, Richards, LJ, Heron, D, Leventer, RJ, Robinson, GA, Ceslis, A, Gibson, E, Giraudat, K, McIlroy, A, Paul, LK, Siffredi, V, Bahlo, M, Barker, M, Blondiaux, E, Edwards, TJ, Garel, C, Heide, S, Keren, B, Mandelstam, SA, Marsh, APL, McGillivray, G, Mignot, C, Moutard, M-L, Nava, C, Pope, K, Rastetter, A, Stephenson, SEM, Valence, S, de Villemeur, TB, Wood, A, Anderson, V, Sherr, EH, Spencer-Smith, M, Knight, JL, Lacaze, E, Depienne, C, Lockhart, PJ, Richards, LJ, Heron, D, Leventer, RJ, Robinson, GA, Ceslis, A, Gibson, E, Giraudat, K, McIlroy, A, Paul, LK, Siffredi, V, Bahlo, M, Barker, M, Blondiaux, E, Edwards, TJ, Garel, C, Heide, S, Keren, B, Mandelstam, SA, Marsh, APL, McGillivray, G, Mignot, C, Moutard, M-L, Nava, C, Pope, K, Rastetter, A, Stephenson, SEM, Valence, S, de Villemeur, TB, Wood, A, Anderson, V, and Sherr, EH

Abstract

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.

Published
2020

41. Developmental and symptom profiles in early-onset psychosis

Author

Ferrafiat, Vladimir, Raffin, Marie, Freri, Elena, Granata, Tiziana, Nardocci, Nardo, Zibordi, Federica, Bodeau, Nicolas, Benarous, Xavier, Olliac, Bertrand, Riquin, Elise, Viaux, Sylvie, Haroche, Julien, Amoura, Zahir, Gérardin, Priscille, Consoli, Angèle, Zahoui, Mohamed, Zhou, Bo, Bilan, Frederic, Zhang, Xianglong, Gilbert-Dussardier, Brigitte, Viaux-Savelon, Sylvie, Pattni, Reenal, Ho, Steve, Urban, Alexander, Delion, Pierre, Labreuche, Julien, Deplanque, Dominique, Duhamel, Alain, Lallié, Céline, Ravary, Maud, Goëb, Jean-Louis, Medjkane, François, Gauthier, Soizic, Anzalone, Salvatore, Zaoui, Mohamed, Chetouani, Mohamed, Villa, François, Berthoz, Alain, Angeard, N., Huerta, E., Gargiulo, M., Servais, L., Eymard, B., Chérot, E., Keren, B., Dubourg, C., Carré, W., Fradin, M., Lavillaureix, A., Afenjar, A., Burglen, L., Whalen, S., Charles, P., Marey, I., Heide, S., Jacquette, A., Heron, D., Doummar, D., Rodriguez, D., Billette de Villemeur, T., Moutard, M.-L., Guët, A., Périsse, D., Demurger, F., Quelin, C., Depienne, C., Odent, S., Nava, C., David, V., Pasquier, L., Mignot, C., Giannitelli, Marianna, Levinson, Douglas, Cohen, David, Xavier, Jean, Laurent-Levinson, Claudine, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut des Systèmes Intelligents et de Robotique (ISIR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Fédération hospitalo-universitaire de psychiatrie de l'enfant et de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Stanford University, Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Perception, Interaction, Robotique sociales (PIROS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Physiologie de la Perception et de l'Action (LPPA), Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD [France-Ouest]), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Environnements et Paléoenvironnements OCéaniques (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, National Alliance for Research on Schizophrenia and Depression, Centre de Référence des Maladies Rares à Expression Psychiatrique, Department of Child and Adolescent Psychiatry, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Stanford Schizophrenia Genetics Research Fund, Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences Cognitives et Sciences Affectives (SCALab) - UMR 9193 (SCALab), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Service de génétique clinique, and hôpital Sud

