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2. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Author

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

Abstract

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

Published
2023

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

Author

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

Abstract

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

Published
2023

6. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Author

Scala, M., Nishikawa, M., Ito, H., Tabata, H., Khan, T., Accogli, A., Davids, L., Ruiz, A., Chiurazzi, Pietro, Cericola, G., Schulte, B., Monaghan, K. G., Begtrup, A., Torella, A., Pinelli, M., Denomme-Pichon, A. -S., Vitobello, A., Racine, C., Mancardi, M. M., Kiss, C., Guerin, A., Wu, W., Vila, E. G., Mak, B. C., Martinez-Agosto, J. A., Gorin, M. B., Duz, B., Bayram, Y., Carvalho, C. M. B., Vengoechea, J. E., Chitayat, D., Tan, T. Y., Callewaert, B., Kruse, B., Bird, L. M., Faivre, L., Zollino, Marcella, Biskup, S., Striano, P., Nigro, V., Severino, M., Capra, V., Costain, G., Nagata, K. -I., Brown, G., Butte, M. J., Dell'Angelica, E. C., Dorrani, N., Douine, E. D., Fogel, B. L., Gutierrez, I., Huang, A., Krakow, D., Lee, H., Loo, S. K., Martin, M. G., Mcgee, E., Nelson, S. F., Nieves-Rodriguez, S., Palmer, C. G. S., Papp, J. C., Parker, N. H., Renteria, G., Sinsheimer, J. S., Wan, J., Wang, L. -K., Perry, K. W., Brunetti-Pierri, N., Casari, G., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Scala, Marcello, Nishikawa, Masashi, Ito, Hidenori, Tabata, Hidenori, Khan, Tayyaba, Accogli, Andrea, Davids, Laura, Ruiz, Anna, Chiurazzi, Pietro, Cericola, Gabriella, Schulte, Björn, Monaghan, Kristin G, Begtrup, Amber, Torella, Annalaura, Pinelli, Michele, Denommé-Pichon, Anne Sophie, Vitobello, Antonio, Racine, Caroline, Mancardi, Maria Margherita, Kiss, Courtney, Guerin, Andrea, Wu, Wendy, Gabau Vila, Elisabeth, Mak, Bryan C, Martinez-Agosto, Julian A, Gorin, Michael B, Duz, Bugrahan, Bayram, Yavuz, Carvalho, Claudia M B, Vengoechea, Jaime E, Chitayat, David, Tan, Tiong Yang, Callewaert, Bert, Kruse, Bernd, Bird, Lynne M, Faivre, Laurence, Zollino, Marcella, Biskup, Saskia, Striano, Pasquale, Nigro, Vincenzo, Severino, Mariasavina, Capra, Valeria, Costain, Gregory, Nagata, Koh Ichi, and Nagata, Koh-Ichi

Subjects
brain development, Settore MED/03 - GENETICA MEDICA, Medical and Health Sciences, Telethon Undiagnosed Diseases Program, Mice, Neurodevelopmental Disorder, Medicine and Health Sciences, Animals, Humans, 2.1 Biological and endogenous factors, Aetiology, Neurons, Pediatric, neuronal migration, Neurology & Neurosurgery, Animal, axon guidance, Psychology and Cognitive Sciences, p21-Activated Kinase, Neurosciences, Biology and Life Sciences, Undiagnosed Diseases Network, Neuron, rac GTP-Binding Proteins, Brain Disorders, RAC3, Phenotype, p21-Activated Kinases, Neurodevelopmental Disorders, small GTPase, Neurological, Congenital Structural Anomalies, Neurology (clinical), Human
Abstract

