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3. MAPK AND AKT/MTOR INHIBITION IMPROVES CHILDHOOD RASOPATHY-ASSOCIATED CARDIOMYOPATHY

Author

Andelfinger, G., primary, Zenker, M., additional, Norrish, G., additional, Russell, M., additional, Meisner, J., additional, Peng, D., additional, Prendiville, T., additional, Kleinmahon, J., additional, Kantor, P., additional, Sen, D Gottlieb, additional, Human, D., additional, Ewert, P., additional, Krueger, M., additional, Reber, D., additional, Donner, B., additional, Hart, C., additional, Odri-Komazec, I., additional, Rupp, S., additional, Hahn, A., additional, Hanser, A., additional, Hofbeck, M., additional, Draaisma, J., additional, Udink ten Cate, F., additional, Mussa, A., additional, Ferrero, G., additional, Vaujois, L., additional, Raboisson, M., additional, Delrue, M., additional, Marquis, C., additional, Théorêt, Y., additional, Kaski, J., additional, Gelb, B., additional, and Wolf, C., additional

Published
2022
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5. 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
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6. Missense variants affecting the actin-binding domains of PLS3 cause X-linked congenital diaphragmatic hernia and body wall defects

Author

Hernandez P, Gilbert-Dussardier B, Boris Keren, Ai X, Eric L. Bogenschutz, J. Wells, Zeynep Coban-Akdemir, Julia Wynn, Frédéric Frénois, Contreras Htm, Lupski, Andres Hernandez-Garcia, Ropers Hh, Lu Qiao, Florence Petit, Yonath H, Richard S. Maser, Anne-Sophie Jourdain, Delrue M, Giampietro Pf, Clark Rd, Wendy K. Chung, Harrison Brand, McCulley D, Tiana M. Scott, Mauro Longoni, Bult Cj, Patricia K. Donahoe, Barbara R. Pober, Frances A. High, Rebecca Hernan, Maria Loscertales, Yufeng Shen, Daryl A. Scott, Devisme L, Dysart Mj, Daniel G. Calame, and Hu H

Subjects
Genetics, Stress fiber, PLS3, medicine, Missense mutation, Congenital diaphragmatic hernia, Biology, medicine.disease, Actin cytoskeleton, Phenotype, Exome, Actin
Abstract

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with a novel X-linked condition characterized by diaphragm defects, variable anterior body wall anomalies, and/or facial dysmorphism. Using linkage analysis and whole exome or whole genome sequencing, we identified novel missense variants in the actin binding domains of plastin 3 (PLS3), a gene encoding an actin bundling protein, that co-segregate with disease in all families. Loss-of-function variants in PLS3 have been described previously in association with X-linked osteoporosis. To address these seemingly disparate clinical phenotypes, we performed in silico protein modeling and cellular overexpression experiments, which suggest that the affected residues in individuals with CDH are important for actin binding and result in disorganization of the actin cytoskeleton and a reduction in normal actin stress fiber formation. A mouse knock-in model of a variant identified in one of the families, p.W499C, shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal wall defects. Both the mouse model and one surviving adult patient with a PLS3 variant were observed to have increased, rather than decreased, bone mineral density. Together, these clinical and functional data in human and mouse reveal that specific missense variants affecting the actin binding domains of PLS3 may have a gain-of-function effect and cause a new Mendelian disorder.

Published
2021
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8. Étude prospective des événements thromboemboliques veineux chez les patients hospitalisés pour COVID-19 : anomalies associées de l’hémostase et suivi clinicobiologique à 6 mois

Author

Delrue, M., primary, Stephanian, A., additional, Neuwirth, M., additional, Voicu, S., additional, Chousterman, B., additional, Bonnin, P., additional, Joly, B., additional, Brumpt, C., additional, Veyradier, A., additional, Sène, D., additional, Megarbane, B., additional, and Siguret, V., additional

Published
2021
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10. Leucocytes, D-dimères et Ferritinémie comme Facteurs Prédictifs Indépendants d’Embolie Pulmonaire suspectée à l’admission chez les patients COVID-19 hospitalisés hors réanimation : étude rétrospective multicentrique française CLOTVID

