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1. A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort

Author

Garret, Philippine, Chevarin, Martin, Vitobello, Antonio, Verdez, Simon, Fournier, Cyril, Verloes, Alain, Tisserant, Emilie, Vabres, Pierre, Prevel, Orlane, Philippe, Christophe, Denommé-Pichon, Anne-Sophie, Bruel, Ange-Line, Mau-Them, Frédéric Tran, Safraou, Hana, Boughalem, Aïcha, Costa, Jean-Marc, Trost, Detlef, Thauvin-Robinet, Christel, Faivre, Laurence, and Duffourd, Yannis

Published
2023
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2. Correction: Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples

Author

Wijngaard, Robin, Demidov, German, O’Gorman, Luke, Corominas-Galbany, Jordi, Yaldiz, Burcu, Steyaert, Wouter, de Boer, Elke, Vissers, Lisenka E. L. M., Kamsteeg, Erik-Jan, Pfundt, Rolph, Swinkels, Hilde, den Ouden, Amber, te Paske, Iris B. A. W., de Voer, Richarda M., Faivre, Laurence, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Vitobello, Antonio, Chevarin, Martin, Straub, Volker, Töpf, Ana, van der Kooi, Anneke J., Magrinelli, Francesca, Rocca, Clarissa, Hanna, Michael G., Vandrovcova, Jana, Ossowski, Stephan, Laurie, Steven, and Gilissen, Christian

Published
2024
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3. YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse

Author

Denommé-Pichon, Anne-Sophie, Collins, Stephan C., Bruel, Ange-Line, Mikhaleva, Anna, Wagner, Christel, Vancollie, Valerie E., Thomas, Quentin, Chevarin, Martin, Weber, Mathys, Prada, Carlos E., Overs, Alexis, Palomares-Bralo, María, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Busa, Tiffany, Legius, Eric, Bacino, Carlos A., Rosenfeld, Jill A., Le Guyader, Gwenaël, Egloff, Matthieu, Le Guillou, Xavier, Mencarelli, Maria Antonietta, Renieri, Alessandra, Grosso, Salvatore, Levy, Jonathan, Dozières, Blandine, Desguerre, Isabelle, Vitobello, Antonio, Duffourd, Yannis, Lelliott, Christopher J., Thauvin-Robinet, Christel, Philippe, Christophe, Faivre, Laurence, and Yalcin, Binnaz

Published
2023
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5. Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway

Author

Delanne, Julian, Lecat, Magaly, Blackburn, Patrick R., Klee, Eric W., Stumpel, Constance T.R.M., Stegmann, Sander, Stevens, Servi J.C., Nava, Caroline, Heron, Delphine, Keren, Boris, Mahida, Sonal, Naidu, Sakkubai, Babovic-Vuksanovic, Dusica, Herkert, Johanna C., Torring, Pernille M., Kibæk, Maria, De Bie, Isabelle, Pfundt, Rolph, Hendriks, Yvonne M.C., Ousager, Lilian Bomme, Bend, Renee, Warren, Hannah, Skinner, Steven A., Lyons, Michael J., Pöe, Charlotte, Chevarin, Martin, Jouan, Thibaud, Garde, Aurore, Thomas, Quentin, Kuentz, Paul, Tisserant, Emilie, Duffourd, Yannis, Philippe, Christophe, Faivre, Laurence, and Thauvin-Robinet, Christel

Published
2023
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6. Same performance of exome sequencing before and after fetal autopsy for congenital abnormalities: toward a paradigm shift in prenatal diagnosis?

Author

Bourgon, Nicolas, Garde, Aurore, Bruel, Ange-Line, Lefebvre, Mathilde, Mau-Them, Frederic Tran, Moutton, Sebastien, Sorlin, Arthur, Nambot, Sophie, Delanne, Julian, Chevarin, Martin, Pöe, Charlotte, Thevenon, Julien, Lehalle, Daphné, Jean-Marçais, Nolween, Kuentz, Paul, Lambert, Laetitia, El Chehadeh, Salima, Schaefer, Elise, Willems, Marjolaine, Laffargue, Fanny, Francannet, Christine, Fradin, Mélanie, Gaillard, Dominique, Blesson, Sophie, Goldenberg, Alice, Capri, Yline, Sagot, Paul, Rousseau, Thierry, Simon, Emmanuel, Binquet, Christine, Ascencio, Marie-Laure, Duffourd, Yannis, Philippe, Christophe, Faivre, Laurence, Vitobello, Antonio, and Thauvin-Robinet, Christel

Published
2022
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7. Clinical phenotype of the PIK3R1-related vascular overgrowth syndrome

Author

Kuentz, Paul, primary, Engel, Camille, additional, Laeng, Mathieu, additional, Chevarin, Martin, additional, Duffourd, Yannis, additional, Martel, Jéhanne, additional, Piard, Juliette, additional, Morice-Picard, Fanny, additional, Aubert, Helene, additional, Bessis, Didier, additional, Guerrot, Anne-Marie, additional, Maruani, Annabel, additional, Boccara, Olivia, additional, Mazereeuw-Hautier, Juliette, additional, Ott, Hagen, additional, Phan, Alice, additional, Puzenat, Eve, additional, Quelin, Chloe, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, and Vabres, Pierre, additional

Published
2024
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8. Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

Author

Thomas, Quentin, Gautier, Thierry, Marafi, Dana, Besnard, Thomas, Willems, Marjolaine, Moutton, Sébastien, Isidor, Bertand, Cogné, Benjamin, Conrad, Solène, Tenconi, Romano, Iascone, Maria, Sorlin, Arthur, Masurel, Alice, Dabir, Tabib, Jackson, Adam, Banka, Siddharth, Delanne, Julian, Lupski, James R., Saadi, Nebal Waill, Alkuraya, Fowzan S., Zahrani, Fatema Al, Agrawal, Pankaj B., England, Eleina, Madden, Jill A., Posey, Jennifer E., Burglen, Lydie, Rodriguez, Diana, Chevarin, Martin, Nguyen, Sylvie, Mau-Them, Frédéric Tran, Duffourd, Yannis, Garret, Philippine, Bruel, Ange-Line, Callier, Patrick, Marle, Nathalie, Denomme-Pichon, Anne-Sophie, Duplomb, Laurence, Philippe, Christophe, Thauvin-Robinet, Christel, Govin, Jérôme, Faivre, Laurence, and Vitobello, Antonio

Published
2021
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9. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Author