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

Published
2022

9. Further delineation of auriculocondylar syndrome based on 14 novel cases and reassessment of 25 published cases

Author

Vegas, N, Demir, Z, Gordon, CT, Breton, S, Tavares, VLR, Moisset, H, Zechi-Ceide, R, Kokitsu-Nakata, NM, Kido, Y, Marlin, S, Halem, SG, Meerschaut, I, Callewaert, B, Chung, B, Revencu, N, Lehalle, D, Petit, F, Propst, EJ, Papsin, BC, Phillips, JH, Jakobsen, L, Le Tanno, P, Thevenon, J, McGaughran, J, Gerkes, EH, Leoni, C, Kroisel, P, Tan, TY, Henderson, A, Terhal, P, Basel-Salmon, L, Alkindy, A, White, SM, Passos-Bueno, MR, Pingault, V, De Pontual, L, Amiel, J, Vegas, N, Demir, Z, Gordon, CT, Breton, S, Tavares, VLR, Moisset, H, Zechi-Ceide, R, Kokitsu-Nakata, NM, Kido, Y, Marlin, S, Halem, SG, Meerschaut, I, Callewaert, B, Chung, B, Revencu, N, Lehalle, D, Petit, F, Propst, EJ, Papsin, BC, Phillips, JH, Jakobsen, L, Le Tanno, P, Thevenon, J, McGaughran, J, Gerkes, EH, Leoni, C, Kroisel, P, Tan, TY, Henderson, A, Terhal, P, Basel-Salmon, L, Alkindy, A, White, SM, Passos-Bueno, MR, Pingault, V, De Pontual, L, and Amiel, J

Abstract

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by mandibular hypoplasia and an auricular defect at the junction between the lobe and helix, known as a "Question Mark Ear" (QME). Several additional features, originating from the first and second branchial arches and other tissues, have also been reported. ACS is genetically heterogeneous with autosomal dominant and recessive modes of inheritance. The mutations identified to date are presumed to dysregulate the endothelin 1 signaling pathway. Here we describe 14 novel cases and reassess 25 published cases of ACS through a questionnaire for systematic data collection. All patients harbor mutation(s) in PLCB4, GNAI3, or EDN1. This series of patients contributes to the characterization of additional features occasionally associated with ACS such as respiratory, costal, neurodevelopmental, and genital anomalies, and provides management and monitoring recommendations.

Published
2022

10. Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA

Author

Meerschaut, Ilse, Steyaert, W.A.R., Bove, Thierry, Francois, Katrien, Martens, Thomas, Groote, Katya De, Wolf, Daniel De, Callewaert, B., Meerschaut, Ilse, Steyaert, W.A.R., Bove, Thierry, Francois, Katrien, Martens, Thomas, Groote, Katya De, Wolf, Daniel De, and Callewaert, B.

Abstract

Contains fulltext : 253059.pdf (Publisher’s version ) (Open Access)

Published
2022

11. Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes

Author

Scala, M, Nishikawa, M, Ito, H, Tabata, H, Khan, T, Accogli, A, Davids, L, Ruiz, A, Chiurazzi, P, Cericola, G, Schulte, B, Monaghan, KG, Begtrup, A, Torella, A, Pinelli, M, Denomme-Pichon, AS, Vitobello, A, Racine, C, Mancardi, MM, Kiss, C, Guerin, A, Wu, W, Vila, EG, Mak, BC, Martinez-Agosto, JA, Gorin, MB, Duz, B, Bayram, Y, Carvalho, CMB, Vengoechea, JE, Chitayat, D, Tan, TY, Callewaert, B, Kruse, B, Bird, LM, Faivre, L, Zollino, M, Biskup, S, Striano, P, Nigro, V, Severino, M, Capra, V, Costain, G, Nagata, K-I, Scala, M, Nishikawa, M, Ito, H, Tabata, H, Khan, T, Accogli, A, Davids, L, Ruiz, A, Chiurazzi, P, Cericola, G, Schulte, B, Monaghan, KG, Begtrup, A, Torella, A, Pinelli, M, Denomme-Pichon, AS, Vitobello, A, Racine, C, Mancardi, MM, Kiss, C, Guerin, A, Wu, W, Vila, EG, Mak, BC, Martinez-Agosto, JA, Gorin, MB, Duz, B, Bayram, Y, Carvalho, CMB, Vengoechea, JE, Chitayat, D, Tan, TY, Callewaert, B, Kruse, B, Bird, LM, Faivre, L, Zollino, M, Biskup, S, Striano, P, Nigro, V, Severino, M, Capra, V, Costain, G, and Nagata, K-I

Abstract

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical ne

Published
2022

14. Mowat-Wilson syndrome:growth charts

Author

Ivanovski I., Djuric O., Broccoli S., Caraffi S. G., Accorsi P., Adam M. P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D. M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J. E. K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R. S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M. L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E. T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M. E., Iughetti L., Bernasconi S., Giorgi Rossi P., Garavelli L., HUSLAB, Clinicum, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Ivanovski I., Djuric O., Broccoli S., Caraffi S.G., Accorsi P., Adam M.P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D.M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J.E.K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R.S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M.L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E.T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M.E., Iughetti L., Bernasconi S., Giorgi Rossi P., and Garavelli L.

