Search

Your search keyword '"Isidor, B"' showing total 650 results
Start Over Author "Isidor, B"
650 results on '"Isidor, B"'

3. RNA variant assessment using transactivation and transdifferentiation

Author

Nicolas-Martinez, EC, Robinson, O, Pflueger, C, Gardner, A, Corbett, MA, Ritchie, T, Kroes, T, van Eyk, CL, Scheffer, IE, Hildebrand, MS, Barnier, J-V, Rousseau, V, Genevieve, D, Haushalter, V, Piton, A, Denommé-Pichon, A-S, Bruel, A-L, Nambot, S, Isidor, B, Grigg, J, Gonzalez, T, Ghedia, S, Marchant, RG, Bournazos, A, Wong, W-K, Webster, RI, Evesson, FJ, Jones, KJ, PERSYST Investigator Team, Cooper, ST, Lister, R, Gecz, J, Jolly, LA, Berkovic, SF, Delatycki, M, Nicolas-Martinez, EC, Robinson, O, Pflueger, C, Gardner, A, Corbett, MA, Ritchie, T, Kroes, T, van Eyk, CL, Scheffer, IE, Hildebrand, MS, Barnier, J-V, Rousseau, V, Genevieve, D, Haushalter, V, Piton, A, Denommé-Pichon, A-S, Bruel, A-L, Nambot, S, Isidor, B, Grigg, J, Gonzalez, T, Ghedia, S, Marchant, RG, Bournazos, A, Wong, W-K, Webster, RI, Evesson, FJ, Jones, KJ, PERSYST Investigator Team, Cooper, ST, Lister, R, Gecz, J, Jolly, LA, Berkovic, SF, and Delatycki, M

Abstract

Understanding the impact of splicing and nonsense variants on RNA is crucial for the resolution of variant classification as well as their suitability for precision medicine interventions. This is primarily enabled through RNA studies involving transcriptomics followed by targeted assays using RNA isolated from clinically accessible tissues (CATs) such as blood or skin of affected individuals. Insufficient disease gene expression in CATs does however pose a major barrier to RNA based investigations, which we show is relevant to 1,436 Mendelian disease genes. We term these "silent" Mendelian genes (SMGs), the largest portion (36%) of which are associated with neurological disorders. We developed two approaches to induce SMG expression in human dermal fibroblasts (HDFs) to overcome this limitation, including CRISPR-activation-based gene transactivation and fibroblast-to-neuron transdifferentiation. Initial transactivation screens involving 40 SMGs stimulated our development of a highly multiplexed transactivation system culminating in the 6- to 90,000-fold induction of expression of 20/20 (100%) SMGs tested in HDFs. Transdifferentiation of HDFs directly to neurons led to expression of 193/516 (37.4%) of SMGs implicated in neurological disease. The magnitude and isoform diversity of SMG expression following either transactivation or transdifferentiation was comparable to clinically relevant tissues. We apply transdifferentiation and/or gene transactivation combined with short- and long-read RNA sequencing to investigate the impact that variants in USH2A, SCN1A, DMD, and PAK3 have on RNA using HDFs derived from affected individuals. Transactivation and transdifferentiation represent rapid, scalable functional genomic solutions to investigate variants impacting SMGs in the patient cell and genomic context.

