Search

Your search keyword '"Menten, B"' showing total 346 results
Start Over Author "Menten, B"
346 results on '"Menten, B"'

2. E-book: Verloskunde - Uitgave 2023

Author

Vos, S., primary, Van den Bergh, B., additional, Roels, H.A., additional, Martens, D., additional, Kindermans, H., additional, Nawrot, T.S., additional, Rombaut, J., additional, Coryn, N., additional, Salihi, R., additional, Tummers, P., additional, Biesemans, Y., additional, Roets, E., additional, Baetens, M., additional, Roelens, K., additional, Menten, B., additional, Vandewal, A., additional, Thaens, A., additional, Fransis, S., additional, Finoulst, M., additional, Vankrunkelsven, P., additional, Van Tongerloo, A., additional, Verdin, H., additional, Blaumeiser, B., additional, Polster, L., additional, Coucke, P.J., additional, and Janssens, S., additional

Published
2023
Full Text
View/download PDF

5. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

Author

Tavernier, S. J., Athanasopoulos, V., Verloo, P., Behrens, G., Staal, J., Bogaert, D. J., Naesens, L., De Bruyne, M., Van Gassen, S., Parthoens, E., Ellyard, J., Cappello, J., Morris, L. X., Van Gorp, H., Van Isterdael, G., Saeys, Y., Lamkanfi, M., Schelstraete, P., Dehoorne, J., Bordon, V., Van Coster, R., Lambrecht, B. N., Menten, B., Beyaert, R., Vinuesa, C. G., Heissmeyer, V., Dullaers, M., and Haerynck, F.

Published
2019
Full Text
View/download PDF

6. Characterization of ovarian tissue oocytes from transgender men reveals poor calcium release and embryo development, which might be overcome by spindle transfer

Author

Christodoulaki, A, primary, He, H, additional, Zhou, M, additional, Cardona Barberán, A, additional, De Roo, C, additional, Chuva De Sousa Lopes, S M, additional, Baetens, M, additional, Menten, B, additional, Van Soom, A, additional, De Sutter, P, additional, Weyers, S, additional, Boel, A, additional, Stoop, D, additional, and Heindryckx, B, additional

Published
2023
Full Text
View/download PDF

8. Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

Author

Tavernier, S. J., Athanasopoulos, V., Verloo, P., Behrens, G., Staal, J., Bogaert, D. J., Naesens, L., De Bruyne, M., Van Gassen, S., Parthoens, E., Ellyard, J., Cappello, J., Morris, L. X., Van Gorp, H., Van Isterdael, G., Saeys, Y., Lamkanfi, M., Schelstraete, P., Dehoorne, J., Bordon, V., Van Coster, R., Lambrecht, B. N., Menten, B., Beyaert, R., Vinuesa, C. G., Heissmeyer, V., Dullaers, M., and Haerynck, F.

Published
2019
Full Text
View/download PDF

18. Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Author

Bijlsma, E.K., Gijsbers, A.C.J., Schuurs-Hoeijmakers, J.H.M., van Haeringen, A., Fransen van de Putte, D.E., Anderlid, B.-M., Lundin, J., Lapunzina, P., Pérez Jurado, L.A., Delle Chiaie, B., Loeys, B., Menten, B., Oostra, A., Verhelst, H., Amor, D.J., Bruno, D.L., van Essen, A.J., Hordijk, R., Sikkema-Raddatz, B., Verbruggen, K.T., Jongmans, M.C.J., Pfundt, R., Reeser, H.M., Breuning, M.H., and Ruivenkamp, C.A.L.

Published
2009
Full Text
View/download PDF

22. Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma

Author

Creytens, D., Folpe, A.L., Koelsche, C., Mentzel, T., Ferdinande, L., Gorp, J.M. van, Linden, M. Van der, Raman, L., Menten, B., Fritchie, K., Deimling, A. von, Dorpe, J. Van, Flucke, U.E., Creytens, D., Folpe, A.L., Koelsche, C., Mentzel, T., Ferdinande, L., Gorp, J.M. van, Linden, M. Van der, Raman, L., Menten, B., Fritchie, K., Deimling, A. von, Dorpe, J. Van, and Flucke, U.E.

Abstract

Item does not contain fulltext, Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid p

Published
2021

25. GENType: all-in-one preimplantation genetic testing by pedigree haplotyping and copy number profiling suitable for third-party reproduction.