Subjects
Male, 0301 basic medicine, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences, Pediatrics, Microcephaly, FEATURES, lcsh:Medicine, CHILDREN, 030105 genetics & heredity, Head circumference, DISEASE, 0302 clinical medicine, Intellectual disability, Medicine and Health Sciences, Genetics(clinical), Pharmacology (medical), Mowat-Wilson syndrome, Child, Genetics (clinical), Body mass index, ZEB2, 2. Zero hunger, education.field_of_study, 0303 health sciences, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti, Mowat-Wilson syndrome, ZEB2, Growth charts, Weight, Length, Height, Head circumference, Body mass index, BM, 1184 Genetics, developmental biology, physiology, General Medicine, STATISTICS, 3. Good health, MORFOMETRIA, Italy, 030220 oncology & carcinogenesis, Female, medicine.medical_specialty, Mowat–Wilson syndrome, Length, Population, BMI, Growth charts, Height, Weight, Growth chart, 03 medical and health sciences, AGE, Intellectual Disability, medicine, Humans, In patient, Hirschsprung Disease, education, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Physical development, MUTATIONS, business.industry, Research, lcsh:R, Infant, Newborn, Facies, Infant, medicine.disease, Repressor Proteins, DELINEATION, INDIVIDUALS, 030104 developmental biology, 3111 Biomedicine, business
Abstract

Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2,865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Published
2020

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

Author

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

Abstract

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

Published
2021

16. Antecedents and impacts of behavioral adaptation of electronic medical records

Author

Callewaert, B (Bart)

Subjects
facilitating conditions, electronic medical records, perceived personal benefits, task-technology adaptation, decision-making effectiveness, personal innovativeness, computer self-efficacy
Abstract

Considering time constraints and staff shortage in health care oblige, EMR systems have to fit perfectly with the workflows, with interpersonal communication and with data needs. In this perspective, this study questions whether computer self-efficacy and personal innovativeness of health staff enhance their capacity to adapt the electronic medical records system to the tasks to be performed and does this adaptation behavior entail increased personal benefits for the physician and an improved medical decision-making. Although personal innovativeness proves to be an antecedent of behavioral adaptation of electronic medical records (EMR), which on its turn favors perceived personal benefits, the research question cannot be answered positively. This research reveals nevertheless that two settings are interesting for further research: EMR adaptation behaviors in emergency departments and the relation between the use of EMR by less qualified staff and care effectiveness.

Published
2020

17. Effect of mutation type and location on clinical outcome in 1,013 probands with marfan syndrome or related phenotypes and FBN1 mutations: an international study

Author

Faivre, L., Collod-Beroud, G., Loeys, B.L., Child, A., Binquet, C., Gautier, E., Callewaert, B., Arbustini, E., Mayer, K., Arslan-Kirchner, M., Kiotsekoglou, A., Comeglio, P., Marziliano, N., Dietz, H.C., Halliday, D., Beroud, C., Bonithon-Kopp, C., Claustres, M., Muti, C., Plauchu, H., Robinson, P.N., Ades, L.C., Biggin, A., Benetts, B., Brett, M., Holman, K.J., De Backer, J., Coucke, P., Francke, U., De Paepe, A., Jondeau, G., and Boileau, C.

Subjects
Gene mutations -- Research, Physiology, Pathological -- Research, Fibrin -- Research, Marfan syndrome -- Genetic aspects, Biological sciences
Abstract

The correlation between the fibrillin-1 genotype and the nature and severity of the clinical phenotype is studied. It is concluded that the correlation found between different mutation types and clinical manifestations might indicate different underlying pathophysiologic mechanism, both genetic and functional.