Author

Thoreau, B., primary, Galland, J., additional, Delrue, M., additional, Neuwirth, M., additional, Stepanian, A., additional, Chauvin, A., additional, Devaux, M., additional, London, J., additional, Amador-Borrero, B., additional, Mangin, O., additional, Sellier, P.O., additional, Mouly, S., additional, Kevorkian, J., additional, Siguret, V., additional, Vodovar, D., additional, and Sene, D., additional

Published
2021
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11. Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability

Author

Callier, P, Aral, B, Hanna, N, Lambert, S, Dindy, H, Ragon, C, Payet, M, Collod-Beroud, G, Carmignac, V, Delrue, M A, Goizet, C, Philip, N, Busa, T, Dulac, Y, Missotte, I, Sznajer, Y, Toutain, A, Francannet, C, Megarbane, A, Julia, S, Edouard, T, Sarda, P, Amiel, J, Lyonnet, S, Cormier-Daire, V, Gilbert, B, Jacquette, A, Heron, D, Collignon, P, Lacombe, D, Morice-Picard, F, Jouk, P S, Cusin, V, Willems, M, Sarrazin, E, Amarof, K, Coubes, C, Addor, M C, Journel, H, Colin, E, Van Kien, Khau P, Baumann, C, Leheup, B, Coignard, Martin- D, Doco-Fenzy, M, Goldenberg, A, Plessis, G, Thevenon, J, Pasquier, L, Odent, S, Vabres, P, Huet, F, Marle, N, Boidron, Mosca- AL, Mugneret, F, Gauthier, S, Binquet, C, Thauvin-Robinet, C, Jondeau, G, Boileau, C, and Faivre, L

Published
2013
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14. Genotype-phenotype correlation in Costello syndrome:HRAS mutation analysis in 43 cases

Author

Kerr, B, Delrue, M-A, Sigaudy, S, Perveen, R, Marche, M, Burgelin, I, Stef, M, Tang, B, Eden, O B, O’Sullivan, J, De Sandre-Giovannoli, A, Reardon, W, Brewer, C, Bennett, C, Quarell, O, M’Cann, E, Donnai, D, Stewart, F, Hennekam, R, Cavé, H, Verloes, A, Philip, N, Lacombe, D, Levy, N, Arveiler, B, and Black, G

Published
2006

15. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases

Author

Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O.B., OESullivan, J., De Sandre-Giovannoli, A., Reardon, W., Brewer, C., Bennett, C., Quarell, O., MECann, E., Donnai, D., Stewart, F., Hennekam, R., Cave, H., Verloes, A., Philip, N., Lacombe, D., Levy, N., Arveiler, B., and Black, G.

Subjects
Multiple abnormalities -- Genetic aspects, Multiple abnormalities -- Causes of, Multiple abnormalities -- Research, Gene mutations -- Analysis, Health
Published
2006

16. Phenotype delineation of ZNF462 related syndrome

Author

Kruszka, P, Hu, T, Hong, S, Signer, R, Cogne, B, Isidor, B, Mazzola, SE, Giltay, JC, van Gassen, KLI, England, EM, Pais, L, Ockeloen, CW, Sanchez-Lara, PA, Kinning, E, Adams, DJ, Treat, K, Torres-Martinez, W, Bedeschi, MF, Iascone, M, Blaney, S, Bell, O, Tan, TY, Delrue, M-A, Jurgens, J, Barry, BJ, Engle, EC, Savage, SK, Fleischer, N, Martinez-Agosto, JA, Boycott, K, Zackai, EH, Muenke, M, Kruszka, P, Hu, T, Hong, S, Signer, R, Cogne, B, Isidor, B, Mazzola, SE, Giltay, JC, van Gassen, KLI, England, EM, Pais, L, Ockeloen, CW, Sanchez-Lara, PA, Kinning, E, Adams, DJ, Treat, K, Torres-Martinez, W, Bedeschi, MF, Iascone, M, Blaney, S, Bell, O, Tan, TY, Delrue, M-A, Jurgens, J, Barry, BJ, Engle, EC, Savage, SK, Fleischer, N, Martinez-Agosto, JA, Boycott, K, Zackai, EH, and Muenke, M

Abstract

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.