Author

Witte, L De, Raman, L, Baetens, M, Koker, A De, Callewaert, N, Symoens, S, Tilleman, K, Meerschaut, F Vanden, Dheedene, A, Menten, B, De Witte, L, De Koker, A, and Vanden Meerschaut, F

Subjects
HUMAN reproduction, BLASTOCYST, ANEUPLOIDY, GENETICS, PREIMPLANTATION genetic diagnosis, GENETIC testing, HAPLOTYPES, CHROMOSOME abnormalities, RESEARCH funding, GENETIC techniques, GENEALOGY, LONGITUDINAL method
Abstract

Study Question: Is it possible to develop a comprehensive pipeline for all-in-one preimplantation genetic testing (PGT), also suitable for parents-only haplotyping and, for the first time, third-party reproduction?Summary Answer: Optimized reduced representation sequencing (RRS) by GENType, along with a novel analysis platform (Hopla), enables cheap, accurate and comprehensive PGT of blastocysts, even without the inclusion of additional family members or both biological parents for genome-wide embryo haplotyping.What Is Known Already: Several haplotyping strategies have proven to be effective for comprehensive PGT. However, these methods often rely on microarray technology, whole-genome sequencing (WGS) or a combination of strategies, hindering sample throughput and cost-efficiency. Moreover, existing tools (including other RRS-based strategies) require both prospective biological parents for embryo haplotyping, impeding application in a third-party reproduction setting.Study Design, Size, Duration: This study included a total of 257 samples. Preliminary technical validation was performed on 81 samples handpicked from commercially available cell lines. Subsequently, a clinical validation was performed on a total of 72 trophectoderm biopsies from 24 blastocysts, tested for a monogenic disorder (PGT-M) (n = 15) and/or (sub)chromosomal aneuploidy (PGT-SR/PGT-A) (n = 9). Once validated, our pipeline was implemented in a diagnostic setting on 104 blastocysts for comprehensive PGT.Participants/materials, Setting, Methods: Samples were whole-genome amplified (WGA) and processed by GENType. Quality metrics, genome-wide haplotypes, b-allele frequencies (BAFs) and copy number profiles were generated by Hopla. PGT-M results were deduced from relative haplotypes, while PGT-SR/PGT-A results were inferred from read-count analysis and BAF profiles. Parents-only haplotyping was assessed by excluding additional family members from analysis and using an independently diagnosed embryo as phasing reference. Suitability for third-party reproduction through single-parent haplotyping was evaluated by excluding one biological parent from analysis. Results were validated against reference PGT methods.Main Results and the Role Of Chance: Genome-wide haplotypes of single cells were highly accurate (mean > 99%) compared to bulk DNA. Unbalanced chromosomal abnormalities (>5 Mb) were detected by GENType. For both PGT-M as well as PGT-SR/PGT-A, our technology demonstrated 100% concordance with reference PGT methods for diverse WGA methods. Equally, for parents-only haplotyping and single-parent haplotyping (of autosomal dominant disorders and X-linked disorders), PGT-M results were fully concordant. Furthermore, the origin of trisomies in PGT-M embryos was correctly deciphered by Hopla.Limitations, Reasons For Caution: Intrinsic to linkage-analysis strategies, de novo single-nucleotide variants remain elusive. Moreover, parents-only haplotyping is not a stand-alone approach and requires prior diagnosis of at least one reference embryo by an independent technology (i.e. direct mutation analysis) for haplotype phasing. Using a haplotyping approach, the presence of a homologous recombination site across the chromosome is biologically required to distinguish meiotic II errors from mitotic errors during trisomy origin investigation.Wider Implications Of the Findings: We offer a generic, fully automatable and accurate pipeline for PGT-M, PGT-A and PGT-SR as well as trisomy origin investigation without the need for personalized assays, microarray technology or WGS. The unique ability to perform single-parent assisted haplotyping of embryos paves the way for cost-effective PGT in a third-party reproduction setting.Study Funding/competing Interest(s): L.D.W. is supported by the Research Foundation Flanders (FWO; 1S74619N). L.R. and B.M. are funded by Ghent University and M.B., S.S., K.T., F.V.M. and A.D. are supported by Ghent University Hospital. Research in the N.C. lab was funded by Ghent University, VIB and Kom op Tegen Kanker. A.D.K and N.C. are co-inventors of patent WO2017162754A1. The other authors have no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

26. Comparative analysis of mouse and human preimplantation development following POU5F1 CRISPR/Cas9 targeting reveals interspecies differences

Author

Stamatiadis, P, primary, Boel, A, additional, Cosemans, G, additional, Popovic, M, additional, Bekaert, B, additional, Guggilla, R, additional, Tang, M, additional, De Sutter, P, additional, Van Nieuwerburgh, F, additional, Menten, B, additional, Stoop, D, additional, Chuva de Sousa Lopes, S M, additional, Coucke, P, additional, and Heindryckx, B, additional

Published
2021
Full Text
View/download PDF

29. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Author

van Bon, B W M, Mefford, H C, Menten, B, Koolen, D A, Sharp, A J, Nillesen, W M, Innis, J W, de Ravel, T J L, Mercer, C L, Fichera, M, Stewart, H, Connell, L E, Õunap, K, Lachlan, K, Castle, B, Van der Aa, N, van Ravenswaaij, C, Nobrega, M A, Serra-Juhé, C, Simonic, I, de Leeuw, N, Pfundt, R, Bongers, E M, Baker, C, Finnemore, P, Huang, S, Maloney, V K, Crolla, J A, van Kalmthout, M, Elia, M, Vandeweyer, G, Fryns, J P, Janssens, S, Foulds, N, Reitano, S, Smith, K, Parkel, S, Loeys, B, Woods, C G, Oostra, A, Speleman, F, Pereira, A C, Kurg, A, Willatt, L, Knight, S J L, Vermeesch, J R, Romano, C, Barber, J C, Mortier, G, Pérez-Jurado, L A, Kooy, F, Brunner, H G, Eichler, E E, Kleefstra, T, and de Vries, B B A