Carmignac, Virginie, Mignot, Cyril, Blanchard, Emmanuelle, Kuentz, Paul, Aubriot-Lorton, Marie-Hélène, Parker, Victoria E. R., Sorlin, Arthur, Fraitag, Sylvie, Courcet, Jean-Benoît, Duffourd, Yannis, Rodriguez, Diana, Knox, Rachel G., Polubothu, Satyamaanasa, Boland, Anne, Olaso, Robert, Delepine, Marc, Darmency, Véronique, Riachi, Melissa, Quelin, Chloé, Rollier, Paul, Goujon, Louise, Grotto, Sarah, Capri, Yline, Jacquemont, Marie-Line, Odent, Sylvie, Amram, Daniel, Chevarin, Martin, Vincent-Delorme, Catherine, Catteau, Benoît, Guibaud, Laurent, Arzimanoglou, Alexis, Keddar, Malika, Sarret, Catherine, Callier, Patrick, Bessis, Didier, Geneviève, David, Deleuze, Jean-François, Thauvin, Christel, Semple, Robert K., Philippe, Christophe, Rivière, Jean-Baptiste, Kinsler, Veronica A., Faivre, Laurence, and Vabres, Pierre

Published
2021
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10. Allelic heterogeneity in a patient with postzygotic MTOR‐related hypomelanosis of Ito with neurodevelopmental abnormalities

Author

Engel, Camille, primary, Chevarin, Martin, additional, Piard, Juliette, additional, Abad, Marine, additional, Thomas, Quentin, additional, Carmignac, Virginie, additional, Duffourd, Yannis, additional, Lemesle‐Martin, Martine, additional, Tarris, Georges, additional, Thauvin‐Robinet, Christel, additional, Vabres, Pierre, additional, Faivre, Laurence, additional, and Kuentz, Paul, additional

Published
2024
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11. Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders

Author

Tran Mau-Them, Frederic, Moutton, Sebastien, Racine, Caroline, Vitobello, Antonio, Bruel, Ange-Line, Nambot, Sophie, Kushner, Steven A., de Vrij, Femke M. S., Lehalle, Daphné, Jean-Marçais, Nolwenn, Lecoquierre, François, Delanne, Julian, Thevenon, Julien, Poe, Charlotte, Jouan, Thibaut, Chevarin, Martin, Geneviève, David, Willems, Marjolaine, Coubes, Christine, Houcinat, Nada, Masurel-Paulet, Alice, Mosca-Boidron, Anne-Laure, Tisserant, Emilie, Callier, Patrick, Sorlin, Arthur, Duffourd, Yannis, Faivre, Laurence, Philippe, Christophe, and Thauvin-Robinet, Christel

Published
2020
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12. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20

Author

Juven, Aurélien, Nambot, Sophie, Piton, Amélie, Jean-Marçais, Nolwenn, Masurel, Alice, Callier, Patrick, Marle, Nathalie, Mosca-Boidron, Anne-Laure, Kuentz, Paul, Philippe, Christophe, Chevarin, Martin, Duffourd, Yannis, Gautier, Elodie, Munnich, Arnold, Rio, Marlène, Rondeau, Sophie, El Chehadeh, Salima, Schaefer, Élise, Gérard, Bénédicte, Bouquillon, Sonia, Delorme, Catherine Vincent, Francannet, Christine, Laffargue, Fanny, Gouas, Laetitia, Isidor, Bertrand, Vincent, Marie, Blesson, Sophie, Giuliano, Fabienne, Pichon, Olivier, Le Caignec, Cédric, Journel, Hubert, Perrin-Sabourin, Laurence, Fabre-Teste, Jennifer, Martin, Dominique, Vieville, Gaelle, Dieterich, Klaus, Lacombe, Didier, Denommé-Pichon, Anne-Sophie, Thauvin-Robinet, Christel, and Faivre, Laurence

Published
2020
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13. Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests

Author

Thauvin-Robinet, Christel, Thevenon, Julien, Nambot, Sophie, Delanne, Julian, Kuentz, Paul, Bruel, Ange-Line, Chassagne, Aline, Cretin, Elodie, Pelissier, Aurore, Peyron, Chritine, Gautier, Elodie, Lehalle, Daphné, Jean-Marçais, Nolwenn, Callier, Patrick, Mosca-Boidron, Anne-Laure, Vitobello, Antonio, Sorlin, Arthur, Tran Mau-Them, Frédéric, Philippe, Christophe, Vabres, Pierre, Demougeot, Laurent, Poé, Charlotte, Jouan, Thibaud, Chevarin, Martin, Lefebvre, Mathilde, Bardou, Marc, Tisserant, Emilie, Luu, Maxime, Binquet, Christine, Deleuze, Jean-François, Verstuyft, Céline, Duffourd, Yannis, and Faivre, Laurence

Published
2019
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14. Low risk of embryonic and other cancers in PIK3CA‐related overgrowth spectrum: Impact on screening recommendations

Author

Faivre, Laurence, primary, Crépin, Jean‐Charles, additional, Réda, Manon, additional, Nambot, Sophie, additional, Carmignac, Virginie, additional, Abadie, Caroline, additional, Mirault, Tristan, additional, Faure‐Conter, Cécile, additional, Mazereeuw‐Hautier, Juliette, additional, Maza, Aude, additional, Puzenat, Eve, additional, Collonge‐Rame, Marie‐Agnès, additional, Bursztejn, Anne‐Claire, additional, Philippe, Christophe, additional, Thauvin‐Robinet, Christel, additional, Chevarin, Martin, additional, Abasq‐Thomas, Claire, additional, Amiel, Jeanne, additional, Arpin, Stéphanie, additional, Barbarot, Sébastien, additional, Baujat, Geneviève, additional, Bessis, Didier, additional, Bourrat, Emmanuelle, additional, Boute, Odile, additional, Chassaing, Nicolas, additional, Coubes, Christine, additional, Demeer, Bénédicte, additional, Edery, Patrick, additional, El Chehadeh, Salima, additional, Goldenberg, Alice, additional, Hadj‐Rabia, Smail, additional, Haye, Damien, additional, Isidor, Bertrand, additional, Jacquemont, Marie‐Line, additional, Van Kien, Philippe Khau, additional, Lacombe, Didier, additional, Lehalle, Daphné, additional, Lambert, Laetitia, additional, Martin, Ludovic, additional, Maruani, Annabel, additional, Morice‐Picard, Fanny, additional, Petit, Florence, additional, Phan, Alice, additional, Pinson, Lucile, additional, Rossi, Massimiliano, additional, Touraine, Renaud, additional, Vanlerberghe, Clémence, additional, Vincent, Marie, additional, Vincent‐Delorme, Catherine, additional, Whalen, Sandra, additional, Willems, Marjolaine, additional, Marle, Nathalie, additional, Verkarre, Virginie, additional, Devalland, Christine, additional, Devouassoux‐Shisheboran, Mojgan, additional, Abad, Marine, additional, Rioux‐Leclercq, Nathalie, additional, Bonniaud, Bertille, additional, Duffourd, Yannis, additional, Martel, Jehanne, additional, Binquet, Christine, additional, Kuentz, Paul, additional, and Vabres, Pierre, additional

Published
2023
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15. Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses

Author

Bourchany, Aurélie, Thauvin-Robinet, Christel, Lehalle, Daphné, Bruel, Ange-Line, Masurel-Paulet, Alice, Jean, Nolwenn, Nambot, Sophie, Willems, Marjorie, Lambert, Laetitia, El Chehadeh-Djebbar, Salima, Schaefer, Elise, Jaquette, Aurélia, St-Onge, Judith, Poe, Charlotte, Jouan, Thibaud, Chevarin, Martin, Callier, Patrick, Mosca-Boidron, Anne-Laure, Laurent, Nicole, Lefebvre, Mathilde, Huet, Frédéric, Houcinat, Nada, Moutton, Sébastien, Philippe, Christophe, Tran-Mau-Them, Frédéric, Vitobello, Antonio, Kuentz, Paul, Duffourd, Yannis, Rivière, Jean-Baptiste, Thevenon, Julien, and Faivre, Laurence

Published
2017
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16. Correction to: Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Author

Carmignac, Virginie, Mignot, Cyril, Blanchard, Emmanuelle, Kuentz, Paul, Aubriot-Lorton, Marie-Hélène, Parker, Victoria E. R., Sorlin, Arthur, Fraitag, Sylvie, Courcet, Jean-Benoît, Duffourd, Yannis, Rodriguez, Diana, Knox, Rachel G., Polubothu, Satyamaanasa, Boland, Anne, Olaso, Robert, Delepine, Marc, Darmency, Véronique, Riachi, Melissa, Quelin, Chloé, Rollier, Paul, Goujon, Louise, Grotto, Sarah, Capri, Yline, Jacquemont, Marie-Line, Odent, Sylvie, Amram, Daniel, Chevarin, Martin, Vincent-Delorme, Catherine, Catteau, Benoît, Guibaud, Laurent, Arzimanoglou, Alexis, Keddar, Malika, Sarret, Catherine, Callier, Patrick, Bessis, Didier, Geneviève, David, Deleuze, Jean-François, Thauvin, Christel, Semple, Robert K., Philippe, Christophe, Rivière, Jean-Baptiste, Kinsler, Veronica A., Faivre, Laurence, and Vabres, Pierre

Published
2021
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17. Spectre clinique et mutationnel des malformations vasculaires cutanées hypertrophiques associées aux variants de PIK3R1

Author

Kuentz, Paul, Engel, Camille, Laeng, Mathieu, Chevarin, Martin, Aubert, Hélène, Mercier, Sandra, Isidor, Bertrand, Phan, Alice, Boccara, Olivia, Bessis, Didier, Morice-Picard, Fanny, Ott, Hagen, Guérot, Anne-Marie, Mazereeuw-Hautier, Juliette, Maruani, Annabel, Puzenat, Eve, Thauvin-Robinet, Christel, Faivre, Laurence, and Vabres, Pierre

Published
2023
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18. Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples

Author

Wijngaard, Robin, Demidov, German, O’Gorman, Luke, Corominas-Galbany, Jordi, Yaldiz, Burcu, Steyaert, Wouter, de Boer, Elke, Vissers, Lisenka E. L. M., Kamsteeg, Erik-Jan, Pfundt, Rolph, Swinkels, Hilde, den Ouden, Amber, te Paske, Iris B. A. W., de Voer, Richarda M., Faivre, Laurence, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Vitobello, Antonio, Chevarin, Martin, Straub, Volker, Töpf, Ana, van der Kooi, Anneke J., Magrinelli, Francesca, Rocca, Clarissa, Hanna, Michael G., Vandrovcova, Jana, Ossowski, Stephan, Laurie, Steven, and Gilissen, Christian

Abstract

Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. In this study, we benchmarked six MEI detection tools (ERVcaller, MELT, Mobster, SCRAMble, TEMP2 and xTea) on ES data and on GS data from publicly available genomic samples (HG002, NA12878). For all the tools we evaluated sensitivity and precision of different filtering strategies. Results show that there were substantial differences in tool performance between ES and GS data. MELT performed best with ES data and its combination with SCRAMble increased substantially the detection rate of MEIs. By applying both tools to 10,890 ES samples from Solve-RD and 52,624 samples from Radboudumc we were able to diagnose 10 patients who had remained undiagnosed by conventional ES analysis until now. Our study shows that MELT and SCRAMble can be used reliably to identify clinically relevant MEIs in ES data. This may lead to an additional diagnosis for 1 in 3000 to 4000 patients in routine clinical ES.

Published
2024
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19. Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases

Author

Racine, Caroline, Denommé-Pichon, Anne-Sophie, Engel, Camille, Tran Mau-them, Frederic, Bruel, Ange-Line, Vitobello, Antonio, Safraou, Hana, Sorlin, Arthur, Nambot, Sophie, Delanne, Julian, Garde, Aurore, Colin, Estelle, Moutton, Sébastien, Thevenon, Julien, Jean-Marcais, Nolwenn, Willems, Marjolaine, Geneviève, David, Pinson, Lucile, Perrin, Laurence, Laffargue, Fanny, Lespinasse, James, Lacaze, Elodie, Molin, Arnaud, Gerard, Marion, Lambert, Laetitia, Benigni, Charlotte, Patat, Olivier, Bourgeois, Valentin, Poe, Charlotte, Chevarin, Martin, Couturier, Victor, Garret, Philippine, Philippe, Christophe, Duffourd, Yannis, Faivre, Laurence, and Thauvin-Robinet, Christel

Abstract

PurposeWide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).MethodsFrom 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).ResultsMMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).ConclusionMMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.

Published
2024
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20. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author

Colin, Estelle, primary, Duffourd, Yannis, additional, Chevarin, Martin, additional, Tisserant, Emilie, additional, Verdez, Simon, additional, Paccaud, Julien, additional, Bruel, Ange-Line, additional, Tran Mau-Them, Frédéric, additional, Denommé-Pichon, Anne-Sophie, additional, Thevenon, Julien, additional, Safraou, Hana, additional, Besnard, Thomas, additional, Goldenberg, Alice, additional, Cogné, Benjamin, additional, Isidor, Bertrand, additional, Delanne, Julian, additional, Sorlin, Arthur, additional, Moutton, Sébastien, additional, Fradin, Mélanie, additional, Dubourg, Christèle, additional, Gorce, Magali, additional, Bonneau, Dominique, additional, El Chehadeh, Salima, additional, Debray, François-Guillaume, additional, Doco-Fenzy, Martine, additional, Uguen, Kevin, additional, Chatron, Nicolas, additional, Aral, Bernard, additional, Marle, Nathalie, additional, Kuentz, Paul, additional, Boland, Anne, additional, Olaso, Robert, additional, Deleuze, Jean-François, additional, Sanlaville, Damien, additional, Callier, Patrick, additional, Philippe, Christophe, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, and Vitobello, Antonio, additional

Published
2023
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21. The “extreme phenotype approach” applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