Published
2019

19. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Author

D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L. G., Hippolyte, L., Hanson, E., Maillard, A. M., Faucett, W. A., Mace, A., Pain, A., Bernier, R., Chawner, S. J. R. A., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gerard, M., Goin-Kochel, R. P., Grant, E., Hunter, J. V., Isidor, B., Jacquette, A., Jonch, A. E., Keren, B., Lacombe, D., Le Caignec, C., Martin, C. L., Mannik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M. J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J. A., Spence, S. J., Steinman, K. J., Tjernagel, J., Van Haelst, M., Shen, Y., Draganski, B., Sherr, E. H., Ledbetter, D. H., van den Bree, M. B. M., Beckmann, J. S., Spiro, J. E., Reymond, A., Jacquemont, S., Chung, W. K., Knoers, N. V. A. M., Martinet, D., Belfiore, M., Cuvellier, J. -C., Devries, B., Delrue, M. -A., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, M. A., Minet, J. -C., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, B. H., Koolen, D. A., Vulto-Van Silfhout, A., de Leeuw, N., Rosanfeld, J. A., Filges, I., Achatz, E., Roetzer, K. M., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, P. M., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, G. P., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Freminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, R. F., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., 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., Endre, J., 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., La, K., Levy, S., Lian, A., Llorens, A. V., Loftus, K., 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, T. P. L., Shaw, D., Sinha, T., Smith, B., Snow, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Blaumeiser, Bettina, Kooy, Frank, Other departments, Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, Knoers, VA., Martinet, D., Belfiore, M., Cuvellier, JC., de Vries, B., Delrue, MA., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Minet, JC., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, BH., Koolen, DA., Vulto-van Silfhout, A., de Leeuw, N., Rosenfeld, JA., Filges, I., Achatz, E., Roetzer, KM., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, PM., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, GP., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Fréminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, RF., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, AL., Benedetti, M., Berg, J., Berman, J., Berry, LN., Bibb, AL., Blaskey, L., Brennan, J., Brewton, CM., 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, AG., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, JE., Evans, YL., Findlay, A., Fischbach, GD., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, SE., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, FI., Jenkins J.<Suffix>3rd</Suffix>, Jeremy, RJ., Johnson, K., Kanne, SM., Kessler, S., Khan, SY., Ku, M., Kuschner, E., Laakman, AL., Lam, P., Lasala, MW., Lee, H., LaGuerre, K., Levy, S., Lian Cavanagh, A., Llorens, AV., Loftus Campe, K., Luks, TL., Marco, EJ., Martin, S., Martin, AJ., Marzano, G., Masson, C., McGovern, KE., McNally Keehn, R., Miller, DT., Miller, FK., Moss, TJ., Murray, R., Nagarajan, SS., Nowell, KP., Owen, J., Paal, AM., Packer, A., Page, PZ., Paul, BM., Peters, A., Peterson, D., Poduri, A., Pojman, NJ., Porche, K., Proud, MB., Qasmieh, S., Ramocki, MB., Reilly, B., Roberts, TP., Shaw, D., Sinha, T., Smith-Packard, B., Snow Gallagher, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
Male, 0301 basic medicine, Proband, Pediatrics, Autism Spectrum Disorder, Developmental Disabilities, Chromosome Disorders, Comorbidity, Nonverbal learning disorder, Cohort Studies, Cognition, 0302 clinical medicine, Cerebellum, Chromosome Duplication, Gene duplication, Copy-number variation, Non-U.S. Gov't, Child, 2. Zero hunger, Intelligence quotient, Research Support, Non-U.S. Gov't, Middle Aged, Psychiatry and Mental health, Microcephaly, Female, Schizophrenic Psychology, Chromosome Deletion, Psychology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, Adult, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, Research Support, Nervous System Malformations, Article, Chromosomes, Young Adult, 03 medical and health sciences, Intellectual Disability, Journal Article, medicine, Humans, Autistic Disorder, Preschool, Psychiatry, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Epilepsy, Pair 16, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Case-control study, Autism Spectrum Disorder/epidemiology, Autism Spectrum Disorder/genetics, Autistic Disorder/epidemiology, Autistic Disorder/genetics, Case-Control Studies, Cerebellum/abnormalities, Child, Preschool, Chromosome Disorders/epidemiology, Chromosome Disorders/genetics, Chromosomes, Human, Pair 16/genetics, Developmental Disabilities/epidemiology, Developmental Disabilities/genetics, Epilepsy/epidemiology, Epilepsy/genetics, Intellectual Disability/epidemiology, Intellectual Disability/genetics, Microcephaly/epidemiology, Microcephaly/genetics, Nervous System Malformations/epidemiology, Nervous System Malformations/genetics, Schizophrenia/epidemiology, Schizophrenia/genetics, medicine.disease, 030104 developmental biology, Chromosomes, Human, Pair 16, Schizophrenia, Autism, Human medicine, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 167711.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Published
2016
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26. Imbalance between procoagulant factors and natural coagulation inhibitors contributes to hypercoagulability in the critically ill COVID-19 patient: clinical implications.