Published
2009
Full Text
View/download PDF

33. Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation (Nature Communications, (2019), 10, 1, (4779), 10.1038/s41467-019-12704-6)

Author

Tavernier, S.J. (Simon), Athanasopoulos, V. (V.), Verloo, P. (Patrick), Behrens, G. (G.), Staal, J. (J.), Bogaert, D.J.A. (Delfien), Naesens, L. (L.), De Bruyne, M. (M.), Van Gassen, S. (S.), Parthoens, E. (Eef), Ellyard, J. (J.), Cappello, J. (J.), Morris, L.X. (L. X.), Van Gorp, H. (H.), Van Isterdael, G. (Gert), Saeys, Y. (Yvan), Lamkanfi, M. (Mohamed), Schelstraete, P. (P.), Dehoorne, J. (J.), Bordon, V., Coster, R.N.A. (R. N A) van, Lambrecht, B.N.M. (Bart), Menten, B., Beyaert, R. (Rudi), Vinuesa, C.G. (C. G.), Heissmeyer, V. (V.), Dullaers, M., Haerynck, F. (F.), Tavernier, S.J. (Simon), Athanasopoulos, V. (V.), Verloo, P. (Patrick), Behrens, G. (G.), Staal, J. (J.), Bogaert, D.J.A. (Delfien), Naesens, L. (L.), De Bruyne, M. (M.), Van Gassen, S. (S.), Parthoens, E. (Eef), Ellyard, J. (J.), Cappello, J. (J.), Morris, L.X. (L. X.), Van Gorp, H. (H.), Van Isterdael, G. (Gert), Saeys, Y. (Yvan), Lamkanfi, M. (Mohamed), Schelstraete, P. (P.), Dehoorne, J. (J.), Bordon, V., Coster, R.N.A. (R. N A) van, Lambrecht, B.N.M. (Bart), Menten, B., Beyaert, R. (Rudi), Vinuesa, C.G. (C. G.), Heissmeyer, V. (V.), Dullaers, M., and Haerynck, F. (F.)

Abstract

The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Information file, in which only the first page of the file was included. The HTML has been updated to include a corrected and complete version of the Supplementary Information file.

Published
2019
Full Text
View/download PDF

34. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

Author

Tavernier, S.J. (Simon), Athanasopoulos, V. (V.), Verloo, P. (Patrick), Behrens, G. (G.), Staal, J. (J.), Bogaert, D.J.A. (Delfien), Naesens, L. (L.), De Bruyne, M. (M.), Van Gassen, S. (S.), Parthoens, E. (Eef), Ellyard, J. (J.), Cappello, J. (J.), Morris, L.X. (L. X.), Van Gorp, H. (H.), Van Isterdael, G. (Gert), Saeys, Y. (Yvan), Lamkanfi, M. (Mohamed), Schelstraete, P. (P.), Dehoorne, J. (J.), Bordon, V., Coster, R.N.A. (R. N A) van, Lambrecht, B.N.M. (Bart), Menten, B., Beyaert, R. (Rudi), Vinuesa, C.G. (C. G.), Heissmeyer, V. (V.), Dullaers, M., Haerynck, F. (F.), Tavernier, S.J. (Simon), Athanasopoulos, V. (V.), Verloo, P. (Patrick), Behrens, G. (G.), Staal, J. (J.), Bogaert, D.J.A. (Delfien), Naesens, L. (L.), De Bruyne, M. (M.), Van Gassen, S. (S.), Parthoens, E. (Eef), Ellyard, J. (J.), Cappello, J. (J.), Morris, L.X. (L. X.), Van Gorp, H. (H.), Van Isterdael, G. (Gert), Saeys, Y. (Yvan), Lamkanfi, M. (Mohamed), Schelstraete, P. (P.), Dehoorne, J. (J.), Bordon, V., Coster, R.N.A. (R. N A) van, Lambrecht, B.N.M. (Bart), Menten, B., Beyaert, R. (Rudi), Vinuesa, C.G. (C. G.), Heissmeyer, V. (V.), Dullaers, M., and Haerynck, F. (F.)

Abstract

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

Published
2019
Full Text
View/download PDF

35. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation

Author

Tavernier, SJ, Athanasopoulos, V, Verloo, P, Behrens, G, Staal, J, Bogaert, DJ, Naesens, L, de Bruyne, M, Van Gassen, S, Parthoens, E, Ellyard, J, Cappello, J, Morris, LX, Van Gorp, H, Van Isterdael, G, Saeys, Y, Lamkanfi, M, Schelstraete, P, Dehoorne, J, Bordon, V, Van Coster, R, Lambrecht, Bart, Menten, B, Beyaert, R, Vinuesa, CG, Heissmeyer, V, Dullaers, M, Haerynck, F, Tavernier, SJ, Athanasopoulos, V, Verloo, P, Behrens, G, Staal, J, Bogaert, DJ, Naesens, L, de Bruyne, M, Van Gassen, S, Parthoens, E, Ellyard, J, Cappello, J, Morris, LX, Van Gorp, H, Van Isterdael, G, Saeys, Y, Lamkanfi, M, Schelstraete, P, Dehoorne, J, Bordon, V, Van Coster, R, Lambrecht, Bart, Menten, B, Beyaert, R, Vinuesa, CG, Heissmeyer, V, Dullaers, M, and Haerynck, F