Published
2024

4. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Author

Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., Vasileiou G., Bosch, E, Popp, B, Güse, E, Skinner, C, van der Sluijs, P, Maystadt, I, Pinto, A, Renieri, A, Bruno, L, Granata, S, Marcelis, C, Baysal, Ö, Hartwich, D, Holthöfer, L, Isidor, B, Cogne, B, Wieczorek, D, Capra, V, Scala, M, De Marco, P, Ognibene, M, Jamra, R, Platzer, K, Carter, L, Kuismin, O, van Haeringen, A, Maroofian, R, Valenzuela, I, Cuscó, I, Martinez-Agosto, J, Rabani, A, Mefford, H, Pereira, E, Close, C, Anyane-Yeboa, K, Wagner, M, Hannibal, M, Zacher, P, Thiffault, I, Beunders, G, Umair, M, Bhola, P, Mcginnis, E, Millichap, J, van de Kamp, J, Prijoles, E, Dobson, A, Shillington, A, Graham, B, Garcia, E, Galindo, M, Ropers, F, Nibbeling, E, Hubbard, G, Karimov, C, Goj, G, Bend, R, Rath, J, Morrow, M, Millan, F, Salpietro, V, Torella, A, Nigro, V, Kurki, M, Stevenson, R, Santen, G, Zweier, M, Campeau, P, Severino, M, Reis, A, Accogli, A, Vasileiou, G, Bosch E., Popp B., Güse E., Skinner C., van der Sluijs P. J., Maystadt I., Pinto A. M., Renieri A., Bruno L. P., Granata S., Marcelis C., Baysal Ö., Hartwich D., Holthöfer L., Isidor B., Cogne B., Wieczorek D., Capra V., Scala M., De Marco P., Ognibene M., Jamra R. A., Platzer K., Carter L. B., Kuismin O., van Haeringen A., Maroofian R., Valenzuela I., Cuscó I., Martinez-Agosto J. A., Rabani A. M., Mefford H. C., Pereira E. M., Close C., Anyane-Yeboa K., Wagner M., Hannibal M. C., Zacher P., Thiffault I., Beunders G., Umair M., Bhola P. T., McGinnis E., Millichap J., van de Kamp J. M., Prijoles E. J., Dobson A., Shillington A., Graham B. H., Garcia E. J., Galindo M. K., Ropers F. G., Nibbeling E. A. R., Hubbard G., Karimov C., Goj G., Bend R., Rath J., Morrow M. M., Millan F., Salpietro V., Torella A., Nigro V., Kurki M., Stevenson R. E., Santen G. W. E., Zweier M., Campeau P. M., Severino M., Reis A., Accogli A., and Vasileiou G.

Abstract

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non -truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.(c) 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2023

6. 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

7. 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
Full Text
View/download PDF

8. Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Author

Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, Curry, C.J., Wojcik, M.H., Srivastava, S., Agrawal, P.B., Balci, T.B., Callewaert, B., Calvo, P.L., Carli, D., Caudle, M., Colaiacovo, S., Cross, L., Demetriou, K., Drazba, K., Dutra-Clarke, M., Edwards, M., Genetti, C.A., Grange, D.K., Hickey, S.E., Isidor, B., Küry, S., Lachman, H.M., Lavillaureix, A., Lyons, M.J., Marcelis, C.L.M., Marco, E.J., Martinez-Agosto, J.A., Nowak, C., Pizzol, A., Planes, M., Prijoles, E.J., Riberi, E., Rush, E.T., Russell, B.E., Sachdev, R., Schmalz, B., Shears, D., Stevenson, D.M., Wilson, K., Jansen, S, Vries, B.B.A. de, and Curry, C.J.

Abstract

01 juli 2023, Item does not contain fulltext, Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Published
2023

9. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

Author

Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., Kleefstra, T., Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., and Kleefstra, T.

Abstract

Item does not contain fulltext, De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Published
2023

10. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

Author

Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., Vasileiou, G., Bosch, E., Popp, B., Güse, E., Skinner, C., Sluijs, P.J. van der, Maystadt, I., Pinto, Ameet J., Renieri, A., Bruno, L.P., Granata, S., Marcelis, C.L., Baysal, Ö., Hartwich, D., Holthöfer, L., Isidor, B., Cogne, B., Wieczorek, D., Capra, V., Scala, M., Marco, P. De, Ognibene, M., Jamra, R.A., Platzer, K., Carter, L.B., Kuismin, O., Haeringen, A. van, Maroofian, R., Valenzuela, I., Cuscó, I., Martinez-Agosto, J.A., Rabani, A.M., Mefford, H.C., Pereira, E.M., Close, C., Anyane-Yeboa, K., Wagner, M., Hannibal, M.C., Zacher, P., Thiffault, I., Beunders, G., Umair, M., Bhola, P.T., McGinnis, E., Millichap, J., Kamp, J.M. van de, Prijoles, E.J., Dobson, A., Shillington, A., Graham, B.H., Garcia, E.J., Galindo, M.K., Ropers, F.G., Nibbeling, E.A., Hubbard, G., Karimov, C., Goj, G., Bend, R., Rath, J., Morrow, M.M., Millan, F., Salpietro, V., Torella, A., Nigro, V., Kurki, M., Stevenson, R.E., Santen, G.W.E., Zweier, M., Campeau, P.M., Severino, M., Reis, A., Accogli, A., and Vasileiou, G.