Author

VOICU, S., DELRUE, M., CHOUSTERMAN, B. G., STÉPANIAN, A., BONNIN, P., MALISSIN, I., DEYE, N., NEUWIRTH, M., KETFI, C., MEBAZAA, A., SIGURET, V., and MÉGARBANE, B.

Abstract

OBJECTIVE: Coronavirus Disease- 2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE). PATIENTS AND METHODS: We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis. RESULTS: Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years [53-69] (median [25th-75th percentiles]); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 [25-32]; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L [6.1-8.6]), D-dimer (3,360 ng/mL [1668-7575]), factor V (166 IU/ dL [136-195]) and factor VIII activities (294 IU/dL [223-362]). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value [area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001]. CONCLUSIONS: Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE. [ABSTRACT FROM AUTHOR]

Published
2020

28. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, Mignot, C, Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, and Mignot, C

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Published
2017

34. Non-Destructive Evaluation of Kissing Bonds using Local Defect Resonance (LDR) Spectroscopy: A Simulation Study

Author

S. Delrue, M. Tabatabaeipour, J. Hettler, K. Van Den Abeele

Abstract

With the growing demand from industry to optimize and further develop existing Non-Destructive Testing & Evaluation (NDT&E) techniques or new methods to detect and characterize incipient damage with high sensitivity and increased quality, ample efforts have been devoted to better understand the typical behavior of kissing bonds, such as delaminations and cracks. Recently, it has been shown experimentally that the nonlinear ultrasonic response of kissing bonds could be enhanced by using Local Defect Resonance (LDR) spectroscopy. LDR spectroscopy is an efficient NDT technique that takes advantage of the characteristic frequencies of the defect (defect resonances) in order to provide maximum acoustic wave-defect interaction. In fact, for nonlinear methodologies, the ultrasonic excitation of the sample should occur at either multiples or integer ratios of the characteristic defect resonance frequencies, in order to obtain the highest signal-to-noise response in the nonlinear LDR spectroscopy. In this paper, the potential of using LDR spectroscopy for the detection, localization and characterization of kissing bonds is illustrated using a 3D simulation code for elastic wave propagation in materials containing closed but dynamically active cracks or delaminations. Using the model, we are able to define an appropriate method, based on the Scaling Subtraction Method (SSM), to determine the local defect resonance frequencies of a delamination in a composite plate and to illustrate an increase in defect nonlinearity due to LDR. The simulation results will help us to obtain a better understanding of the concept of LDR and to assist in the further design and testing of LDR spectroscopy for the detection, localization and characterization of kissing bonds.

Published
2015
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35. Une pyélonéphrite atypique…

Author

Delrue, M., primary, Marthe, A., additional, Ostrowka, C., additional, Grasland, A., additional, Faucon, A.L., additional, Azarine, A., additional, Mahe, I., additional, and Aslangul, E., additional

Published
2016
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37. Abstracts of papers Pharmaceutical and biomedical analysis meeting