Published
2019

37. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics

Subjects
0301 basic medicine, Male, Microcephaly, Autism Spectrum Disorder, Obesity/genetics, Settore MED/03 - GENETICA MEDICA, Body Mass Index, Microcephaly/genetics, Gene duplication, Chromosome Duplication, ddc:576.5, Copy-number variation, Child, In Situ Hybridization, In Situ Hybridization, Fluorescence, Genetics, medicine.diagnostic_test, Chromosome Mapping, Middle Aged, Phenotype, Chromatin, Chemistry, Psychiatry and Mental Health, Child, Preschool, Female, Original Article, Chromosomes, Human, Pair 16/genetics, Megalencephaly/genetics, Chromosome Deletion, Autistic Disorder/genetics, Molecular Biology, Cellular and Molecular Neuroscience, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, DNA Copy Number Variations, Locus (genetics), DNA Copy Number Variations/genetics, Biology, Aged, Autistic Disorder, Chromosomes, Human, Pair 16, Humans, Infant, Intellectual Disability, Megalencephaly, Obesity, Chromosomes, Fluorescence, Chromatin/metabolism, 03 medical and health sciences, medicine, Preschool, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, medicine.disease, Intellectual Disability/genetics, Autism Spectrum Disorder/genetics, 030104 developmental biology, Human medicine, Chromosome Mapping/methods, Fluorescence in situ hybridization
Abstract

Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Published
2015

39. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, C. (Claire), Brand, H. (Harrison), Collins, R.L. (Ryan L.), Kammin, T. (Tammy), Mitchell, E. (Elyse), Hodge, J.C. (Jennelle C.), Hanscom, C. (Carrie), Pillalamarri, V. (Vamsee), Seabra, C.M. (Catarina M.), Abbott, M.-A. (Mary-Alice), Abdul-Rahman, O.A. (Omar), Aberg, E. (Erika), Adley, R. (Rhett), Alcaraz-Estrada, S.L. (Sofia L.), Alkuraya, F.S. (Fowzan S), An, Y. (Yu), Anderson, M.-A. (Mary-Anne), Antolik, C. (Caroline), Anyane-Yeboa, K. (Kwame), Atkin, J.F. (Joan), Bartell, T. (Tina), Bernstein, J.A. (Jonathan A.), Beyer, E. (Elizabeth), Blumenthal, I. (Ian), Bongers, E. (Ernie), Brilstra, E.H. (Eva H.), Brown, C.W. (Chester W.), Brüggenwirth, H.T. (Hennie), Callewaert, L., Chiang, C. (Colby), Corning, K. (Ken), Cox, H. (H.), Cuppen, E. (Edwin), Currall, B.B. (Benjamin B.), Cushing, T. (Tom), David, D. (Dezso), Deardorff, M.A. (Matthew), Dheedene, A. (Annelies), D'Hooghe, M. (Marc), Vries, B. (Boukje) de, Earl, D.L. (Dawn L.), Ferguson, H.L. (Heather L.), Fisher, H. (Heather), Fitzpatrick, D.R. (David R.), Gerrol, P. (Pamela), Giachino, D. (Daniela), Glessner, J.T. (Joseph T.), Gliem, T. (Troy), Grady, M. (Margo), Graham, B.H. (Brett H.), Griffis, C. (Cristin), Gripp, K.W. (Karen), Gropman, A.L. (Andrea L.), Hanson-Kahn, A. (Andrea), Harris, D.J. (David J.), Hayden, M.A. (Mark A.), Hill, R. (Rosamund), Hochstenbach, R. (Ron), Hoffman, J.D. (Jodi D.), Hopkin, R., Hubshman, M.W. (Monika W.), Innes, M., Irons, M. (Mira), Irving, M. (Melita), Jacobsen, J.C. (Jessie C.), Janssens, S. (Sandra), Jewett, T. (Tamison), Johnson, J.P. (John P.), Jongmans, M.C.J. (Marjolijn), Kahler, S.G. (Stephen G.), Koolen, D.A. (David), Korzelius, J. (Jerome), Kroisel, P. (Peter), Lacassie, Y. (Yves), Lawless, W. (William), Lemyre, E. (Emmanuelle), Leppig, K. (Kathy), Levin, A.V. (Alex V.), Li, H. (Haibo), Li, H. (Hong), Liao, E.C. (Eric C.), Lim, C. (Cynthia), Lose, E.J. (Edward J.), Lucente, D. (Diane), MacEra, M.J. (Michael J.), Manavalan, P. (Poornima), Mandrile, G. (Giorgia), Marcelis, C.L.M. (Carlo), Margolin, L. (Lauren), Mason, T. (Tamara), Masser-Frye, D. (Diane), McClellan, M.W. (Michael W.), Zepeda Mendoza, C.J. (Cinthya J.), Menten, B., Middelkamp, S. (Sjors), Mikami, L.R. (Liya R.), Moe, E. (Emily), Mohammed, S. (Shabaz), Mononen, T. (Tarja), Mortenson, M.E. (Megan E.), Moya, G. (Graciela), Nieuwint, A.W. (Aggie W.), Ordulu, Z. (Zehra), Parkash, S. (Sandhya), Pauker, S.P. (Susan P.), Pereira, S. (Shahrin), Perrin, D. (Danielle), Phelan, K. (Katy), Piña Aguilar, R.E. (Raul E.), Poddighe, P. (Pino), Pregno, G. (Giulia), Raskin, S. (Salmo), Reis, L. (Linda), Rhead, W. (William), Rita, D. (Debra), Renkens, I. (Ivo), Roelens, F. (Filip), Ruliera, J. (Jayla), Rump, P. (Patrick), Schilit, S.L.P. (Samantha L.P.), Shaheen, R. (Ranad), Sparkes, R. (Rebecca), Spiegel, E. (Erica), Stevens, B. (Blair), Stone, M.R. (Matthew R.), Tagoe, J. (Julia), Thakuria, J.V. (Joseph V.), Bon, B. (Bregje) van, van de Kamp, J.M. (Jiddeke M.), Van Der Burgt, I. (Ineke), Essen, T. (Ton) van, Ravenswaaij-Arts, C.M.A. (Conny) van, Van Roosmalen, M.J. (Markus J.), Vergult, S. (Sarah), Volker-Touw, C.M.L. (Catharina M.L.), Warburton, D. (Dorothy), Waterman, M.J. (Matthew J.), Wiley, S. (Susan), Wilson, A. (Anna), Yerena-De Vega, M.D.L.C.A. (Maria De La Concepcion A), Zori, R.T. (Roberto T.), Levy, B. (Brynn), Brunner, H.G. (Han), Leeuw, N. (Nicole) de, Kloosterman, W.P. (Wigard), Thorland, E.C. (Erik C.), Morton, C.C. (Cynthia), Gusella, J.F. (James), Talkowski, M.E. (Michael E.), Redin, C. (Claire), Brand, H. (Harrison), Collins, R.L. (Ryan L.), Kammin, T. (Tammy), Mitchell, E. (Elyse), Hodge, J.C. (Jennelle C.), Hanscom, C. (Carrie), Pillalamarri, V. (Vamsee), Seabra, C.M. (Catarina M.), Abbott, M.