Abstract

Contains fulltext : 299984.pdf (Publisher’s version ) (Open Access), PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated., 01 november 2023

Published
2023

11. Additional file 1 of Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting

Author

Soilly, AL, Robert-Viard, C, Besse, C, Bruel, AL, Gerard, B, Boland, A, Piton, A, Duffourd, Y, Muller, J, Poë, C, Jouan, T, El Doueiri, S, Faivre, L, Bacq-Daian, D, Isidor, B, Genevieve, D, Odent, S, Philip, N, Doco-Fenzy, M, Lacombe, D, Asensio, ML, Deleuze, JF, Binquet, C, Thauvin-Robinet, C, and Lejeune, C

Abstract

Additional file 1. Resources used (year 2018). Full details of resources used.

Published
2023
Full Text
View/download PDF

12. Syndromes avec malformations vasculaires cutanées hypertrophiques associés aux mutations du gène PIK3R1

Author

Engel, C., primary, Laeng, M., additional, Martel, J., additional, Piard, J., additional, Isidor, B., additional, Phan, A., additional, Boccara, O., additional, Bessis, D., additional, Morice-Picard, F., additional, Ott, H., additional, Guerot, A.M., additional, Mazereeuw-Hautier, J., additional, Maruani, A., additional, Puzenat, E., additional, Aubert, H., additional, Faivre, L., additional, Kuentz, P., additional, and Vabres, P., additional

Published
2022
Full Text
View/download PDF

15. 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
View/download PDF

16. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., and Clinical Genetics

Subjects
Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Hypertelorism, Developmental Disabilities, speech impairment, Genetic Variation, ASXL3, BRPS, Young Adult, Phenotype, ASXL3-related syndrome, Bainbridge–Ropers syndrome, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Mutation, Humans, Muscle Hypotonia, Female, Genetic Predisposition to Disease, Child, Transcription Factors
Abstract

Item does not contain fulltext The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021

17. 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

18. Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Author

Cuinat, S., Nizon, M., Isidor, B., Stegmann, Alexander, Jaarsveld, R.H. van, Gassen, K.L.I. van, Smagt, J.J. van der, Volker-Touw, C.M., Holwerda, S.J.B., Terhal, P.A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A.A., Yasaei, H., Ousager, L.B., Brasch-Andersen, C., Deb, W., Besnard, T., Simon, M.E., Amsterdam, K.H., Verbeek, N.E., Matalon, D., Dykzeul, N., White, S., Spiteri, E., Devriendt, K., Boogaerts, A., Willemsen, M.H., Brunner, H.G., Sinnema, M., Vries, B.B. de, Gerkes, E.H., Pfundt, R.P., Izumi, K., Krantz, I.D., Xu, Z.L., Murrell, J.R., Valenzuela, I., Cusco, I., Rovira-Moreno, E., Yang, Y., Bizaoui, V., Patat, O., Faivre, L., Tran-Mau-Them, F., Vitobello, A., Denommé-Pichon, A.S., Philippe, C., Bezieau, S., Cogné, B., Cuinat, S., Nizon, M., Isidor, B., Stegmann, Alexander, Jaarsveld, R.H. van, Gassen, K.L.I. van, Smagt, J.J. van der, Volker-Touw, C.M., Holwerda, S.J.B., Terhal, P.A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A.A., Yasaei, H., Ousager, L.B., Brasch-Andersen, C., Deb, W., Besnard, T., Simon, M.E., Amsterdam, K.H., Verbeek, N.E., Matalon, D., Dykzeul, N., White, S., Spiteri, E., Devriendt, K., Boogaerts, A., Willemsen, M.H., Brunner, H.G., Sinnema, M., Vries, B.B. de, Gerkes, E.H., Pfundt, R.P., Izumi, K., Krantz, I.D., Xu, Z.L., Murrell, J.R., Valenzuela, I., Cusco, I., Rovira-Moreno, E., Yang, Y., Bizaoui, V., Patat, O., Faivre, L., Tran-Mau-Them, F., Vitobello, A., Denommé-Pichon, A.S., Philippe, C., Bezieau, S., and Cogné, B.

Abstract

Contains fulltext : 282702.pdf (Publisher’s version ) (Closed access), PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.