Author

Bandhoe, A. U., Paalman, A. C. A., Underberg, W. J. M., Beijnen, J. H., Bekers, O., Otagiri, M., Bult, A., Beuman, Gert, van der Heijden, Jacques, Janss, Jenny, Ceelen, P. R. J., Feenstra-Bielders, G. G. L. M., Groeneveld, D. J., de Boer, D., Rutten, M. J. A., de Jong, E. G., Maes, R. A. A., van Rossum, J. M., de Groot, G., Kopps, R., Savelkoul, T. J. F., van Vloten, P., de Jonag, E. G., van Ooyen, R., Kiffers, J., de Kroon, I. F. I., Langendijk, P. N. J., de Goede, P. N. F. C., De Smet, M., Musch, C., Peeters, A., Buydens, L., Massart, D. L., De Turck, K., Cachet, Th., Hoogmartens, J., Delrue, M., Lannoo, P., Drenth, B. F. H., Beckeringh, F. J., Bosman, J., Feitsma, K. G., van Nijhuisvan Dam, A., Driebergen, R. J., van Gorp, J. A., Ensing, K., Farlam, A., de Jong, G. J., Frel, R. W., Brinkman, U. A. Th., Gerding, T. K., van de Grampel, V. J. M., Niemeijer, N. R., de Zeeuw, R. A., Tepper, P. G., Horn, A. S., Halvax, J. J., Wiese, G., van Bennekom, W. P., Hindriks, Rik, Buydens, Lutgarde, Peeters, Anne, de Smet, Marina, Massart, Luc, Blokland, Aric, Vink, Jan, Keizers, S., de Jong, E. G., Niessen, W. M. A., Verhey, E. R., LaVos, G. F., Tjaden, U. R., van der Greef, J., Ooms, J. A., Haak, G. S. J., Grooten, G., Pattyn, G., Sandra, P., David, F., van Oosterom, A. T., de Bruijn, E. A., Pouwelse, A. V., de Jong, D., Lammers, N. G. F. M., van den Berg, J. H. M., Quintens, I., Roets, E., Reeuwijk, H. J. E. M., Lingeman, H., Keizer, H. J., Rosing, H., Elferink, F., van de Vaart, F. J., Kloeg, P. H. A. M., Sauter, André, Stegehuis, D. S., Reinhoud, N. J., Steijger, O. M., Hilhorst, J. J. L., Holthuis, J. J. M., Underberg-Chitoe, U. K., Meenhorst, P. L., Van den Mooter, G., Hauchecorne, R., Vinckier, C., van der Horst, A., Martens, H. J. M., van der Horst, F. A. L., Post, M. H., van Ginkel, L. A., Zoontjes, P. W., van Blitterswijk, H., Stephany, R. W., van Gijn, R., Bakker, C. H., Koks, C. H. W., Rodenhuis, S., van Opstal, M. A. J., van den Horst, F. A. L., Krabbenborg, P., van Tellingen, O., Woude, H. R. v. d., van Beers, C. J. T., Nooyen, W. J., Varossieau, F. J., Los, G., Nagel, J. D., McVie, J. G., Veen, R. N., Land, J. T. Op 't, Vendrig, D. E. M. M., Teeuwsen, J., Verlaar, F. C. A. M., Trum, T. J. H. M., de Kleijn, J. P., Vervoort, R., Vrieling, M., Maris, F., Hindriks, H., Walhagen, A., Edholm, L. -E., Heeremans, C. E. M., and van der Hoeven, R. A. M.

Published
1989
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38. Are all Xq26.2 duplications overlapping <italic>GPC3</italic> on array‐CGH a cause of Simpson‐Golabi‐Behmel syndrome? When do we need transcript analysis?

Author

Hammouche, E., Cottereau, E., Vuillaume, M.‐L., Moizard, M.‐P., Toutain, A., Delrue, M.‐A., Maftei, C., Perrin, L., Baumann, C., Dupont, C., and Drunat, S.

Subjects
X-linked genetic disorders, CHROMOSOME duplication, CONGENITAL disorders, COMPARATIVE genomic hybridization, GENETIC transcription
Abstract

The article presents a case study of two patients with Simpson-Golabi-Behmel syndrome (SGBS) caused by the loss of-function of the glypican-3 gene (GPC3) and which showed Xq26.2 duplication. It informs about the tandem duplication of GPC3 identified by array comparative genomic hybridization (array-CGH). It also recommends a molecular transcription analysis to assess a possible gene disruption.