Author

Chevarin, Martin, primary, Alcantara, Diana, additional, Albuisson, Juliette, additional, Collonge-Rame, Marie-Agnès, additional, Populaire, Céline, additional, Selmani, Zohair, additional, Baurand, Amandine, additional, Sawka, Caroline, additional, Bertolone, Geoffrey, additional, Callier, Patrick, additional, Duffourd, Yannis, additional, Jonveaux, Philippe, additional, Bignon, Yves-Jean, additional, Coupier, Isabelle, additional, Cornelis, François, additional, Cordier, Christophe, additional, Mozelle-Nivoix, Monique, additional, Rivière, Jean-Baptiste, additional, Kuentz, Paul, additional, Thauvin, Christel, additional, Boidot, Romain, additional, Ghiringhelli, François, additional, O'Driscoll, Marc, additional, Faivre, Laurence, additional, and Nambot, Sophie, additional

Published
2023
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22. A second look at exome sequencing data: detecting mobile elements insertion in a rare disease cohort

Author

Garret, Philippine, primary, Chevarin, Martin, additional, Vitobello, Antonio, additional, Verdez, Simon, additional, Fournier, Cyril, additional, Verloes, Alain, additional, Tisserant, Emilie, additional, Vabres, Pierre, additional, Prevel, Orlane, additional, Philippe, Christophe, additional, Denommé-Pichon, Anne-Sophie, additional, Bruel, Ange-Line, additional, Mau-Them, Frédéric Tran, additional, Safraou, Hana, additional, Boughalem, Aïcha, additional, Costa, Jean-Marc, additional, Trost, Detlef, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, and Duffourd, Yannis, additional

Published
2022
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23. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Author

Colin, Estelle, primary, Duffourd, Yannis, additional, Tisserant, Emilie, additional, Relator, Raissa, additional, Bruel, Ange-Line, additional, Tran Mau-Them, Frédéric, additional, Denommé-Pichon, Anne-Sophie, additional, Safraou, Hana, additional, Delanne, Julian, additional, Jean-Marçais, Nolwenn, additional, Keren, Boris, additional, Isidor, Bertrand, additional, Vincent, Marie, additional, Mignot, Cyril, additional, Heron, Delphine, additional, Afenjar, Alexandra, additional, Heide, Solveig, additional, Faudet, Anne, additional, Charles, Perrine, additional, Odent, Sylvie, additional, Herenger, Yvan, additional, Sorlin, Arthur, additional, Moutton, Sébastien, additional, Kerkhof, Jennifer, additional, McConkey, Haley, additional, Chevarin, Martin, additional, Poë, Charlotte, additional, Couturier, Victor, additional, Bourgeois, Valentin, additional, Callier, Patrick, additional, Boland, Anne, additional, Olaso, Robert, additional, Philippe, Christophe, additional, Sadikovic, Bekim, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, Deleuze, Jean-François, additional, and Vitobello, Antonio, additional

Published
2022
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25. Evaluation of Next-Generation Sequencing Applied to Cryptosporidium parvum and Cryptosporidium hominis Epidemiological Study

Author

Bailly, Eloïse, primary, Valot, Stéphane, additional, Vincent, Anne, additional, Duffourd, Yannis, additional, Grangier, Nadège, additional, Chevarin, Martin, additional, Costa, Damien, additional, Razakandrainibe, Romy, additional, Favennec, Loïc, additional, Basmaciyan, Louise, additional, and Dalle, Frédéric, additional

Published
2022
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26. A Genotype-First Approach in Individuals with Variable Intellectual Disability Permits BRWD3 Mutations’ Diagnosis

Author

Delanne, Julian, primary, Lecat, Magali, additional, Blackburn, Patrick, additional, Klee, Eric, additional, Stumpel, Constance, additional, Stegmann, Sander, additional, Stevens, Servi, additional, Nava, Caroline, additional, Heron, Delphine, additional, Keren, Boris, additional, Mahida, Sonal, additional, Naidu, Sakkubai, additional, Babovic-Vuksanovic, Dusica, additional, Herkert, Johanna, additional, Toerring, Pernille, additional, Kibæk, Maria, additional, De Bie, Isabelle, additional, Pfundt, Rolph, additional, Hendriks, Yvonne, additional, Ousager, Lilian Bomme, additional, Bend, Renee, additional, Warren, Hannah, additional, Skinner, Steve, additional, Lyons, Michael, additional, Poe, Charlotte, additional, Chevarin, Martin, additional, Jouan, Thibaud, additional, Garde, Aurore, additional, Thomas, Quentin, additional, Kuentz, Paul, additional, Tisserant, Emilie, additional, Duffourd, Yannis, additional, Philippe, Christophe, additional, Faivre, Laurence, additional, and Thauvin, Christel, additional

Published
2022
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27. Recherche des bases moléculaires des phénotypes extrêmes de cancer par séquençage d'exome

Author

Chevarin, Martin, Equipe GAD (LNC - U1231), 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-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, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), and Chevarin, Martin

Subjects
ATR, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Prédisposition, Exome, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Phénotype extrême, Cancer
Abstract

Certains cancers peuvent être qualifiés de « phénotypes extrêmes ». Il s’agit soit de formes sporadiques particulièrement précoces, soit de formes familiales avec un excès de cancers dans une même branche parentale. La présence de plusieurs tumeurs primitives, de tumeurs bilatérales ou l'association de plusieurs cancers rares chez un même patient ou au sein d’une même famille, peut également entrer dans cette catégorie. Devant ces présentations, une prédisposition génétique est très fortement suspectée.L'analyse de panels de gènes connus pour être impliqués dans les formes mendéliennes de cancer est la pratique courante pour identifier la mutation responsable d'une prédisposition au cancer. Cependant, elle ne permet d’identifier la mutation responsable de la prédisposition génétique que dans 10% des cas. Il reste donc de nombreuses cas avec une prédisposition génétique au cancer indiscutable mais sans diagnostique moléculaire. Cela représente une difficulté majeure pour les oncogénéticiens souhaitant proposer une surveillance et un conseil génétique des plus adaptés aux patients et à leurs apparentés.Le séquençage de l’exome, de 27 patients présentant des phénotypes extrêmes de cancer, a permis d'identifier 9 gènes candidats pour une prédisposition génétique au cancer :- Trois de ces gènes candidats (ATR, DLC1 et TP53I3) ont été retrouvés à partir de cas familiaux de cancers du sein masculin, un cancer particulièrement rare. Le séquençage ciblé de ces gènes dans une cohorte de réplication a permis d’identifier des récurrences pour ATR et DLC1 et des analyses fonctionnelles ont permis de préciser la pathogénicité des certaines de ces variations.- Deux variations ont été identifiées dans des gènes déjà connus comme responsables de prédisposition génétique au cancer. L’une d’elle a été identifiée dans le gène PALB2 avec une localisation de cancer pulmonaire inhabituelle, diagnostiqué à 26 ans. La seconde est une variation hétérozygote du gène BLM dans un cancer de l’ovaire à 30 ans.- Les quatre autres variations candidates concernent des gènes impliqués dans les processus d’apoptose (BIK et DFFA), de régulation épigénétique (SETD2) ou de régulation de la prolifération cellulaire (FAT4).Ces résultats montrent la pertinence d'utiliser le séquençage d’exome et une approche de phénotypes extrêmes pour identifier des variations rares dans de nouveaux gènes candidats de prédisposition au cancer.