Published
2022

19. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author

Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, Tan, TY, Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, and Tan, TY

Abstract

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Published
2022

20. 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

21. Le syndrome Dicer1 : cas d’une repousse thyroïdienne après thyroïdectomie

Author

Cristovao, L., Drui, D., Baron, S., Thebaud, E., Mirallie, E., Sagan, C., Isidor, B., and Delemazure Chesneau, A.S.

Abstract

Le syndrome DICER1, prédisposition rare dont les principales pathologies sont rencontrées en pédiatrie : tumeurs malignes dont pleuropneumoblastomes, tumeurs ovariennes de Seroli-Leydig et tumeurs bénignes dont goitres plus ou moins nodulaires. Patiente de 17 ans, avec variant pathogène de DIGER1 découverte à la suite du diagnostic de tumeur Sertoli-Leydig, présentait un goitre multinodulaire (GMN). Dans ses antécédents familiaux on notait un GMN chez son père, l’une de ses tantes paternelles et sa grand-mère-paternelle. La thyroïdectomie a permis de confirmer la bénignité à l’anatomopathologie. Le suivi trimestriel révèle des difficultés d’observance de l’hormonothérapie substitutive avec une TSH montant jusqu’à 136 uUl/ml. À 3 ans de la thyroïdectomie, la palpation cervicale révélait des nodules thyroïdiens. L’échographie confirmait une repousse thyroïdienne, siège de nombreux nodules dont la cytologie des plus suspects était Bethesda3. Devant l’aspect de cette repousse, un bilan pré opératoire est réalisé. La thyroglobuline était à 668ng/ml en regard d’une TSH à 0,15 uUI/ml. Le scanner-cervico-thoracique montrait des localisations cervicales multiples, en faveur d’une repousse bilatérale dans la loge de thyroïdectomie et de nodules sous-cutanés atteignant jusque 3cm. Une reprise chirurgicale est réalisée permettant la résection de nombreux nodules de tissu thyroïdien. L’anatomopathologique confirmait un parenchyme thyroïdien plurinodulaire avec des secteurs d’hyperplasie papillaire, typique du DICER1, sans caractère suspect. Une totalisation par IRAthérapie sera discutée en fonction de la thryroglobuline postopératoire, compte tenu des multiples nodules de récidive et d’une chirurgie possiblement incomplète. Il n’existe pas dans la littérature de cas similaire avec repousse thyroïdienne complète après thyroïdectomie totale dans le DICER1.

Published
2024
Full Text
View/download PDF

22. PURA-Related Developmental and Epileptic Encephalopathy

Author

Johannesen, K.M., Gardella, E., Gjerulfsen, C.E., Bayat, A., Rouhl, R.P.W., Reijnders, M., Whalen, S., Keren, B., Buratti, J., Courtin, T., Wierenga, K.J., Isidor, B., Piton, A., Faivre, L., Garde, A., Moutton, S., Tran-Mau-Them, F., Denomme-Pichon, A.S., Coubes, C., Larson, A., Esser, M.J., Appendino, J.P., Al-Hertani, W., Gamboni, B., Mampel, A., Mayorga, L., Orsini, A., Bonuccelli, A., Suppiej, A., Van-Gils, J., Vogt, J., Damioli, S., Giordano, L., Moortgat, S., Wirrell, E., Hicks, S., Kini, U., Noble, N., Stewart, H., Asakar, S., Cohen, J.S., Naidu, S.R., Collier, A., Brilstra, E.H., Li, M.H., Brew, C., Bigoni, S., Ognibene, D., Ballardini, E., Ruivenkamp, C., RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and MUMC+: DA KG Polikliniek (9)

Subjects
ALPHA, DELINEATION, EPILEPSIES, DE-NOVO MUTATIONS, MORTALITY, FEATURES, PHENOTYPE, CLASSIFICATION, POSTNATAL BRAIN-DEVELOPMENT
Abstract

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-alpha, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Published
2021