Published
2018
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39. Practical Guidelines for Managing Patients with 22q11.2 Deletion Syndrome

Author

Bassett, A, McDonald McGinn, D, Devriendt, K, Digilio, M, Goldenberg, P, Habel, A, Marino, B, Oskarsdottir, S, Philip, N, Sullivan, K, Swillen, A, Vorstman, J, Abadie, V, Allgrove, J, Amati, F, Baker, K, Baylis, A, Beaujard, M, Beemer, F, Boers, M, Bolton, P, Boot, E, Brigstocke, S, Burtey, S, Campbell, L, Chabloz, M, Chow, E, Clayton Smith, J, Cubells, J, Debbané, M, Delrue, M, De Smedt, B, Duijff, S, Eicher, P, Emanuel, B, Evers, L, Flahault, A, Forsythe, A, Frebourg, T, Gennery, A, Goldmuntz, E, Gosling, A, Handler, S, Heine Suñer, D, Hilmarsson, A, Hogan, A, Hordijk, R, Howley, S, Illingworth, E, Jackson, O, Joyce, H, Kawame, H, Kelly, R, Kemp, A, Kempf, L, Kimpen, J, Kirschner, R, Klaassen, P, Kumararatne, D, Lambert, M, Lima, K, Lindsay, E, Macerola, S, Malki, M, Marlin, S, Mascarenhas, M, Monks, S, Moran, V, Morrow, B, Moss, E, Murphy, C, Naqvi, N, Nielsen, B, Niklasson, L, Nordgarden, H, Oenema Mostert, C, Ottet, M, Pasca, C, Pasquariello, P, Persson, C, Portnoi, M, Prasad, S, Rockers, K, Saitta, S, Scambler, P, Schaer, M, Schneider, M, Sell, D, Solot, C, Sommerlad, B, Unanue, N, Sundram, F, Van Aken, K, van Amelsvoort, T, van der Molen, A, Widdershoven, J, Zackai, E, Schneider, Maud, Debbané, Martin, Schaer, Marie, and Schneider, Michel

Subjects
Male, medicine.medical_specialty, Pediatrics, Genetic Techniques/standards, Chromosomes, Human, Pair 22, Physical examination, Genetic Counseling, Scoliosis, Short stature, Article, 03 medical and health sciences, 0302 clinical medicine, ddc:150, DiGeorge syndrome, medicine, DiGeorge Syndrome, Humans, Pediatrics, Perinatology, and Child Health, Child, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, medicine.disease, 3. Good health, Surgery, Settore MED/03 - Genetica Medica, Hypoparathyroidism, Genetic Techniques, Pediatrics, Perinatology and Child Health, Practice Guidelines as Topic, Etiology, Genetic Counseling/standards, Sacral dimple, Asymmetric crying facies, medicine.symptom, Chromosome Deletion, business, DiGeorge Syndrome/diagnosis/genetics/therapy, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 22/genetics
Abstract