-A. (Mary-Alice), Abdul-Rahman, O.A. (Omar), Aberg, E. (Erika), Adley, R. (Rhett), Alcaraz-Estrada, S.L. (Sofia L.), Alkuraya, F.S. (Fowzan S), An, Y. (Yu), Anderson, M.-A. (Mary-Anne), Antolik, C. (Caroline), Anyane-Yeboa, K. (Kwame), Atkin, J.F. (Joan), Bartell, T. (Tina), Bernstein, J.A. (Jonathan A.), Beyer, E. (Elizabeth), Blumenthal, I. (Ian), Bongers, E. (Ernie), Brilstra, E.H. (Eva H.), Brown, C.W. (Chester W.), Brüggenwirth, H.T. (Hennie), Callewaert, L., Chiang, C. (Colby), Corning, K. (Ken), Cox, H. (H.), Cuppen, E. (Edwin), Currall, B.B. (Benjamin B.), Cushing, T. (Tom), David, D. (Dezso), Deardorff, M.A. (Matthew), Dheedene, A. (Annelies), D'Hooghe, M. (Marc), Vries, B. (Boukje) de, Earl, D.L. (Dawn L.), Ferguson, H.L. (Heather L.), Fisher, H. (Heather), Fitzpatrick, D.R. (David R.), Gerrol, P. (Pamela), Giachino, D. (Daniela), Glessner, J.T. (Joseph T.), Gliem, T. (Troy), Grady, M. (Margo), Graham, B.H. (Brett H.), Griffis, C. (Cristin), Gripp, K.W. (Karen), Gropman, A.L. (Andrea L.), Hanson-Kahn, A. (Andrea), Harris, D.J. (David J.), Hayden, M.A. (Mark A.), Hill, R. (Rosamund), Hochstenbach, R. (Ron), Hoffman, J.D. (Jodi D.), Hopkin, R., Hubshman, M.W. (Monika W.), Innes, M., Irons, M. (Mira), Irving, M. (Melita), Jacobsen, J.C. (Jessie C.), Janssens, S. (Sandra), Jewett, T. (Tamison), Johnson, J.P. (John P.), Jongmans, M.C.J. (Marjolijn), Kahler, S.G. (Stephen G.), Koolen, D.A. (David), Korzelius, J. (Jerome), Kroisel, P. (Peter), Lacassie, Y. (Yves), Lawless, W. (William), Lemyre, E. (Emmanuelle), Leppig, K. (Kathy), Levin, A.V. (Alex V.), Li, H. (Haibo), Li, H. (Hong), Liao, E.C. (Eric C.), Lim, C. (Cynthia), Lose, E.J. (Edward J.), Lucente, D. (Diane), MacEra, M.J. (Michael J.), Manavalan, P. (Poornima), Mandrile, G. (Giorgia), Marcelis, C.L.M. (Carlo), Margolin, L. (Lauren), Mason, T. (Tamara), Masser-Frye, D. (Diane), McClellan, M.W. (Michael W.), Zepeda Mendoza, C.J. (Cinthya J.), Menten, B., Middelkamp, S. (Sjors), Mikami, L.R. (Liya R.), Moe, E. (Emily), Mohammed, S. (Shabaz), Mononen, T. (Tarja), Mortenson, M.E. (Megan E.), Moya, G. (Graciela), Nieuwint, A.W. (Aggie W.), Ordulu, Z. (Zehra), Parkash, S. (Sandhya), Pauker, S.P. (Susan P.), Pereira, S. (Shahrin), Perrin, D. (Danielle), Phelan, K. (Katy), Piña Aguilar, R.E. (Raul E.), Poddighe, P. (Pino), Pregno, G. (Giulia), Raskin, S. (Salmo), Reis, L. (Linda), Rhead, W. (William), Rita, D. (Debra), Renkens, I. (Ivo), Roelens, F. (Filip), Ruliera, J. (Jayla), Rump, P. (Patrick), Schilit, S.L.P. (Samantha L.P.), Shaheen, R. (Ranad), Sparkes, R. (Rebecca), Spiegel, E. (Erica), Stevens, B. (Blair), Stone, M.R. (Matthew R.), Tagoe, J. (Julia), Thakuria, J.V. (Joseph V.), Bon, B. (Bregje) van, van de Kamp, J.M. (Jiddeke M.), Van Der Burgt, I. (Ineke), Essen, T. (Ton) van, Ravenswaaij-Arts, C.M.A. (Conny) van, Van Roosmalen, M.J. (Markus J.), Vergult, S. (Sarah), Volker-Touw, C.M.L. (Catharina M.L.), Warburton, D. (Dorothy), Waterman, M.J. (Matthew J.), Wiley, S. (Susan), Wilson, A. (Anna), Yerena-De Vega, M.D.L.C.A. (Maria De La Concepcion A), Zori, R.T. (Roberto T.), Levy, B. (Brynn), Brunner, H.G. (Han), Leeuw, N. (Nicole) de, Kloosterman, W.P. (Wigard), Thorland, E.C. (Erik C.), Morton, C.C. (Cynthia), Gusella, J.F. (James), and Talkowski, M.E. (Michael E.)