Subjects
Adult, Psychosis, Adolescent, Early onset psychosis, 03 medical and health sciences, [SCCO]Cognitive science, 0302 clinical medicine, Cluster analysis, Humans, Medicine, Medical diagnosis, Child, Children, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Psychopathology, business.industry, Neuropsychology, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Symptom profiles, Psychotic Disorders, Schizophrenia, Cohort, Factor analysis, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Psychotic disorders in children are more heterogeneous than is captured by categorical diagnoses. In a new cohort of children and adolescents, we evaluated the relationships among age at onset (AAO), clinical symptoms and developmental impairments. Patients with schizophrenia and other "spectrum" psychotic diagnoses (N = 88; AAO 6-17, mean 12.6) were evaluated with diagnostic interviews, a new clinical scale (Lifetime Dimensions of Psychosis Scale-Child and Adolescent), and neuropsychological and medical evaluations. Key findings were replicated in an adult cohort of 2420 cases, including 127 with retrospective AAO13. Factor and cluster analyses were carried out to identify clinical profiles. Five clinical factors were identified in each cohort: Positive, Bizarre Positive, Negative/Formal Thought Disorder, Depression and Mania. Earlier AAO predicted severity of bizarre positive symptoms in children and of bizarre and other symptoms in adults. Four clinical clusters in the child cohort were characterized by: more severe bizarre positive symptoms (N = 31); negative symptoms (N = 15); premorbid autism spectrum features and developmental delay (N = 12); and depressive symptoms with heterogeneous diagnoses and mild positive/negative symptoms (N = 25). Previous factor-analytic studies of childhood psychosis did not specifically consider bizarre positive symptoms. Here, bizarre positive symptoms emerged as clinical markers of severe, childhood-onset psychosis similar to adult schizophrenia. The four clusters are clinically meaningful and useful for treatment planning and potentially for biological research. Childhood-onset cases are rare and thus difficult to study, but additional, larger cohorts may be useful in dissecting the biological and developmental heterogeneity of psychotic disorders.

Published
2019

46. Deciphering the natural history of SCA7 in children

Author

Bah, M. G., primary, Rodriguez, D., additional, Cazeneuve, C., additional, Mochel, F., additional, Devos, D., additional, Suppiej, A., additional, Roubertie, A., additional, Meunier, I., additional, Gitiaux, C., additional, Curie, A., additional, Klapczynski, F., additional, Allani‐Essid, N., additional, Carneiro, M., additional, Van Minkelen, R., additional, Kievit, A., additional, Fluss, J., additional, Leheup, B., additional, Ratbi, L., additional, Héron, D., additional, Gras, D., additional, Do Cao, J., additional, Pichard, S., additional, Strubi‐Villaume, I., additional, Audo, I., additional, Lesca, G., additional, Charles, P., additional, Dubois, F., additional, Comet‐Didierjean, P., additional, Capri, Y., additional, Barondiot, C., additional, Barathon, M., additional, Ewenczyk, C., additional, Durr, A., additional, and Mignot, C., additional

Published
2020
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47. Prospective interest in deploying multi-omics approaches to solve unsolved patients with suspected monogenic developmental delay syndromes

Author

Duffourd, Y., Tisserant, E., Plagos, A., Callier, P., Tran-Them, F. Mau, Bruel, A., Denomme-Pichon, A., Philippe, C., Isidor, B., Heide, S., Afenjar, A., Rodriguez, D., Mignot, C., Heron, D., Vincent, M., Charles, P., Moutton, S., Jean, N., Odent, S., Dubourg, C., Faudet, A., Keren, B., Cogne, B., Boland, A., Olaso, R., Thauvin, C., Faivre, L., Deleuze, Jean-Francois, Vitobello, A., 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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, Plateau technique de Biologie [CHU de Dijon], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Dijon, Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2019