Published
2007

18. Homozygous EMILIN1 loss-of-function variants impair both elastin and collagen fiber formation and cause a novel entity with arterial tortuosity and osteopenia

Author

Beyens, A., Adamo, C., Gulec, E. Yilmaz, Gezdirici, A., Bonaldo, P., Bornaun, H., Brauchle, E., Brinckmann, J., Devine, W. P., Gangaram, B., Sasaki, T., Schenke-Layland, K., Symoens, S., Tam, A., Sengle, G., Callewaert, B., Beyens, A., Adamo, C., Gulec, E. Yilmaz, Gezdirici, A., Bonaldo, P., Bornaun, H., Brauchle, E., Brinckmann, J., Devine, W. P., Gangaram, B., Sasaki, T., Schenke-Layland, K., Symoens, S., Tam, A., Sengle, G., and Callewaert, B.

Published
2020

19. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Author

Yan, KZ, Rousseau, J, Machol, K, Cross, LA, Agre, KE, Gibson, CF, Goverde, Anne, Engleman, KL, Verdin, H, De Baere, E, Potocki, L, Zhou, DH, Cadieux-Dion, M, Bellus, GA, Wagner, MD, Hale, RJ, Esber, N, Riley, AF, Solomon, BD, Cho, M T, McWalter, K, Eyal, R, Hainlen, MK, Mendelsohn, BA, Porter, HM, Lanpher, BC, Lewis, AM, Savatt, J, Thiffault, I, Callewaert, B, Campeau, PM, Yang, XJ, Yan, KZ, Rousseau, J, Machol, K, Cross, LA, Agre, KE, Gibson, CF, Goverde, Anne, Engleman, KL, Verdin, H, De Baere, E, Potocki, L, Zhou, DH, Cadieux-Dion, M, Bellus, GA, Wagner, MD, Hale, RJ, Esber, N, Riley, AF, Solomon, BD, Cho, M T, McWalter, K, Eyal, R, Hainlen, MK, Mendelsohn, BA, Porter, HM, Lanpher, BC, Lewis, AM, Savatt, J, Thiffault, I, Callewaert, B, Campeau, PM, and Yang, XJ

Published
2020

21. The new Ghent criteria for Marfan syndrome: what do they change?

Author

Faivre, L, Collod-Beroud, G, Adès, L, Arbustini, E, Child, A, Callewaert, B L, Loeys, B, Binquet, C, Gautier, E, Mayer, K, Arslan-Kirchner, M, Grasso, M, Beroud, C, Hamroun, D, Bonithon-Kopp, C, Plauchu, H, Robinson, P N, De Backer, J, Coucke, P, Francke, U, Bouchot, O, Wolf, J E, Stheneur, C, Hanna, N, Detaint, D, De Paepe, A, Boileau, C, and Jondeau, G

Published
2012
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22. Pathogenic FBN1 Mutations in 146 Adults Not Meeting Clinical Diagnostic Criteria for Marfan Syndrome: Further Delineation of Type 1 Fibrillinopathies and Focus on Patients With an Isolated Major Criterion

Author

Faivre, L., Collod-Beroud, G., Callewaert, B., Child, A., Loeys, B. L., Binquet, C., Gautier, E., Arbustini, E., Mayer, K., Arslan-Kirchner, M., Kiotsekoglou, A., Comeglio, P., Grasso, M., Beroud, C., Bonithon-Kopp, C., Claustres, M., Stheneur, C., Bouchot, O., Wolf, J. E., Robinson, P. N., Adès, L., De Backer, J., Coucke, P., Francke, U., De Paepe, A., Boileau, C., and Jondeau, G.