Abstract

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA br

Published
2017
Full Text
View/download PDF

41. 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

42. Direct comparison of distinct naive pluripotent states in human embryonic stem cells

Author

Warrier, S., primary, Van der Jeught, M., additional, Duggal, G., additional, Tilleman, L., additional, Sutherland, E., additional, Taelman, J., additional, Popovic, M., additional, Lierman, S., additional, Chuva De Sousa Lopes, S., additional, Van Soom, A., additional, Peelman, L., additional, Van Nieuwerburgh, F., additional, De Coninck, D. I. M., additional, Menten, B., additional, Mestdagh, P., additional, Van de Sompele, J., additional, Deforce, D., additional, De Sutter, P., additional, and Heindryckx, B., additional

Published
2017
Full Text
View/download PDF

43. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Author

Szafranski, P., Gambin, T., Dharmadhikari, A.V., Akdemir, K.C., Jhangiani, S.N., Schuette, J., Godiwala, N., Yatsenko, S.A., Sebastian, J., Madan-Khetarpal, S., Surti, U., Abellar, R.G., Bateman, D.A., Wilson, A.L., Markham, M.H., Slamon, J., Santos-Simarro, F., Palomares, M., Nevado, J., Lapunzina, P., Chung, B.H., Wong, W.L., Chu, Y.W., Mok, G.T., Kerem, E., Reiter, J., Ambalavanan, N., Anderson, S.A., Kelly, D.R., Shieh, J., Rosenthal, T.C., Scheible, K., Steiner, L., Iqbal, M.A., McKinnon, M.L., Hamilton, S.J., Schlade-Bartusiak, K., English, D., Hendson, G., Roeder, E.R., DeNapoli, T.S., Littlejohn, R.O., Wolff, D.J., Wagner, C.L., Yeung, A., Francis, D., Fiorino, E.K., Edelman, M., Fox, J., Hayes, D.A., Janssens, S., Baere, E. De, Menten, B., Loccufier, A., Vanwalleghem, L., Moerman, P., Sznajer, Y., Lay, A.S., Kussmann, J.L., Chawla, J., Payton, D.J., Phillips, G.E., Brosens, E., Tibboel, D., Klein, A., Maystadt, I., Fisher, R., Sebire, N., Male, A., Chopra, M., Pinner, J., Malcolm, G., Peters, G., Arbuckle, S., Lees, M., Mead, Z., Quarrell, O., Sayers, R., Owens, M., Shaw-Smith, C., Lioy, J., McKay, E., Leeuw, N. de, Feenstra, I., Spruijt, L., Elmslie, F., Thiruchelvam, T., Bacino, C.A., Langston, C., Lupski, J.R., Sen, P., Popek, E., Stankiewicz, P., Szafranski, P., Gambin, T., Dharmadhikari, A.V., Akdemir, K.C., Jhangiani, S.N., Schuette, J., Godiwala, N., Yatsenko, S.A., Sebastian, J., Madan-Khetarpal, S., Surti, U., Abellar, R.G., Bateman, D.A., Wilson, A.L., Markham, M.H., Slamon, J., Santos-Simarro, F., Palomares, M., Nevado, J., Lapunzina, P., Chung, B.H., Wong, W.L., Chu, Y.W., Mok, G.T., Kerem, E., Reiter, J., Ambalavanan, N., Anderson, S.A., Kelly, D.R., Shieh, J., Rosenthal, T.C., Scheible, K., Steiner, L., Iqbal, M.A., McKinnon, M.L., Hamilton, S.J., Schlade-Bartusiak, K., English, D., Hendson, G., Roeder, E.R., DeNapoli, T.S., Littlejohn, R.O., Wolff, D.J., Wagner, C.L., Yeung, A., Francis, D., Fiorino, E.K., Edelman, M., Fox, J., Hayes, D.A., Janssens, S., Baere, E. De, Menten, B., Loccufier, A., Vanwalleghem, L., Moerman, P., Sznajer, Y., Lay, A.S., Kussmann, J.L., Chawla, J., Payton, D.J., Phillips, G.E., Brosens, E., Tibboel, D., Klein, A., Maystadt, I., Fisher, R., Sebire, N., Male, A., Chopra, M., Pinner, J., Malcolm, G., Peters, G., Arbuckle, S., Lees, M., Mead, Z., Quarrell, O., Sayers, R., Owens, M., Shaw-Smith, C., Lioy, J., McKay, E., Leeuw, N. de, Feenstra, I., Spruijt, L., Elmslie, F., Thiruchelvam, T., Bacino, C.A., Langston, C., Lupski, J.R., Sen, P., Popek, E., and Stankiewicz, P.

Abstract

Contains fulltext : 168023.pdf (publisher's version ) (Closed access), Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Published
2016

45. OC06.04: The Belgian approach to meet the challenge in interpreting prenatal microarray results

Author

Muys, J., primary, Blaumeiser, B., additional, Janssens, K., additional, Bandelier, C., additional, Gatot, J., additional, Van Den Bogaert, A., additional, Vermeesch, J., additional, Rombout, S., additional, Menten, B., additional, Pichon, B., additional, Keymolen, K., additional, Van Den Bogaert, K., additional, Janssens, S., additional, Caberg, J., additional, Désir, J., additional, Sznajer, Y., additional, Destree, A., additional, and Jacquemyn, Y., additional

Published
2016
Full Text
View/download PDF

46. Phenotypic and molecular insights into CASK-related disorders in males

Author

Moog, U., Bierhals, T., Brand, K, Bautsch, J., Biskup, S., Brune, T., Denecke, J., Die-Smulders, C.E.M. de, Evers, C., Hempel, M., Henneke, M., Yntema, H.G., Menten, B., Pietz, J., Pfundt, R.P., Schmidtke, J., Steinemann, D., Stumpel, C.T., Maldergem, L. Van, Kutsche, K., Moog, U., Bierhals, T., Brand, K, Bautsch, J., Biskup, S., Brune, T., Denecke, J., Die-Smulders, C.E.M. de, Evers, C., Hempel, M., Henneke, M., Yntema, H.G., Menten, B., Pietz, J., Pfundt, R.P., Schmidtke, J., Steinemann, D., Stumpel, C.T., Maldergem, L. Van, and Kutsche, K.

Abstract

Contains fulltext : 153652.pdf (publisher's version ) (Open Access), BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) s

Published
2015

47. Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Author

Rocker, N. de, Vergult, S., Koolen, D.A., Jacobs, E., Hoischen, A., Zeesman, S., Bang, B., Bena, F., Bockaert, N., Bongers, E.M.H.F., Ravel, T. de, Devriendt, K., Giglio, S., Faivre, L., Joss, S., Maas, S., Marle, N., Novara, F., Nowaczyk, M.J., Peeters, H., Polstra, A., Roelens, F., Rosenberg, C., Thevenon, J., Tumer, Z., Vanhauwaert, S., Varvagiannis, K., Willaert, A., Willemsen, M.H., Willems, M., Zuffardi, O., Coucke, P., Speleman, F., Eichler, E.E., Kleefstra, T., Menten, B., Rocker, N. de, Vergult, S., Koolen, D.A., Jacobs, E., Hoischen, A., Zeesman, S., Bang, B., Bena, F., Bockaert, N., Bongers, E.M.H.F., Ravel, T. de, Devriendt, K., Giglio, S., Faivre, L., Joss, S., Maas, S., Marle, N., Novara, F., Nowaczyk, M.J., Peeters, H., Polstra, A., Roelens, F., Rosenberg, C., Thevenon, J., Tumer, Z., Vanhauwaert, S., Varvagiannis, K., Willaert, A., Willemsen, M.H., Willems, M., Zuffardi, O., Coucke, P., Speleman, F., Eichler, E.E., Kleefstra, T., and Menten, B.