Published
2019

28. Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation

Author

Da Costa, Romain, De Almeida, Steven, Chevarin, Martin, Hadj-Rabia, Smail, Leclerc-Mercier, Stéphanie, Thauvin-Robinet, Christel, Garrido, Carmen, Faivre, Laurence, Vabres, Pierre, Duplomb, Laurence, Jego, Gaëtan, Equipe GAD (LNC - U1231), 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-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, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe HSPpathies (LNC - U1231), and Service de Dermatologie (CHU de Dijon)

Subjects
[SDV]Life Sciences [q-bio]
Published
2020
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29. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author

Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot, Kruisselbrink, Teresa, Lanpher, Brendan, Klee, Eric, Fiala, Elise, Grange, Dorothy, Meschino, Wendy, Hiatt, Susan, Cooper, Gregory, Olivié, Hilde, Smith, Wendy, Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan, Miramar, Dolores, van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna, Pajusalu, Sander, Õunap, Katrin, Filiano, James, Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William, Hevner, Robert, Thauvin-Robinet, Christel, Couvet, Sandrine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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, FHU TRANSLAD (CHU de Dijon), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Department of Pediatrics [Seattle], University of Washington [Seattle], Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), 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), Genetics of Neurodevelopment (GENDEV), 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)-Université Claude Bernard Lyon 1 (UCBL), Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Centre Hospitalier Intercommunal de Créteil (CHIC), Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics [Philadelphia, PA, USA], Mayo Clinic [Rochester], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Genetics [Saint-Louis], HudsonAlpha Institute for Biotechnology [Huntsville, AL], University Hospitals Leuven [Leuven], Maine Medical Center, University of British Columbia [Vancouver], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Meyer Children's Hospital [Florence, Italie], Università degli Studi di Firenze = University of Florence (UniFI), CHU Bordeaux [Bordeaux], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), University Medical Center Groningen [Groningen] (UMCG), University of Tartu, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], UF de Génétique chromosomique [CHU Trousseau], Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), GeneDx [Gaithersburg, MD, USA], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
Proband, Candidate gene, INTELLECTUAL DISABILITY, MESH: Hippocampus, [SDV]Life Sciences [q-bio], MESH: Cognition, MESH: Neocortex, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Animals, MESH: Syndrome, Genetics (clinical), Genetics, PROGENITORS, biology, Phenotype, NEOCORTEX, [SDV] Life Sciences [q-bio], EXPRESSION, GENES, MESH: Mutation, MESH: T-Box Domain Proteins, MESH: Autistic Disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Article, REGION, MESH: Intellectual Disability, NEUROGENESIS, Dysgenesis, FEZF2, medicine, MESH: Mice, MESH: Adolescent, MESH: Humans, MUTATIONS, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Autism, TBR1, business, Neurocognitive, MESH: Female
Abstract

International audience; TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.

Published
2020
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30. Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway.

Author

Bourgon, N., Carmignac, V., Sorlin, A., Duffourd, Y., Philippe, C., Thauvin‐Robinet, C., Guibaud, L., Faivre, L., Vabres, P., Kuentz, P., Tisserand, Emilie, Chevarin, Martin, Delanne, Julian, Jouan, Thibaud, Pöe, Charlotte, Abel, Carine, Allory, Patrick, Amram, Daniel, Attie‐Bitach, Tania, and Aziza, Jacqueline

Subjects
GENETIC variation, CELLULAR signal transduction, FETAL tissues, LYMPHATIC abnormalities, AMNIOTIC liquid
Abstract

Objectives: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K‐AKT‐mTOR signaling pathway. Methods: We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K‐AKT‐mTOR pathway genes by next‐generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid. Results: During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K‐AKT‐mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA‐related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11th case with HMEG. Four fetuses with limb overgrowth also had one or more lymphatic malformations (LM) and harbored a postzygotic PIK3CA variant. NGS on cultured amniocytes performed in 10 cases, of which nine had been found positive on analysis of pathological fetal tissue, showed variants in four, in either PIK3CA, PIK3R2 or AKT3. Conclusions: Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K‐AKT‐mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Published
2022
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31. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author

Garde, Aurore, primary, Cornaton, Jenny, additional, Sorlin, Arthur, additional, Moutton, Sébastien, additional, Nicolas, Claire, additional, Juif, Christine, additional, Geneviève, David, additional, Perrin, Laurence, additional, Khau‐Van‐Kien, Philippe, additional, Smol, Thomas, additional, Vincent‐Delorme, Catherine, additional, Isidor, Bertrand, additional, Cogné, Benjamin, additional, Afenjar, Alexandra, additional, Keren, Boris, additional, Coubes, Christine, additional, Prieur, Fabienne, additional, Toutain, Annick, additional, Trousselet, Yann, additional, Bourgouin, Solène, additional, Gonin‐Olympiade, Coralie, additional, Giraudat, Kim, additional, Piton, Amélie, additional, Gérard, Bénédicte, additional, Odent, Sylvie, additional, Tessier, Fanny, additional, Lemasson, Lola, additional, Heide, Solveig, additional, Gelineau, Anne‐Claire, additional, Sarret, Catherine, additional, Miret, Anne, additional, Schaefer, Elise, additional, Piard, Juliette, additional, Mathevet, Rémi, additional, Boucon, Marion, additional, Bruel, Ange‐Line, additional, Mau‐Them, Frederic Tran, additional, Chevarin, Martin, additional, Vitobello, Antonio, additional, Philippe, Christophe, additional, Thauvin‐Robinet, Christel, additional, and Faivre, Laurence, additional