23. The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals

Author

Giannuzzi, G., Schmidt, P. J., Porcu, E., Willemin, G., Munson, K. M., Nuttle, X., Earl, R., Chrast, J., Hoekzema, K., Risso, D., Mannik, K., De Nittis, P., Baratz, E. D., Attanasio, C., Martin, S., Jacquemont, S., Bottani, A., Gerard, M., Weber, S., Jacquette, A., Lesne, F., Isidor, B., Le Caignec, C., Nizon, M., Vincent-Delorme, C., Gilbert-Dussardier, B., Curro`, A., Renieri, A., Giachino, D., Brusco, A., Herault, Y., Gao, X., Philpott, C. C., Bernier, R. A., Kutalik, Z., Fleming, M. D., Eichler, E. E., Reymond, A., Chercheur indépendant, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Weill Medical College of Cornell University [New York], University of Tartu, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Christian Albrechts University, Department of Psychiatry and Behavioral Sciences, Department of Medical Genetics, Université de Lausanne (UNIL), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), and Université de Lausanne (UNIL)-Université de Lausanne (UNIL)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Chromosome Disorders, 0302 clinical medicine, Chromosome Duplication, Gene duplication, Homeostasis, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 2. Zero hunger, Genetics, iron deficiency anemia, medicine.diagnostic_test, Microcytosis, Anemia, Iron deficiency, 3. Good health, BOLA2, Phenotype, medicine.anatomical_structure, Serum iron, Female, Chromosome Deletion, Heterozygote, DNA Copy Number Variations, Genotype, 16p11.2 copy number variants, Iron, Biology, Article, 03 medical and health sciences, human evolution, gene duplication, human-specific segmental duplications, medicine, Animals, Humans, Autistic Disorder, [SDV.GEN]Life Sciences [q-bio]/Genetics, Proteins, medicine.disease, Red blood cell, 030104 developmental biology, Iron-deficiency anemia, Hemoglobin, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4–BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4–BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e−7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2(+/−) and Bola2(−/−) animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.

Published
2019

25. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian, M., Dingemans, A.J.M., Albaba, S., Richardson, R., Yates, T.M., Cox, H., Douzgou, S., Armstrong, R., Sansbury, F.H., Burke, K.B., Fry, A.E., Ragge, N., Sharif, S., Foster, A., Sandre-Giovannoli, A. De, Elouej, S., Vasudevan, P., Mansour, S., Wilson, K., Stewart, H., Heide, S. van der, Nava, C., Keren, B., Demirdas, S., Brooks, A.S., Vincent, M., Isidor, B., Küry, S., Schouten, M.I., Leenders, E.K.S.M., Chung, W.K., Haeringen, A.V., Scheffner, T., Debray, F.G., White, S.M., Palafoll, M.I.V., Pfundt, R.P., Newbury-Ecob, R., Kleefstra, T., Balasubramanian, M., Dingemans, A.J.M., Albaba, S., Richardson, R., Yates, T.M., Cox, H., Douzgou, S., Armstrong, R., Sansbury, F.H., Burke, K.B., Fry, A.E., Ragge, N., Sharif, S., Foster, A., Sandre-Giovannoli, A. De, Elouej, S., Vasudevan, P., Mansour, S., Wilson, K., Stewart, H., Heide, S. van der, Nava, C., Keren, B., Demirdas, S., Brooks, A.S., Vincent, M., Isidor, B., Küry, S., Schouten, M.I., Leenders, E.K.S.M., Chung, W.K., Haeringen, A.V., Scheffner, T., Debray, F.G., White, S.M., Palafoll, M.I.V., Pfundt, R.P., Newbury-Ecob, R., and Kleefstra, T.

Abstract

Contains fulltext : 245024.pdf (Publisher’s version ) (Open Access), Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.

Published
2021

26. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., Tümer, Z., Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., and Tümer, Z.

Abstract

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access), PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021

27. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.

Abstract

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Published
2021

28. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Author

Verberne, E.A., Goh, S., England, J., Ginkel, M. van, Rafael-Croes, L., Maas, S., Polstra, A., Zarate, Y.A., Bosanko, K.A., Pechter, K.B., Bedoukian, E., Izumi, K., Chaudhry, A., Robin, N.H., Boothe, M., Lippa, N.C., Aggarwal, V., Vivo, D.C. De, Lehman, A., Study, C., Stockler, S., Bruel, A.L., Isidor, B., Lemons, J., Rodriguez-Buritica, D.F., Richmond, C.M., Stark, Z., Agrawal, P.B., Kooy, R.F., Meuwissen, M.E.C., Koolen, D.A., Pfundt, R.P., Lieden, A., Anderlid, B.M., Glatz, D., Mannens, M., Bakshi, M., Mallette, F.A., Haelst, M.M. van, Campeau, P.M., Verberne, E.A., Goh, S., England, J., Ginkel, M. van, Rafael-Croes, L., Maas, S., Polstra, A., Zarate, Y.A., Bosanko, K.A., Pechter, K.B., Bedoukian, E., Izumi, K., Chaudhry, A., Robin, N.H., Boothe, M., Lippa, N.C., Aggarwal, V., Vivo, D.C. De, Lehman, A., Study, C., Stockler, S., Bruel, A.L., Isidor, B., Lemons, J., Rodriguez-Buritica, D.F., Richmond, C.M., Stark, Z., Agrawal, P.B., Kooy, R.F., Meuwissen, M.E.C., Koolen, D.A., Pfundt, R.P., Lieden, A., Anderlid, B.M., Glatz, D., Mannens, M., Bakshi, M., Mallette, F.A., Haelst, M.M. van, and Campeau, P.M.