Published
2009
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23. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands

Author

Faivre, L, Collod-Beroud, G, Child, A, Callewaert, B, Loeys, B L, Binquet, C, Gautier, E, Arbustini, E, Mayer, K, Arslan-Kirchner, M, Stheneur, C, Kiotsekoglou, A, Comeglio, P, Marziliano, N, Halliday, D, Beroud, C, Bonithon-Kopp, C, Claustres, M, Plauchu, H, Robinson, P N, Adès, L, De Backer, J, Coucke, P, Francke, U, De Paepe, A, Boileau, C, and Jondeau, G

Published
2008
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24. Arterial Tortuosity Syndrome: Clinical and Molecular Findings in 12 Newly Identified Families

Author

Callewaert, B. L., Willaert, A., Kerstjens-Frederikse, W. S., De Backer, J., Devriendt, K., Albrecht, B., Ramos-Arroyo, M. A., Doco-Fenzy, M., Hennekam, R. C.M., Pyeritz, R. E., Krogmann, O. N., Gillessen-kaesbach, G., Wakeling, E. L., Nik-zainal, S., Francannet, C., Mauran, P., Booth, C., Barrow, M., Dekens, R., Loeys, B. L., Coucke, P. J., and De Paepe, A. M.

Published
2008
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25. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author

Diets, I.J., Donk, R. van der, Baltrunaite, K., Waanders, E., Reijnders, M.R.F., Dingemans, A.J., Pfundt, R.P., Vulto-van Silfhout, A.T., Wiel, L.J.M. van de, Gilissen, C.F., Thevenon, J., Perrin, L., Afenjar, A., Nava, C., Keren, B., Bartz, S., Peri, B., Beunders, G., Verbeek, N., Gassen, K. van, Thiffault, I., Cadieux-Dion, M., Huerta-Saenz, L., Wagner, M., Konstantopoulou, V., Vodopiutz, J., Griese, M., Boel, A., Callewaert, B., Brunner, H.G., Kleefstra, T., Hoogerbrugge, N., Vries, B.B. de, Hwa, V., Dauber, A., Hehir-Kwa, J.Y., Kuiper, R.P, Jongmans, M.C.J., Diets, I.J., Donk, R. van der, Baltrunaite, K., Waanders, E., Reijnders, M.R.F., Dingemans, A.J., Pfundt, R.P., Vulto-van Silfhout, A.T., Wiel, L.J.M. van de, Gilissen, C.F., Thevenon, J., Perrin, L., Afenjar, A., Nava, C., Keren, B., Bartz, S., Peri, B., Beunders, G., Verbeek, N., Gassen, K. van, Thiffault, I., Cadieux-Dion, M., Huerta-Saenz, L., Wagner, M., Konstantopoulou, V., Vodopiutz, J., Griese, M., Boel, A., Callewaert, B., Brunner, H.G., Kleefstra, T., Hoogerbrugge, N., Vries, B.B. de, Hwa, V., Dauber, A., Hehir-Kwa, J.Y., Kuiper, R.P, and Jongmans, M.C.J.

Abstract

Contains fulltext : 202646.pdf (publisher's version ) (Open Access), By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.

Published
2019

27. 59. PREIMPLANTATION GENETIC TESTING FOR HERITABLE CONNECTIVE TISSUE DISEASES

Author

Symoens, S., primary, Van Tongerloo, A., additional, Van Acker, P., additional, Van Holm, E., additional, Weytens, J., additional, Geril, A., additional, De Croo, I., additional, Hellemans, S., additional, Szymczak, V., additional, Malfait, F., additional, Vanakker, O., additional, Callewaert, B., additional, De Backer, J., additional, De Paepe, A., additional, De Sutter, P., additional, Coucke, P., additional, and Janssens, S., additional

Published
2019
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28. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Author

Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, Garavelli, L, Ivanovski, I, Djuric, O, Caraffi, SG, Santodirocco, D, Pollazzon, M, Rosato, S, Cordelli, D M, Abdalla, E, Accorsi, P, Adam, MP, Ajmone, PF, Badura-Stronka, M, Baldo, C, Baldi, M, Bayat, A, Bigoni, S, Bonvicini, F, Breckpot, J, Callewaert, B, Cocchi, G, Cuturilo, G, De Brasi, D, DeVriendt, K, Dinulos, MB, Hjortshoj, TD, Epifanio, R, Faravelli, F, Fiumara, A, Formisano, D, Giordano, L, Grasso, M, Gronborg, S, Iodice, A, Iughetti, L, Kuburovic, V, Kutkowska-Kazmierczak, A, Lacombe, D, Lo Rizzo, C, Luchetti, A, Malbora, B, Mammi, I, Mari, F, Montorsi, G, Moutton, S, Moller, RS, Muschke, P, Nielsen, JEK, Obersztyn, E, Pantaleoni, C, Pellicciari, A, Pisanti, MA, Prpic, I, Poch-Olive, ML, Raviglione, F, Renieri, A, Ricci, E, Rivieri, F, Santen, GW, Savasta, S, Scarano, G, Schanze, I, Selicorni, A, Silengo, M, Smigiel, R, Spaccini, L, Sorge, G, Szczaluba, K, Tarani, L, Tone, LG, Toutain, A, Trimouille, A, Valera, ET, Vergano, SS, Zanotta, N, Zenker, M, Conidi, Andrea, Zollino, M, Rauch, A, Zweier, C, and Garavelli, L