A 12-year-old boy currently is followed by multiple sub-specialists for problems caused by the chromosome 22q11.2 deletion syndrome (22q11DS) (Figure). He was born via spontaneous vaginal delivery, weighing 3033 g, to a 31-year-old G3P3 mother after a full-term pregnancy complicated only by mild polyhydramnios. Family history was non-contributory. Apgar scores were 8 at 1 minute and 9 at 5 minutes. With the exception of a weak cry, the results of the infant’s initial examination were unremarkable, and he was moved to the well-baby nursery. Shortly thereafter, a cardiac murmur was noted, the cardiology department was consulted, and the child was transferred to a local tertiary care facility with a diagnosis of tetralogy of Fallot. Stable, he was discharged home at 3 days of life. Figure Mild dysmorphic facial features of a boy aged 11 years with 22q11.2DS, including a short forehead, hooded eyelids with upslanting palpebral fissures, malar flatness, bulbous nasal tip with hypoplastic alae nasi, and protuberant ears. At 5 days of life, he had jerky movements. On presentation to the local emergency department, his total calcium level was 4.7 mg/dL, and later partial hypoparathyroidism was diagnosed. At that time, a consulting geneticist suggested the diagnosis of chromosome 22q11DS. Weeks later, the family received a telephone call confirming the diagnosis with fluorescence in situ hybridization (FISH). No additional information about the diagnosis, prognosis, etiology, or recurrence risk was provided until the child was 5 months of age, when he underwent cardiac repair at a third hospital, where a comprehensive 22q11DS program was in operation. In the interim, the child had feeding difficulties requiring supplemental nasogastric tube feeds, nasal regurgitation, and gastroesophageal reflux, while the parents searched the internet for reliable information about their son’s diagnosis. Subsequent notable abnormalities and interventions included: recurrent otitis media with bilateral myringotomy tube placement at 6 months; angioplasty with left pulmonary artery stent placement after the identification of pulmonary artery stenosis with bilateral pleural effusions at age 6 years; chronic upper respiratory infections with significant T cell dysfunction requiring live viral vaccines to be held until age 7 years; velopharyngeal incompetence necessitating posterior pharyngeal flap surgery at 7 years; enamel hypoplasia and numerous caries resulting in 3 separate dental procedures under general cardiac anesthesia beginning at age 7 years; multiple cervical and thoracic vertebral anomalies with thoracic levoconvex scoliosis and upper lumbar dextroscoliosis requiring growing rod placement at age 11 years with subsequent rod extension at ages 11.5 and 12 years; postoperative hypocalcemia; short stature; constipation; and persistent idiopathic thrombocytopenia. Pertinent negative test results included normal renal ultrasound scanning and parental 22q11.2 deletion studies. On physical examination, the boy’s height and weight have consistently tracked just below the fifth percentile, with no evidence of growth hormone deficiency. His head circumference is within reference range at the 25th percentile. Dysmorphic features include: a low anterior hairline; hooded eyelids; malar flatness; normally formed but protuberant ears with attached lobes; a mildly deviated nose with a bulbous nasal tip and hypoplastic alae nasi; asymmetric crying facies with a thin upper lip; mild micrognathia; a sacral dimple; and soft tissue syndactyly of the second and third toes. Developmentally, the boy had mild delays in achieving motor milestones, sitting at 11 months and walking at 18 months. However, he exhibited significant delays in the emergence of language: he never babbled, spoke his first words at age 3 years, and only achieved full conversational speech at 7 years. However, he had relative strengths in receptive language and communicated appropriately by the use of sign language. Now quite conversant, he is mainstreamed in the seventh grade with resource room supports. Moreover, he is affable, but exhibits anxiety and perseverations. Lastly, despite numerous medical, academic, and social challenges, he participates in assisted athletics, is an avid wrestling fan, and enjoys travel. However, his exceptionally supportive parents, siblings, and extended family continue to worry about his long-term outcome and transition of care as he approaches adulthood. As demonstrated by this boy’s complicated course, practical multi-system guidelines are needed to assist the general practitioner and specialists in caring for patients with 22q11DS. Although still under-recognized, detection, including in the prenatal setting, is increasing. Moreover, the phenotypic spectrum is highly variable, and patients may present at any age. Thus, initial guidelines developed by an international panel of experts present the best practice recommendations currently available across the lifespan, with a major focus on the changing issues through childhood development.

Published
2011

47. Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Callier, P, Aral, B, Hanna, N, Lambert, S, Dindy, H, Ragon, C, Payet, M, Collod-Beroud, G, Carmignac, V, Delrue, M A, Goizet, C, Philip, N, Busa, T, Dulac, Y, Missotte, I, Sznajer, Yves, Toutain, A, Francannet, C, Megarbane, A, Julia, S, Edouard, T, Sarda, P, Amiel, J, Lyonnet, S, Cormier-Daire, V, Gilbert, B, Jacquette, A, Heron, D, Collignon, P, Lacombe, D, Morice-Picard, F, Jouk, P S, Cusin, V, Willems, M, Sarrazin, E, Amarof, K, Coubes, C, Addor, M C, Journel, H, Colin, E, Khau Van Kien, P, Baumann, C, Leheup, B, Martin-Coignard, D, Doco-Fenzy, M, Goldenberg, A, Plessis, G, Thevenon, J, Pasquier, L, Odent, S, Vabres, P, Huet, F, Marle, N, Mosca-Boidron, A L, Mugneret, F, Gauthier, S, Binquet, C, Thauvin-Robinet, C, Jondeau, G, Boileau, C, Faivre, L, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Callier, P, Aral, B, Hanna, N, Lambert, S, Dindy, H, Ragon, C, Payet, M, Collod-Beroud, G, Carmignac, V, Delrue, M A, Goizet, C, Philip, N, Busa, T, Dulac, Y, Missotte, I, Sznajer, Yves, Toutain, A, Francannet, C, Megarbane, A, Julia, S, Edouard, T, Sarda, P, Amiel, J, Lyonnet, S, Cormier-Daire, V, Gilbert, B, Jacquette, A, Heron, D, Collignon, P, Lacombe, D, Morice-Picard, F, Jouk, P S, Cusin, V, Willems, M, Sarrazin, E, Amarof, K, Coubes, C, Addor, M C, Journel, H, Colin, E, Khau Van Kien, P, Baumann, C, Leheup, B, Martin-Coignard, D, Doco-Fenzy, M, Goldenberg, A, Plessis, G, Thevenon, J, Pasquier, L, Odent, S, Vabres, P, Huet, F, Marle, N, Mosca-Boidron, A L, Mugneret, F, Gauthier, S, Binquet, C, Thauvin-Robinet, C, Jondeau, G, Boileau, C, and Faivre, L