Abstract

Item does not contain fulltext, PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.

Published
2021

29. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), Kleefstra, T. (Tjitske), Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), and Kleefstra, T. (Tjitske)

Abstract

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

Published
2021
Full Text
View/download PDF

30. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian, M, Dingemans, AJM, Albaba, S, Richardson, R, Yates, TM, Cox, H, Douzgou, S, Armstrong, R, Sansbury, FH, Burke, KB, Fry, AE, Ragge, N, Sharif, S, Foster, A, De Sandre-Giovannoli, A, Elouej, S, Vasudevan, P, Mansour, S, Wilson, K, Stewart, H, Heide, S, Nava, C, Keren, B, Demirdas, S, Brooks, AS, Vincent, M, Isidor, B, Kury, S, Schouten, M, Leenders, E, Chung, WK, Haeringen, AV, Scheffner, T, Debray, F-G, White, SM, Palafoll, MIV, Pfundt, R, Newbury-Ecob, R, Kleefstra, T, Balasubramanian, M, Dingemans, AJM, Albaba, S, Richardson, R, Yates, TM, Cox, H, Douzgou, S, Armstrong, R, Sansbury, FH, Burke, KB, Fry, AE, Ragge, N, Sharif, S, Foster, A, De Sandre-Giovannoli, A, Elouej, S, Vasudevan, P, Mansour, S, Wilson, K, Stewart, H, Heide, S, Nava, C, Keren, B, Demirdas, S, Brooks, AS, Vincent, M, Isidor, B, Kury, S, Schouten, M, Leenders, E, Chung, WK, Haeringen, AV, Scheffner, T, Debray, F-G, White, SM, Palafoll, MIV, Pfundt, R, Newbury-Ecob, R, and Kleefstra, T

Abstract

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.

Published
2021

31. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian M, Dingemans AJM, lbaba S, Richardson R, Yates TM, Cox H, Douzgou S, Armstrong R, Sansbury FH, Burke KB, Fry AE, Ragge N, Sharif S, Foster A, De Sandre-Giovannoli A, Elouej S, Vasudevan P, Mansour S, Wilson K, Stewart H, Heide S, Nava C, Keren B, Demirdas S, Brooks AS, Vincent M, Isidor B, Küry S, Schouten M, Leenders E, Chung WK, van Haeringen A, Scheffner T, Debray F, White SM, Valenzuela Palafoll MI, Pfundt R, Newbury-Ecob R, Kleefstra T, Balasubramanian M, Dingemans AJM, lbaba S, Richardson R, Yates TM, Cox H, Douzgou S, Armstrong R, Sansbury FH, Burke KB, Fry AE, Ragge N, Sharif S, Foster A, De Sandre-Giovannoli A, Elouej S, Vasudevan P, Mansour S, Wilson K, Stewart H, Heide S, Nava C, Keren B, Demirdas S, Brooks AS, Vincent M, Isidor B, Küry S, Schouten M, Leenders E, Chung WK, van Haeringen A, Scheffner T, Debray F, White SM, Valenzuela Palafoll MI, Pfundt R, Newbury-Ecob R, and Kleefstra T

Abstract

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, pediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ eight years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.