Published
2018

29. Major response to adalimumab in patient with Sweet syndrome associated to an acquired cutis laxa.

Author

Rosier, P., Deroux, A., Beyens, A., Callewaert, B., and Leccia, M.‐T.

Subjects
CUTIS laxa, SWEET'S syndrome, ADALIMUMAB, SJOGREN'S syndrome, CROHN'S disease
Abstract

Most of these individuals developed Sweet syndrome in association with chronic inflammatory bowel disease.2-6 Our observation is the first to document the efficacy of this treatment in Marshall's syndrome, both for the inflammatory lesions and the elastolysis. The patients in this manuscript have given written informed consent to publication of his case details. [Extracted from the article]

Published
2022
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31. Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

Author

Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., Wevers, R.A., Damme, T. Van, Gardeitchik, T., Mohamed, M., Guerrero Castillo, S., Freisinger, P., Guillemyn, B., Kariminejad, A., Dalloyaux, D., Kraaij, S.A.W. van, Lefeber, D.J., Syx, D., Steyaert, W., Rycke, R. de, Hoischen, A., Kamsteeg, E.J., Wong, S.Y.W., Scherpenzeel, M. van, Jamali, P., Brandt, U., Nijtmans, L.G.J., Korenke, G.C., Chung, B.H., Mak, C.C., Hausser, I., Kornak, U., Fischer-Zirnsak, B., Strom, T.M., Meitinger, T., Alanay, Y., Utine, G.E., Leung, P.K., Ghaderi-Sohi, S., Coucke, P., Symoens, S., Paepe, A. De, Thiel, C., Haack, T.B., Malfait, F., Morava, E., Callewaert, B., and Wevers, R.A.

Abstract

Contains fulltext : 169752.pdf (publisher's version ) (Closed access), Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.

Published
2017

32. Genomic landscape of balanced cytogenetic abnormalities in subjects with multiple congenital anomalies

Author

Redin, Claire, Brand, Harrison, Collins, Ryan, Hanscom, Carrie, Vamsee, Pillalamarri, Kammin, Tammy, Mitchell, E., Hodge, J.C., Schilit, S., Curall, B.B., Pereira, S., Seabra, C., Stone, M., Lawless, W., Lucente, D., Antolik, C., Hochstenbach, R., Renkens, I., Brilstra, E., Vergult, S., Menten, B., Janssens, S., Callewaert, B., D’heedene, A., D’hooghe, M, Roelens, F., van de Kamp, J., Nieuwint, A., Poddighe, P.J, van Ravenswaaij-Arts, C., Rump, P., van Essen, T., Freixo, J., David, Dezső, Liao, E.C., Leew, N. de, Brunner, H.G., Kloosterman, W., Thorland, E.C., Morton, C.C., Gusella, J.F., and Talkowski, M E.

Subjects
Cytogenetic Abnormalities, Balanced Chromosomal Abnormalities, Doenças Genómicas, Congenital Anomalies, Doenças Genéticas
Abstract