Published
2020
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32. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Lehalle, Daphné, primary, Vabres, Pierre, additional, Sorlin, Arthur, additional, Bierhals, Tatjana, additional, Avila, Magali, additional, Carmignac, Virginie, additional, Chevarin, Martin, additional, Torti, Erin, additional, Abe, Yuichi, additional, Bartolomaeus, Tobias, additional, Clayton-Smith, Jill, additional, Cogné, Benjamin, additional, Cusco, Ivon, additional, Duplomb, Laurence, additional, De Bont, Eveline, additional, Duffourd, Yannis, additional, Duijkers, Floor, additional, Elpeleg, Orly, additional, Fattal, Aviva, additional, Geneviève, David, additional, Guillen Sacoto, Maria J, additional, Guimier, Anne, additional, Harris, David J, additional, Hempel, Maja, additional, Isidor, Bertrand, additional, Jouan, Thibaud, additional, Kuentz, Paul, additional, Koshimizu, Eriko, additional, Lichtenbelt, Klaske, additional, Loik Ramey, Valerie, additional, Maik, Miriam, additional, Miyakate, Sakoto, additional, Murakami, Yoshiko, additional, Pasquier, Laurent, additional, Pedro, Helio, additional, Simone, Laurie, additional, Sondergaard-Schatz, Krista, additional, St-Onge, Judith, additional, Thevenon, Julien, additional, Valenzuela, Irene, additional, Abou Jamra, Rami, additional, van Gassen, Koen, additional, van Haelst, Mieke M, additional, van Koningsbruggen, Silvana, additional, Verdura, Edgard, additional, Whelan Habela, Christa, additional, Zacher, Pia, additional, Rivière, Jean-Baptiste, additional, Thauvin-Robinet, Christel, additional, Betschinger, Joerg, additional, and Faivre, Laurence, additional

Published
2020
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33. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability

Author

Chevarin, Martin, primary, Duffourd, Yannis, additional, A. Barnard, Rebecca, additional, Moutton, Sébastien, additional, Lecoquierre, François, additional, Daoud, Fatma, additional, Kuentz, Paul, additional, Cabret, Caroline, additional, Thevenon, Julien, additional, Gautier, Elodie, additional, Callier, Patrick, additional, St-Onge, Judith, additional, Jouan, Thibaud, additional, Lacombe, Didier, additional, Delrue, Marie Ange, additional, Goizet, Cyril, additional, Morice-Picard, Fanny, additional, Van-Gils, Julien, additional, Munnich, Arnold, additional, Lyonnet, Stanislas, additional, Cormier-Daire, Valérie, additional, Baujat, Geneviève, additional, Holder, Muriel, additional, Petit, Florence, additional, Leheup, Bruno, additional, Odent, Sylvie, additional, Jouk, Pierre-Simon, additional, Lopez, Gipsy, additional, Geneviève, David, additional, Collignon, Patrick, additional, Martin-Coignard, Dominique, additional, Jacquette, Aurélia, additional, Perrin, Laurence, additional, Putoux, Audrey, additional, Sarrazin, Elisabeth, additional, Amarof, Khadija, additional, Missotte, Isabelle, additional, Coubes, Christine, additional, Jagadeesh, Sujatha, additional, Lapi, Elisabetta, additional, Demurger, Florence, additional, Goldenberg, Alice, additional, Doco-Fenzy, Martine, additional, Mignot, Cyril, additional, Héron, Delphine, additional, Jean-Marçais, Nolwenn, additional, Masurel, Alice, additional, El Chehadeh, Salima, additional, Marle, Nathalie, additional, Huet, Frédéric, additional, Binquet, Christine, additional, Collod-Beroud, Gwenaëlle, additional, Arnaud, Pauline, additional, Hanna, Nadine, additional, Boileau, Catherine, additional, Jondeau, Guillaume, additional, Olaso, Robert, additional, Lechner, Doris, additional, Poe, Charlotte, additional, Assoum, Mirna, additional, Carmignac, Virginie, additional, Duplomb, Laurence, additional, Tran Mau-Them, Frédéric, additional, Philippe, Christophe, additional, Vitobello, Antonio, additional, Bruel, Ange-Line, additional, Boland, Anne, additional, Deleuze, Jean-François, additional, Thauvin-Robinet, Christel, additional, Rivière, Jean-Baptiste, additional, O'Roak, Brian J, additional, and Faivre, Laurence, additional

Published
2020
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34. Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

Author

Delplancq, Geoffroy, primary, Tarris, Georges, additional, Vitobello, Antonio, additional, Nambot, Sophie, additional, Sorlin, Arthur, additional, Philippe, Christophe, additional, Carmignac, Virginie, additional, Duffourd, Yannis, additional, Denis, Charlotte, additional, Eicher, Jean Christophe, additional, Chevarin, Martin, additional, Millat, Gilles, additional, Khallouk, Bouchra, additional, Rousseau, Thierry, additional, Falcon‐Eicher, Sylvie, additional, Vasiljevic, Alexandre, additional, Harizay, Fara T., additional, Thauvin‐Robinet, Christel, additional, Faivre, Laurence, additional, and Kuentz, Paul, additional

Published
2020
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35. Interest of exome sequencing trio‐like strategy based on pooled parental DNA for diagnosis and translational research in rare diseases.

Author

Tran Mau‐Them, Frederic, Duffourd, Yannis, Vitobello, Antonio, Bruel, Ange‐Line, Denommé‐Pichon, Anne‐Sophie, Nambot, Sophie, Delanne, Julian, Moutton, Sebastien, Sorlin, Arthur, Couturier, Victor, Bourgeois, Valentin, Chevarin, Martin, Poe, Charlotte, Mosca‐Boidron, Anne‐Laure, Callier, Patrick, Safraou, Hana, Faivre, Laurence, Philippe, Christophe, and Thauvin‐Robinet, Christel

Subjects
RARE diseases, TRANSLATIONAL research, DNA, DIAGNOSIS, COST effectiveness
Abstract

Background: Exome sequencing (ES) has become the most powerful and cost‐effective molecular tool for deciphering rare diseases with a diagnostic yield approaching 30%–40% in solo‐ES and 50% in trio‐ES. We applied an innovative parental DNA pooling method to reduce the parental sequencing cost while maintaining the diagnostic yield of trio‐ES. Methods: We pooled six (Agilent‐CRE‐v2–100X) or five parental DNA (TWIST‐HCE–70X) aiming to detect allelic balance around 8–10% for heterozygous status. The strategies were applied as second‐tier (74 individuals after negative solo‐ES) and first‐tier approaches (324 individuals without previous ES). Results: The allelic balance of parental‐pool variants was around 8.97%. Sanger sequencing uncovered false positives in 1.5% of sporadic variants. In the second‐tier approach, we evaluated than two thirds of the Sanger validations performed after solo‐ES (41/59–69%) would have been saved if the parental‐pool segregations had been available from the start. The parental‐pool strategy identified a causative diagnosis in 18/74 individuals (24%) in the second‐tier and in 116/324 individuals (36%) in the first‐tier approaches, including 19 genes newly associated with human disorders. Conclusions: Parental‐pooling is an efficient alternative to trio‐ES. It provides rapid segregation and extension to translational research while reducing the cost of parental and Sanger sequencing. [ABSTRACT FROM AUTHOR]

Published
2021
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36. Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants

Author

Lecoquierre, François, primary, Duffourd, Yannis, additional, Vitobello, Antonio, additional, Bruel, Ange-Line, additional, Urteaga, Benoit, additional, Coubes, Christine, additional, Garret, Philippine, additional, Nambot, Sophie, additional, Chevarin, Martin, additional, Jouan, Thibaud, additional, Moutton, Sébastien, additional, Tran-Mau-Them, Frédéric, additional, Philippe, Christophe, additional, Sorlin, Arthur, additional, Faivre, Laurence, additional, and Thauvin-Robinet, Christel, additional

Published
2019
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39. Haploinsufficiency of ARFGEF1is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

Author

Thomas, Quentin, Gautier, Thierry, Marafi, Dana, Besnard, Thomas, Willems, Marjolaine, Moutton, Sébastien, Isidor, Bertand, Cogné, Benjamin, Conrad, Solène, Tenconi, Romano, Iascone, Maria, Sorlin, Arthur, Masurel, Alice, Dabir, Tabib, Jackson, Adam, Banka, Siddharth, Delanne, Julian, Lupski, James R., Saadi, Nebal Waill, Alkuraya, Fowzan S., Zahrani, Fatema Al, Agrawal, Pankaj B., England, Eleina, Madden, Jill A., Posey, Jennifer E., Burglen, Lydie, Rodriguez, Diana, Chevarin, Martin, Nguyen, Sylvie, Mau-Them, Frédéric Tran, Duffourd, Yannis, Garret, Philippine, Bruel, Ange-Line, Callier, Patrick, Marle, Nathalie, Denomme-Pichon, Anne-Sophie, Duplomb, Laurence, Philippe, Christophe, Thauvin-Robinet, Christel, Govin, Jérôme, Faivre, Laurence, and Vitobello, Antonio

Abstract

ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

Published
2021
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40. Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis

Author

Nambot, Sophie, primary, Thevenon, Julien, additional, Kuentz, Paul, additional, Duffourd, Yannis, additional, Tisserant, Emilie, additional, Bruel, Ange-Line, additional, Mosca-Boidron, Anne-Laure, additional, Masurel-Paulet, Alice, additional, Lehalle, Daphné, additional, Jean-Marçais, Nolwenn, additional, Lefebvre, Mathilde, additional, Vabres, Pierre, additional, El Chehadeh-Djebbar, Salima, additional, Philippe, Christophe, additional, Tran Mau-Them, Frederic, additional, St-Onge, Judith, additional, Jouan, Thibaud, additional, Chevarin, Martin, additional, Poé, Charlotte, additional, Carmignac, Virginie, additional, Vitobello, Antonio, additional, Callier, Patrick, additional, Rivière, Jean-Baptiste, additional, Faivre, Laurence, additional, and Thauvin-Robinet, Christel, additional

Published
2018
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41. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20missense variant versus a 3q13.31 microdeletion including ZBTB20

Author

Juven, Aurélien, Nambot, Sophie, Piton, Amélie, Jean-Marçais, Nolwenn, Masurel, Alice, Callier, Patrick, Marle, Nathalie, Mosca-Boidron, Anne-Laure, Kuentz, Paul, Philippe, Christophe, Chevarin, Martin, Duffourd, Yannis, Gautier, Elodie, Munnich, Arnold, Rio, Marlène, Rondeau, Sophie, El Chehadeh, Salima, Schaefer, Élise, Gérard, Bénédicte, Bouquillon, Sonia, Delorme, Catherine Vincent, Francannet, Christine, Laffargue, Fanny, Gouas, Laetitia, Isidor, Bertrand, Vincent, Marie, Blesson, Sophie, Giuliano, Fabienne, Pichon, Olivier, Le Caignec, Cédric, Journel, Hubert, Perrin-Sabourin, Laurence, Fabre-Teste, Jennifer, Martin, Dominique, Vieville, Gaelle, Dieterich, Klaus, Lacombe, Didier, Denommé-Pichon, Anne-Sophie, Thauvin-Robinet, Christel, and Faivre, Laurence

Abstract

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20variants were identified as responsible for this syndrome. Indeed, ZBTB20plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype–genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p= 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (pnonsignificant). Corpus callosum dysgenesis (p= 0.00004), hypothyroidism (p= 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.

Published
2020
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42. De novo TBR1variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author

Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot A., Kruisselbrink, Teresa M., Lanpher, Brendan C., Klee, Eric W., Fiala, Elise, Grange, Dorothy K., Meschino, Wendy S., Hiatt, Susan M., Cooper, Gregory M., Olivié, Hilde, Smith, Wendy E., Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan S., Miramar, Dolores, Van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna C., Pajusalu, Sander, Õunap, Katrin, Filiano, James J., Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William B., Hevner, Robert, and Thauvin-Robinet, Christel

Abstract

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1variants and diagnose ASD probands.

Published
2020
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43. Cardiomyopathy due to PRDM16mutation: First description of a fetal presentation, with possible modifier genes

Author

Delplancq, Geoffroy, Tarris, Georges, Vitobello, Antonio, Nambot, Sophie, Sorlin, Arthur, Philippe, Christophe, Carmignac, Virginie, Duffourd, Yannis, Denis, Charlotte, Eicher, Jean Christophe, Chevarin, Martin, Millat, Gilles, Khallouk, Bouchra, Rousseau, Thierry, Falcon‐Eicher, Sylvie, Vasiljevic, Alexandre, Harizay, Fara T., Thauvin‐Robinet, Christel, Faivre, Laurence, and Kuentz, Paul

Abstract

PRDM16(positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074–3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non‐compaction (LVNC) with a PRDM16variant. The third‐trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non‐compaction of the myocardium of the left ventricle. Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16. ES also identified two rare variants of unknown significance, according to the American College of Medical Genetics and Genomics guidelines, in the titin gene (TTN): a de novo missense p.(Lys14773Asn) variant and a c.33043+5A>G variant inherited from the mother. Along with the PRDM16de novo probably pathogenic variant, TTNVOUS variants could possibly contribute to the severity and early onset of the cardiac phenotype. Because of the genetic heterogeneity of cardiomyopathies, large panels or even ES could be considered as the main approaches for the molecular diagnosis, particularly in fetal presentations, where multiple hits seem to be common.