Published
2021

32. DISSEQ: Double-blind Next-Generation-Sequencing technologies (exome and gene panel) in the diagnosis of a cohort of 330 patients with an intellectual disability: concordance, discrepancies, and efficiencies

Author

Bruel, A., Gerard, B., Piton, A., Mau-Them, F. Tran, Sorlin, A., Sorly, A., Lacombe, D., Manouvrier, S., Edery, P., Philip, N., Genevieve, D., Verloes, A., Odent, S., Thevenon, J., Toutain, A., Bonneau, D., El Chehadeh, S., Doco-Fenzy, M., Isidor, B., Goldenberg, A., Vincent-Delorme, C., Boute-Benejean, O., Lambert, L., Asensio, M., Callier, P., Duffourd, Y., Lejeune, C., Christine Binquet, Philippe, C., Faivre, L., Thauvin-Robinet, C., 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), 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), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille Nord de France (COMUE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 ), Centre Hospitalier Universitaire [Grenoble] (CHU), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Centre hospitalier universitaire de Nantes (CHU Nantes), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CRHU Nancy, Chard-Hutchinson, Xavier, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon (CRNL), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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 de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Rennes 1 (UR1), and 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 )

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

International audience

Published
2020

33. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Author

Chassaing, N., Causse, A., Vigouroux, A., Delahaye, A., Alessandri, J.-L., Boespflug-Tanguy, O., Boute-Benejean, O., Dollfus, H., Duban-Bedu, B., Gilbert-Dussardier, B., Giuliano, F., Gonzales, M., Holder-Espinasse, M., Isidor, B., Jacquemont, M.-L., Lacombe, D., Martin-Coignard, D., Mathieu-Dramard, M., Odent, S., Picone, O., Pinson, L., Quelin, C., Sigaudy, S., Toutain, A., Thauvin-Robinet, C., Kaplan, Josseline, and Calvas, Patrick

Published
2014
Full Text
View/download PDF

36. KAT6A Syndrome

Author

Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

37. Phenotypic and genotypic description of 44 patients with variants in DLG4 encoding the post-synaptic density protein PSD-95

Author

Rodriguez-Palmero Seuma, A., Boerrigter, M., Mandrile, G., Pelle, A., Giorgio, E., Lindstrand, A., Johansson, M., Kvarnung, M., Everman, D., Bahrambeigi, V., MacKenzie, A., Morton, J., Ruivenkamp, C., Challman, T., Hurst, A., Hoyer, J., Elmslie, F., Dye, T., Isidor, B., Haldeman-Englert, C., Gomez-Andres, D., Schluter, A., de Man, S., Shieh, J., Prada, C., Moutton, S., Denomme-Pichon, A., Motti, S., Bruel, A., Mau-Them, F. Tran, Reiter, S., van Ravenswaaij-Arts, C., Shaw-Smith, C., Parikh, S., Aldinger, K., Lovgren, A., Rauch, A., Ross, M., Gomez-Puertas, P., de Vries, B., Pujol, A., Tumer, Z., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Published
2020

38. Correction to ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder

Author

Carapito, R. (Raphaël), Ivanova, E. (Ekaterina), Morlon, A. (Aurore), Meng, L. (Linyan), Molitor, A. (Anne), Erdmann, E. (Eva), Kieffer, B. (Bruno), Pichot, A. (Angélique), Naegely, L. (Lydie), Kolmer, A. (Aline), Paul, N. (Nicodème), Hanauer, A. (Antoine), Tran Mau-Them, F. (Frédéric), Jean-Marçais, N. (Nolwenn), Hiatt, S. (Susan), Cooper, G. (Gregory), Tvrdik, T. (Tatiana), Muir, A. (Alison), Dimartino, C. (Clémantine), Chopra, M. (Maya), Amiel, J. (Jeanne), Gordon, C. (Christopher), Dutreux, F. (Fabien), Garde, A. (Aurore), Thauvin-Robinet, C. (Christel), Wang, X. (Xia), Leduc, M. (Magalie), Phillips, M. (Meredith), Crawford, H. (Heather), Kukolich, M. (Mary), Hunt, D. (David), Harrison, V. (Victoria), Kharbanda, M. (Mira), Smigiel, R. (Robert), Gold, N. (Nina), Hung, C. (Christina), Viskochil, D. (David), Dugan, S. (Sarah), Bayrak-Toydemir, P. (Pinar), Joly-Helas, G. (Géraldine), Guerrot, A. (Anne-Marie), Schluth-Bolard, C. (Caroline), Rio, M. (Marlène), Wentzensen, Ingrid M., McWalter, K. (Kirsty), Schnur, R. (Rhonda), Lewis, A. (Andrea), Lalani, S. (Seema), Mensah-Bonsu, N. (Noël), Céraline, J. (Jocelyn), Sun, Z. (Zijie), Ploski, R. (Rafal), Bacino, C. (Carlos), Mefford, H. (Heather), Faivre, L. (Laurence), Bodamer, O. (Olaf), Chelly, J. (Jamel), Isidor, B. (Bertrand), and Bahram, S. (Seiamak)