publicado em: Eur J Hum Gen.2016;24(S1):4. PL2.1 Balanced chromosomal abnormalities (BCAs) represent a unique class of genomic variation that involves large rearrangement of the chromosomes. To date their detection has been limited to cytogenetic resolution as most first-tier genetic screening methods are blind to their presence. We defined the genomic landscape of de novo BCAs associated with human congenial anomalies in 235 subjects using whole-genome sequencing. We observed that 22% of all BCAs harbored additional cryptic complexity, ranging from three breakpoints to chromothripsis events involving up to 57 breakpoints. Compared to random expectations, BCAs were more likely to occur between loci in close physical proximity in the nucleus, and their breakpoints were significantly enriched for evolutionarily constrained and embryonically expressed genes. From our convergent genomic interpretation using orthogonal datasets, we predict that the congenital anomaly phenotype was likely attributable to the BCA in at least 30% of subjects. An additional 4% of BCAs disrupted long-range regulatory regions such as topologically associating domains (TADs) resulting in position effects on genes associated with specific clinical manifestations that were compatible with the proband sequenced here. Remarkably, we observed a cluster of six independent translocations that disrupted a TAD and consequently altered MEF2C expression, mimicking the 5q14.3 microdeletion syndrome. These results suggest that de novo BCAs represent a highly penetrant class of genomic variation associated with congenital anomalies, and that nucleotide resolution offers insights into phenotypic prediction from direct gene disruption and alteration of long-range regulatory domains that are likely to be a significant source of causal variation in human disease. info:eu-repo/semantics/publishedVersion

Published
2016

34. [PP.11.02] FIBROMUSCULAR DYSPLASIA

Author

De Groote, M., primary, Callewaert, B., additional, Hemelsoet, D., additional, Vermassen, F., additional, Billiouw, J.M., additional, De Vriese, A., additional, Montag, I., additional, Van der Niepen, P., additional, and De Backer, T., additional

Published
2016
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36. Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD

Author

Renard, M., Callewaert, B, Baetens, Machteld, Fryns, J.p., Bonduelle, Mary-Louise, Coucke, Paul, Loeys, B., De Paepe, A., De Backer, J., Coats, Andrew J. S., Department of Embryology and Genetics, and Reproduction and Genetics

Subjects
Thoracic aortic aneurysm, MYH11, genetics, ACTA2
Abstract

BACKGROUND: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGF?) signaling (TGF? receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). METHODS AND RESULT: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGF? signaling pathway. CONCLUSIONS: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGF? signaling.

Published
2013

37. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations

Author

Voigt, C., Megarbane, A., Neveling, K., Czeschik, J.C., Albrecht, B., Callewaert, B., Deimling, F. von, Hehr, A., Smeland, M. Falkenberg, Konig, R., Kuechler, A., Marcelis, C., Puiu, M., Reardon, W., Stensland, H.M. Riise, Schweiger, B., Steehouwer, M., Teller, C., Martin, M., Rahmann, S., Hehr, U., Brunner, H.G., Ludecke, H.J., Wieczorek, D., BMC, Ed., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Medizinische Genetik, Sozialpädiatrisches Zentrum Coburg, Zentrum für Humangenetik, Universitätsklinikum Regensburg, Department of Medical Genetics, Division of Child and Adolescent Health-University Hospital of North Norway [Tromsø] (UNN), Humangenetik, Universitätsklinikum Frankfurt, Genetica medicala, Victor Babeş University of Medicine and Pharmacy (UMFT), National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Institut für Humangenetik [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Bioinformatics, Computer Science XI, Technische Universität Dortmund [Dortmund] (TU), Abteilung Genominformatik, Universität Duisburg-Essen [Essen]-Institut für Humangenetik, This work was supported by the German Ministry of Education and Research for the CRANIRARE to DW and the FACE consortium to DW and H-JL (BMBF 01GM1211B and 01GM1109B). BC is a postdoctoral research fellow of the fund for scientific research-flanders., and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Institut für Humangenetik

Subjects
Adult, Male, Adolescent, Medizin, Oto-facial syndrome with midline malformation, [SDV.GEN] Life Sciences [q-bio]/Genetics, HAPLOINSUFFICIENCY, EFTUD2, Genomic disorders and inherited multi-system disorders [IGMD 3], Young Adult, Oto-facial syndrome with midline malformation, Acrofacial dysostosis type Guion-Almeida (AFDGA), SNRNP, Intellectual Disability, Humans, Genetics(clinical), Pharmacology (medical), Mandibulofacial dysostosis type Guion-Almeida (MFDGA), Child, Esophageal Atresia, Genetic Association Studies, Ribonucleoprotein, U5 Small Nuclear, Medicine(all), Acrofacial dysostosis type Guion-Almeida (AFDGA), [SDV.GEN]Life Sciences [q-bio]/Genetics, COMPLEX, Esophageal atresia (EA), Research, Biology and Life Sciences, Sequence Analysis, DNA, NAGER SYNDROME, Peptide Elongation Factors, Phenotype, Child, Preschool, Mutation, Female, MANDIBULOFACIAL DYSOSTOSIS, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], MENTAL-RETARDATION, Mandibulofacial Dysostosis
Abstract