Published
2020
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44. De novomutations in the X-linked TFE3gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Lehalle, Daphné, Vabres, Pierre, Sorlin, Arthur, Bierhals, Tatjana, Avila, Magali, Carmignac, Virginie, Chevarin, Martin, Torti, Erin, Abe, Yuichi, Bartolomaeus, Tobias, Clayton-Smith, Jill, Cogné, Benjamin, Cusco, Ivon, Duplomb, Laurence, De Bont, Eveline, Duffourd, Yannis, Duijkers, Floor, Elpeleg, Orly, Fattal, Aviva, Geneviève, David, Guillen Sacoto, Maria J, Guimier, Anne, Harris, David J, Hempel, Maja, Isidor, Bertrand, Jouan, Thibaud, Kuentz, Paul, Koshimizu, Eriko, Lichtenbelt, Klaske, Loik Ramey, Valerie, Maik, Miriam, Miyakate, Sakoto, Murakami, Yoshiko, Pasquier, Laurent, Pedro, Helio, Simone, Laurie, Sondergaard-Schatz, Krista, St-Onge, Judith, Thevenon, Julien, Valenzuela, Irene, Abou Jamra, Rami, van Gassen, Koen, van Haelst, Mieke M, van Koningsbruggen, Silvana, Verdura, Edgard, Whelan Habela, Christa, Zacher, Pia, Rivière, Jean-Baptiste, Thauvin-Robinet, Christel, Betschinger, Joerg, and Faivre, Laurence

Abstract

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3variant, including the patients that initially allowed reporting TFE3as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

Published
2020
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45. Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing

Author

Bruel, Ange-Line, Nambot, Sophie, Quéré, Virginie, Vitobello, Antonio, Thevenon, Julien, Assoum, Mirna, Moutton, Sébastien, Houcinat, Nada, Lehalle, Daphné, Jean-Marçais, Nolwenn, Chevarin, Martin, Jouan, Thibaud, Poë, Charlotte, Callier, Patrick, Tisserand, Emilie, Philippe, Christophe, Them, Frédéric Tran Mau, Duffourd, Yannis, Faivre, Laurence, and Thauvin-Robinet, Christel

Abstract

In clinical exome sequencing (cES), the American College of Medical Genetics and Genomics recommends limiting variant interpretation to established human-disease genes. The diagnostic yield of cES in intellectual disability and/or multiple congenital anomalies (ID/MCA) is currently about 30%. Though the results may seem acceptable for rare diseases, they mean that 70% of affected individuals remain genetically undiagnosed. Further analysis extended to all mutated genes in a research environment is a valuable strategy for improving diagnostic yields. This study presents the results of systematic research reanalysis of negative cES in a cohort of 313 individuals with ID/MCA. We identified 17 new genes not related to human disease, implicated 22 non-OMIM disease-causing genes recently or previously rarely related to disease, and described 1 new phenotype associated with a known gene. Twenty-six candidate genes were identified and are waiting for future recurrence. Overall, we diagnose 15% of the individuals with initial negative cES, increasing the diagnostic yield from 30% to more than 40% (or 46% if strong candidate genes are considered). This study demonstrates the power of such extended research reanalysis to increase scientific knowledge of rare diseases. These novel findings can then be applied in the field of diagnostics.

Published
2019
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47. Haploinsuffiency of ARFGEF1 is associated with developmental delay, intellectual disability and epilepsy with variable expressivity

Author

Quentin Thomas, Gauthier, Thierry, Marafi, Dana, Bernard, Thomas, Willems, Marjolaine, Moutton, Sebastien, Isidor, Bertrand, Cogne, Benjamin, Conrad, Solene, Tenconi, Romano, Iascone, Maria, Sorlin, Arthur, Masurel, Alice, Dabir, Tabib, Jackson, Adam, Banka, Siddharth, Delanne, Julian, Lupski, James R., Saadi, Nebal W., Alkuraya, Fowzan S., Al Zahrani, Fatema, Agrawal, Pankaj B., England, Eleina, Madden, Jill A., Posey, Jennifer E., Burglen, Lydie, Rodriguez, Diana, Chevarin, Martin, Nguyen, Sylvie, Mau-Them, Frederic Tran, Duffourd, Yannis, Garret, Philippine, Bruel, Ange-Line, Callier, Patrick, Marle, Nathalie, Denomme-Pichon, Anne-Sophie, Duplomb, Laurence, Philippe, Christophe, Thauvin-Robinet, Christel, Govin, Jerome, Faivre, Laurence, and Vitobello, Antonio

48. Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases.

Author

Racine C, Denommé-Pichon AS, Engel C, Tran Mau-Them F, Bruel AL, Vitobello A, Safraou H, Sorlin A, Nambot S, Delanne J, Garde A, Colin E, Moutton S, Thevenon J, Jean-Marçais N, Willems M, Geneviève D, Pinson L, Perrin L, Laffargue F, Lespinasse J, Lacaze E, Molin A, Gerard M, Lambert L, Benigni C, Patat O, Bourgeois V, Poe C, Chevarin M, Couturier V, Garret P, Philippe C, Duffourd Y, Faivre L, and Thauvin-Robinet C

Subjects
Humans, Retrospective Studies, Phenotype, Exome Sequencing, Rare Diseases genetics, Intellectual Disability diagnosis, Intellectual Disability genetics
Abstract

Purpose: Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID)., Methods: From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018)., Results: MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%)., Conclusion: MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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49. Neuropsychological study in 19 French patients with White-Sutton syndrome and POGZ mutations.

Author

Garde A, Cornaton J, Sorlin A, Moutton S, Nicolas C, Juif C, Geneviève D, Perrin L, Khau-Van-Kien P, Smol T, Vincent-Delorme C, Isidor B, Cogné B, Afenjar A, Keren B, Coubes C, Prieur F, Toutain A, Trousselet Y, Bourgouin S, Gonin-Olympiade C, Giraudat K, Piton A, Gérard B, Odent S, Tessier F, Lemasson L, Heide S, Gelineau AC, Sarret C, Miret A, Schaefer E, Piard J, Mathevet R, Boucon M, Bruel AL, Mau-Them FT, Chevarin M, Vitobello A, Philippe C, Thauvin-Robinet C, and Faivre L

Subjects
Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, France, Genetic Predisposition to Disease, Humans, Male, Mutation, Neuropsychological Tests, Phenotype, Young Adult, Autism Spectrum Disorder genetics, Developmental Disabilities genetics, Genetic Variation, Intellectual Disability genetics, Neurocognitive Disorders genetics, Transposases genetics
Abstract

White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2021
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50. Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.

Author

Da Costa R, De Almeida S, Chevarin M, Hadj-Rabia S, Leclerc-Mercier S, Thauvin-Robinet C, Garrido C, Faivre L, Vabres P, Duplomb L, and Jego G

Subjects
Cells, Cultured, Class I Phosphatidylinositol 3-Kinases genetics, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Heat Shock Transcription Factors metabolism, Humans, Lipoma drug therapy, Lipoma genetics, Lipoma pathology, Molecular Targeted Therapy, Musculoskeletal Abnormalities drug therapy, Musculoskeletal Abnormalities genetics, Musculoskeletal Abnormalities pathology, Mutation, Nevus drug therapy, Nevus genetics, Nevus pathology, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Vascular Malformations drug therapy, Vascular Malformations genetics, Vascular Malformations pathology, Cell Proliferation drug effects, Class I Phosphatidylinositol 3-Kinases metabolism, Drug Discovery, Heat Shock Transcription Factors antagonists & inhibitors, Lipoma metabolism, Musculoskeletal Abnormalities metabolism, Nevus metabolism, Vascular Malformations metabolism
Abstract

PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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