Abstract

Item does not contain fulltext, PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.

Published
2015

48. The Belgian MicroArray Prenatal (BEMAPRE) database [Online Abstract]

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Muys,, J., Janssens, K., Vanakker, O., Vilain, C., Smits, G., Bandelier, Claude, Bulk, S., Caberg, J., De Leener, A., De Rademaeker, M., de Ravel de l'Argentière, T., Desir, J., Destree, A., Dheedene, A., Gaillez, S., Grisart, B., Hellin, A., Janssens, S., Keymolen, K., Menten, B., Pichon, B., Ravoet, Marie, Revencu, Nicole, Rombout, S., Staessens, C., Van Den Bogaert, A., Van Den Bogaert, K., Vermeesch, J., Sznajer, Yves, Blaumeiser, B., Jacquemyn, Y., Devriendt, K., European Human Genetics Conference 2015, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Muys,, J., Janssens, K., Vanakker, O., Vilain, C., Smits, G., Bandelier, Claude, Bulk, S., Caberg, J., De Leener, A., De Rademaeker, M., de Ravel de l'Argentière, T., Desir, J., Destree, A., Dheedene, A., Gaillez, S., Grisart, B., Hellin, A., Janssens, S., Keymolen, K., Menten, B., Pichon, B., Ravoet, Marie, Revencu, Nicole, Rombout, S., Staessens, C., Van Den Bogaert, A., Van Den Bogaert, K., Vermeesch, J., Sznajer, Yves, Blaumeiser, B., Jacquemyn, Y., Devriendt, K., and European Human Genetics Conference 2015

Abstract

Objectives : Since 2013, samples for prenatal diagnosis in Belgium are analysed by Chromosomal Microarray Analysis. Interpretation of prenatal copy number variants (CNV) remains difficult given the limited phenotypic information. An Ad Hoc Committee tries to resolve uncertain cases based on literature and experiences with similar variants. A Belgian MicroArray Prenatal (BEMAPRE) database studies the association between laboratory, ultrasound and postnatal data. Method : Our database was customised in consultation with the Centers for Medical Genetics to import, consult and extract genotype-phenotype data. Prenatal cases in which a pathogenic CNV/UV(unclassified variant) >400kb was detected, are imported. Phenotypic data are added postpartum and at the age of 2-3 years. Meta-analysis is performed based on genotype-phenotype data from hundreds of cases. Results : Reporting policy is determined by classification of CNVs (benign, UV and pathogenic). If UVs have intragenic deletions/duplications in a known gene; are mentioned in literature and/or databases; consist of deletions/duplications covering more than 18 genes or comprise an X-linked gene in a XY fetus, likeliness of pathogenicity is evaluated. In case of strong arguments for pathogenicity, parents are tested. They are reported if parental phenotype is potentially divergent or if de novo. Known pathogenic variants, risk factors with high penetrance or ultrasound anomalies and actionable incidental findings are reported. Since 2013, 7875 arrays were performed; 293 (3.72 %) were reported as pathogenic. Conclusions : The BEMAPRE database is a source of scientific, clinical and ethical studies; allows easy communication among Belgian genetic centers and will be made available to other scientists. Most recent data are presented.

Published
2015

50. Genomic and Functional Overlap between Somatic and Germline Chromosomal Rearrangements

Author

Heesch, S. van, Simonis, M., Roosmalen, M.J. van, Pillalamarri, V., Brand, H., Kuijk, E.W., Luca, K.L. de, Lansu, N., Braat, A.K., Menelaou, A., Hao, W., Korving, J., Snijder, S., Veken, L.T. van der, Hochstenbach, R., Knegt, A.C., Duran, K., Renkens, I., Alekozai, N., Jager, M. de, Vergult, S., Menten, B., Bruijn, E. de, Boymans, S., Ippel, E., Binsbergen, E. van, Talkowski, M.E., Lichtenbelt, K., Cuppen, E., Kloosterman, W.P., Heesch, S. van, Simonis, M., Roosmalen, M.J. van, Pillalamarri, V., Brand, H., Kuijk, E.W., Luca, K.L. de, Lansu, N., Braat, A.K., Menelaou, A., Hao, W., Korving, J., Snijder, S., Veken, L.T. van der, Hochstenbach, R., Knegt, A.C., Duran, K., Renkens, I., Alekozai, N., Jager, M. de, Vergult, S., Menten, B., Bruijn, E. de, Boymans, S., Ippel, E., Binsbergen, E. van, Talkowski, M.E., Lichtenbelt, K., Cuppen, E., and Kloosterman, W.P.

Abstract

Contains fulltext : 139109.pdf (publisher's version ) (Open Access), Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted.

Published
2014

Catalog

Books, media, physical & digital resources
See catalog results