48. GRIN2A-related disorders : genotype and functional consequence predict phenotype

Author

Strehlow, V., Heyne, H.O., Vlaskamp, D.R.M., Marwick, K.F.M., Rudolf, G., Bellescize, J. de, Biskup, S., Brilstra, E.H., Brouwer, O.F., Callenbach, P.M.C., Hentschel, J., Hirsch, E., Kind, P.C., Mignot, C., Platzer, K., Rump, P., Skehel, P.A., Wyllie, D.J.A., Hardingham, G.E., Ravenswaaij-Arts, C.M.A. van, Koolen, D.A., Willemsen, M.H., Lesca, G., Lemke, J.R., Clinical Cognitive Neuropsychiatry Research Program (CCNP), UCL - (MGD) Service de pédiatrie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, univOAK, Archive ouverte, University Hospital Leipzig, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Edinburgh, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Centre Hospitalier Universitaire de Lyon (CHU Lyon), CeGaT GmbH, University Medical Center [Utrecht], Hôpital de Hautepierre [Strasbourg], Institute for Stem Cell Science and Regenerative Medicine [Bangalore, Inde] (inStem), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and GRIN2A study group: Alexis Arzimanoglou, Paul B Augustijn, Patrick Van Bogaert, Helene Bourry, Peter Burfeind, Yoyo Chu, Brian Chung, Diane Doummar, Patrick Edery, Aviva Fattal-Valevski, Mélanie Fradin, Marion Gerard, Christa de Geus, Boudewijn Gunning, Danielle Hasaerts, Ingo Helbig, Katherine L Helbig, Rami Jamra, Mélanie Jennesson Lyver, Jolien S Klein Wassink-Ruiter, David A Koolen, Damien Lederer, Roelineke J Lunsing, Mikaël Mathot, Hélène Maurey, Shay Menascu, Anne Michel, Ghayda Mirzaa, Diana Mitter, Hiltrud Muhle, Rikke S Møller, Caroline Nava, Margaret O'Brien, Evelyn van Pinxteren-Nagler, Anne van Riesen, Christelle Rougeot, Damien Sanlaville, Jolanda H Schieving, Steffen Syrbe, Hermine E Veenstra-Knol, Nienke Verbeek, Dorothée Ville, Yvonne J Vos, Pascal Vrielynck, Sabrina Wagner, Sarah Weckhuysen, Marjolein H Willemsen

Subjects
GLUN2A, Adult, Male, Adolescent, Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, VARIANTS, Neurodevelopmental Disorders/genetics, Receptors, N-Methyl-D-Aspartate, Epilepsy/genetics, Cerebellar Cortex, Young Adult, channelopathy, GRIN2A MUTATIONS, Research Support, N.I.H., Extramural, Journal Article, Animals, Humans, Child, EPILEPSY, Cells, Cultured, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, SPECTRUM, learning disability, Receptors, N-Methyl-D-Aspartate/genetics, Research Support, Non-U.S. Gov't, childhood epilepsy, Cerebellar Cortex/metabolism, Infant, ENCEPHALOPATHY, Original Articles, Middle Aged, spike-wave EEG, Rats, Editor's Choice, Phenotype, NMDA, Neurodevelopmental Disorders, Child, Preschool, molecular genetics, SUBUNIT, Mutation, Female, APHASIA, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals., Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10−6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/− cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.

Published
2019

49. Correction to: The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature (Genetics in Medicine, (2018), 10.1038/s41436-018-0339-3)

Author

Piard, J., Hawkes, L., Milh, M., Villard, L., Borgatti, Renato, Romaniello, R., Fradin, M., Capri, Y., Héron, D., Nougues, M. -C., Nava, Consuelo Rubina, Arsene, O. T., Shears, D., Taylor, J., Pagnamenta, A., Taylor, J. C., Sogawa, Y., Johnson, D., Firth, H., Vasudevan, P., Jones, G., Nguyen-Morel, M. -A., Busa, T., Roubertie, A., van den Born, M., Brischoux-Boucher, E., Koenig, M., Mignot, C., Kini, U., and Philippe, C.

Subjects
WWOX-related disorders, Settore M-PSI/08 - PSICOLOGIA CLINICA
Published
2019

50. The phenotypic spectrum of WWOX-related Epileptic Encephalopathy: 20 additional cases and review of the literature

Author

Piard, J., Hawkes, L., Milh, M., Villard, Laurent, Borgatti, R., Fradin, M., Capri, Y., Heron, D., Nougues, M., Nava, C., Arsene, O. Tarta, Shears, D., Sogawa, Y., Johnson, D., Firth, H., Vasudevan, P., Jones, G., Nguyen-Morel, M., Busa, T., Roubertie, A., Born, M., Koenig, M., Brischoux-Boucher, E., Mignot, C., Kini, U., Philippe, C., Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics
Abstract

51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Milan, ITALY, JUN 16-19, 2018; International audience

Published
2019

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