Abstract

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

Published
2013

48. Renal development / Cystic diseases

Author

Yosypiv, I., primary, Song, R., additional, Preston, G., additional, Van Eerde, A. M., additional, Van Binsbergen, E., additional, Konijnenberg, Y., additional, Maiburg, M. C., additional, Lichtenbelt, K., additional, Nikkels, P. G. J., additional, Vd Smagt, J., additional, Renkema, K. Y., additional, Giltay, J. C., additional, De Jong, T. P. V. M., additional, Lilien, M. R., additional, Knoers, N. V. A. M., additional, Gueydan, C., additional, Serena, G., additional, Stephan, G., additional, Koesters, R., additional, Zeineb, B., additional, Laure, D., additional, Catherine, A., additional, Marie-Therese, B., additional, Gauguier, D., additional, Lelongt, B., additional, Moon, S. H., additional, Park, H. C., additional, Lee, H.-Y., additional, Hwang, J. H., additional, Jeong, J. C., additional, Park, J.-Y., additional, Lee, S. W., additional, Hwang, Y.-H., additional, Kang, K. W., additional, Ahn, C., additional, Gattone, V., additional, Carr, A., additional, Crosler-Roberts, R., additional, Wang, X., additional, Liu, Y., additional, Shen, J., additional, Wuthrich, R., additional, Serra, A., additional, Mei, C., additional, Tuta, L., additional, Botea, F., additional, Guigonis, V., additional, Rodier, N., additional, Bahans, C., additional, Decramer, S., additional, Bertholet-Thomas, A., additional, Heidet, L., additional, Eckart, P., additional, Lavocat, M.-P., additional, Vrillon, I., additional, Cloarec, S., additional, Lahoche, A., additional, Bessenay, L., additional, Louillet, F., additional, Roussey, G., additional, Rousset-Riviere, C., additional, Dunand, O., additional, Baudouin, V., additional, Nobili, F., additional, Pietrement, C., additional, De Parscau, L., additional, Gajdos, V., additional, Morin, D., additional, Laffargue, F., additional, Llanas, B., additional, Palcoux, J.-B., additional, Delrue, M.-A., additional, Dizier, E., additional, Taupiac, E., additional, Laroche, C., additional, Lacombe, B., additional, Bourthoumieu, S., additional, El-Meanawy, A., additional, Rufanova, V., additional, and Stelloh, C., additional

Published
2012
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49. Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome

Author

El Chehadeh, S., primary, Aral, B., additional, Gigot, N., additional, Thauvin-Robinet, C., additional, Donzel, A., additional, Delrue, M.-A., additional, Lacombe, D., additional, David, A., additional, Burglen, L., additional, Philip, N., additional, Moncla, A., additional, Cormier-Daire, V., additional, Rio, M., additional, Edery, P., additional, Verloes, A., additional, Bonneau, D., additional, Afenjar, A., additional, Jacquette, A., additional, Heron, D., additional, Sarda, P., additional, Pinson, L., additional, Doray, B., additional, Vigneron, J., additional, Leheup, B., additional, Frances-Guidet, A.-M., additional, Dienne, G., additional, Holder, M., additional, Masurel-Paulet, A., additional, Huet, F., additional, Teyssier, J.-R., additional, and Faivre, L., additional

Published
2010
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50. 264 Mise en place de l’analyse génétique à visée diagnostique du gène de la myociline chez des patients atteints de glaucome primitif à angle ouvert de forme juvénile et de type adulte de forme familiale

Author

Florent, X., primary, Niel, F., additional, Lacombe, D., additional, Riss, I., additional, Mortemousque, B., additional, Malet, F., additional, Dale, V., additional, Delrue, M., additional, Touboul, D., additional, and Colin, J., additional

Published
2005
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