Subjects
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Sciences du Vivant [q-bio]/Biotechnologies
Published
2020

39. 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

40. RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

Author

Palmer, EE, Carroll, R, Shaw, M, Kumar, R, Minoche, AE, Leffler, M, Murray, L, Macintosh, R, Wright, D, Troedson, C, McKenzie, F, Townshend, S, Ward, M, Nawaz, U, Ravine, A, Runke, CK, Thorland, EC, Hummel, M, Foulds, N, Pichon, O, Isidor, B, Le Caignec, C, Demeer, B, Andrieux, J, Albarazi, SH, Bye, A, Sachdev, R, Kirk, EP, Cowley, MJ, Field, M, Gecz, J, Palmer, EE, Carroll, R, Shaw, M, Kumar, R, Minoche, AE, Leffler, M, Murray, L, Macintosh, R, Wright, D, Troedson, C, McKenzie, F, Townshend, S, Ward, M, Nawaz, U, Ravine, A, Runke, CK, Thorland, EC, Hummel, M, Foulds, N, Pichon, O, Isidor, B, Le Caignec, C, Demeer, B, Andrieux, J, Albarazi, SH, Bye, A, Sachdev, R, Kirk, EP, Cowley, MJ, Field, M, and Gecz, J

Abstract

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Published
2020

41. RLIM is a candidate dosage sensitive gene for individuals with varying duplications of Xq13, intellectual disability and recognizable facial features.

Author

Palmer, EE, Caroll, R, Shaw, M, Kumar, R, Nawaz, U, Minoche, A, Leffler, M, Murray, L, Macintosh, R, Wright, D, Troedson, C, McKenzie, F, Townshend, S, Ward, M, Ravine, A, Runke, CK, Thorland, EC, Hummel, M, Foulds, N, Pichon, O, Isidor, B, Le Caignec, C, Bye, A, Sachdev, R, Kirk, EP, Cowley, MJ, Field, M, Gecz, J, Palmer, EE, Caroll, R, Shaw, M, Kumar, R, Nawaz, U, Minoche, A, Leffler, M, Murray, L, Macintosh, R, Wright, D, Troedson, C, McKenzie, F, Townshend, S, Ward, M, Ravine, A, Runke, CK, Thorland, EC, Hummel, M, Foulds, N, Pichon, O, Isidor, B, Le Caignec, C, Bye, A, Sachdev, R, Kirk, EP, Cowley, MJ, Field, M, and Gecz, J

Published
2020

42. 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

44. The impact of the Next Generation Sequencing strategy in the diagnosis of two rare causes of hypertrophic cardiomyopathy: Fabry disease and hereditary transthyretin amyloidosis (ATTR)

Author

Koraichi, F., primary, Ader, F., additional, Donal, E., additional, Bordet, C., additional, De Groote, P., additional, Moerman, A., additional, Faivre, L., additional, Réant, P., additional, Thambo, C., additional, Toutain, A., additional, Babuty, D., additional, Palmyre, A., additional, Nguyen, K., additional, Isidor, B., additional, Brehin, A., additional, Pruny, J., additional, Isnard, R., additional, Richard, P., additional, and Charron, P., additional

Published
2021
Full Text
View/download PDF

48. Tératomes sacrococcygiens

Author

Winer, N., primary, Le Caignec, C., additional, Aubron, F., additional, Isidor, B., additional, David, A., additional, and Leclair, M.D., additional

Published
2011
Full Text
View/download PDF

49. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

Author

Halgren, C, Kjaergaard, S, Bak, M, Hansen, C, El-Schich, Z, Anderson, CM, Henriksen, KF, Hjalgrim, H, Kirchhoff, M, Bijlsma, EK, Nielsen, M, den Hollander, NS, Ruivenkamp, CAL, Isidor, B, Le Caignec, C, Zannolli, R, Mucciolo, M, Renieri, A, Mari, F, Anderlid, B-M, Andrieux, J, Dieux, A, Tommerup, N, and Bache, I

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results