Contains fulltext : 185259.pdf (Publisher’s version ) (Open Access) BACKGROUND: Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). METHODS AND RESULTS: We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. CONCLUSIONS: The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Megarbane et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.

Published
2013

39. Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency

Author

Renard, M, Holm, T, Regan, V, Callewaert, B L, Adès, L C, Baspinar, O, Pickart, A, Dasouki, M, Hoyer, J, Rauch, A, Trapane, P, Earing, M G, Coucke, P J, Sakai, L Y, Dietz, H C, De Paepe, A M, Loeys, B L, and University of Zurich

Subjects
2716 Genetics (clinical), 1311 Genetics, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health
Published
2010

40. Range of motion and repeatability of knee kinematics for eleven clinically relevant motor tasks

Author

Desloovere, Kaat, Wong, P, Swings, L, Callewaert, B, Vandenneucker, Hilde, and Leardini, A

Subjects
human activities
Abstract

Standard gait analysis reports knee joint rotations in the three anatomical planes without addressing their different levels of reliability. Most clinical studies also restrict analysis to knee flexion-extension, because knee abduction-adduction and axial rotation are small with respect to the corresponding amount of measurement artefact. This study analyses a set of 11 motor tasks, in order to identify those that are adequately repeatable and that can induce greater motion at the knee than walking. Ten volunteers (mean ± SD age: 29 ± 9 years) each underwent three motion analysis sessions on different days with a standard gait analysis system and protocol. In each session they performed normal walking, walking with sidestep and crossover turns, ascent onto and descent off a step, descent with sidestep and crossover turns, chair rise, mild and deep squats, and lunge. Range and repeatability of motions in the three anatomical planes were compared by ANOVA. The sidestep turns showed a range of axial rotation significantly larger than that in walking (about 8°), while maintaining similar levels of repeatability. Ascent, chair rise, squat, and lunge showed greater flexion ranges than walking; among these, ascent was the most repeatable. The results show that turning increases knee axial rotation in young subjects significantly. Further, squats and lunges, currently of large interest in orthopaedics and sports research, have smaller repeatability, likely accounted for to the smaller constraints than in the traditional motor tasks. ispartof: Gait & Posture vol:32 issue:4 pages:597-602 ispartof: location:England status: published

Published
2010

41. Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

Author

Fischer, B., Callewaert, B., Schroter, P., Coucke, P.J., Schlack, C., Ott, C.E., Morroni, M., Homann, W., Mundlos, S., Morava, E., Ficcadenti, A., Kornak, U., Fischer, B., Callewaert, B., Schroter, P., Coucke, P.J., Schlack, C., Ott, C.E., Morroni, M., Homann, W., Mundlos, S., Morava, E., Ficcadenti, A., and Kornak, U.

Abstract

Contains fulltext : 136809.pdf (publisher's version ) (Closed access), Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.

Published
2014

42. Absence of Cardiovascular Manifestations in a Haploinsufficient Tgfbr1 Mouse Model

Author

Renard, M, Trachet, B, Casteleyn, C, Campens, L, Cornillie, P, Callewaert, B, Deleye, S, Vandeghinste, B, Heijningen, Paula, Dietz, H, Vos, F, Essers, J., Staelens, S, Segers, P, Loeys, B, Coucke, P, de Paepe, A, Backer, J, Renard, M, Trachet, B, Casteleyn, C, Campens, L, Cornillie, P, Callewaert, B, Deleye, S, Vandeghinste, B, Heijningen, Paula, Dietz, H, Vos, F, Essers, J., Staelens, S, Segers, P, Loeys, B, Coucke, P, de Paepe, A, and Backer, J

Abstract

Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor beta (TGF beta)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGF beta receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGF beta signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno) histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.

Published
2014

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