Search

Your search keyword '"Wiel L"' showing total 36 results
Start Over "Wiel L" Publication Type Electronic Resources
36 results on '"Wiel L"'

1. Addressing the consequences of the corporatization of reproductive medicine

Author

Attinger, SA, Jackson, E, Karpin, I, Kerridge, I, Newson, AJ, Stewart, C, van de Wiel, L, Lipworth, W, Attinger, SA, Jackson, E, Karpin, I, Kerridge, I, Newson, AJ, Stewart, C, van de Wiel, L, and Lipworth, W

Abstract

In Australia and the UK, commercialization and corporatization of assisted reproductive technologies have created a marketplace of clinics, products, and services. While this has arguably increased choice for patients, 'choice', shaped by commercial imperatives may not mean better-quality care. At present, regulation of clinics (including clinic-corporations) and clinicians focuses on the doctor-patient dyad and the clinic-consumer dyad. Scant attention has been paid to the conflicts between the clinic-corporation's duty to its shareholders and investors, the medical profession's duty to the corporations within which they practice, and the obligations of both clinicians and corporations to patients and to health systems. Frameworks of regulation based in corporate governance and business ethics, such as stakeholder models and 'corporate social responsibility', have well-recognized limits and may not translate well into healthcare settings. This means that existing governance frameworks may not meet the needs of patients or health systems. We argue for the development of novel regulatory approaches that more explicitly characterize the obligations that both corporations and clinicians in corporate environments have to patients and to society, and that promote fulfilment of these obligations. We consider mechanisms for application in the multi-jurisdictional setting of Australia, and the single jurisdictional settings of the UK.

Published
2024

5. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, Kremer, H, Wesdorp, M, Gans, P, Schraders, M, Oostrik, J, Huynen, MA, Venselaar, H, Beynon, AJ, van Gaalen, J, Piai, V, Voermans, N, van Rossum, MM, Hartel, B P, Lelieveld, SH, Wiel, L, Verbist, B, Rotteveel, LJ, van Dooren, Marieke, Lichtner, P, Kunst, HPM, Feenstra, I, Admiraal, RJC, Yntema, HG, Hoefsloot, EH, Pennings, RJE, and Kremer, H

Published
2018

6. Real-time Outlier Detection in Time Series Data of Water Sensors

Author

Wiel, L. van de, Feelders, A.J. (Thesis Advisor), Krempl, G.M., Wiel, L. van de, Feelders, A.J. (Thesis Advisor), and Krempl, G.M.

Abstract

We compare multiple methods for real time outlier detection in time series data of water sensors. We present an outlier detection pipeline for this purpose. Multivariate models as well as univariate models are compared empirically by adding simulated outliers to the data to assess model performance. Quantile regression performed by the multi layer perceptron model using the tilted loss function is apt to model time series in a multivariate approach, provided we have access to reliable, correlated time series. Univariate models like auto-regressive models can be useful for detecting specific kinds of outliers such as extreme values. We show that the models are able to detect realistic, real life outliers.

Published
2020

7. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, Koolen, DA, Sa, MJN, Venselaar, H, Wiel, L, Trimouille, A, Lasseaux, E, Naudion, S, Lacombe, D, Piton, A, Vincent-Delorme, C, Zweier, C, Reis, A, Trollmann, R, Ruiz, A, Gabau, E, Vetro, A, Guerrini, R, Bakhtiari, S, Kruer, MC, Amor, DJ, Cooper, MS, Bijlsma, EK, Barakat, TS, van Dooren, MF, van Slegtenhorst, M, Pfundt, R, Gilissen, C, Willemsen, MA, de Vries, BBA, de Brouwer, APM, and Koolen, DA

Abstract

PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Published
2020

8. Real-time Outlier Detection in Time Series Data of Water Sensors

Author

Wiel, L. van de, Feelders, A.J. (Thesis Advisor), Krempl, G.M., Wiel, L. van de, Feelders, A.J. (Thesis Advisor), and Krempl, G.M.

Abstract

We compare multiple methods for real time outlier detection in time series data of water sensors. We present an outlier detection pipeline for this purpose. Multivariate models as well as univariate models are compared empirically by adding simulated outliers to the data to assess model performance. Quantile regression performed by the multi layer perceptron model using the tilted loss function is apt to model time series in a multivariate approach, provided we have access to reliable, correlated time series. Univariate models like auto-regressive models can be useful for detecting specific kinds of outliers such as extreme values. We show that the models are able to detect realistic, real life outliers.

Published
2020

9. A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations

Author

Franzen, S., Berg, E. (Esther) van den, Goudsmit, M., Jurgens, C.K., Wiel, L., Kalkisim, Y., Uysal-Bozkir, O., Ayhan, Y., Nielsen, T.R., Papma, J.M. (Janne), Franzen, S., Berg, E. (Esther) van den, Goudsmit, M., Jurgens, C.K., Wiel, L., Kalkisim, Y., Uysal-Bozkir, O., Ayhan, Y., Nielsen, T.R., and Papma, J.M. (Janne)

Abstract

Objective: Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations. Method: A systematic review was performed using six databases, without restrictions on the year or language of publication. Results: Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer’s disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n

Published
2019
Full Text
View/download PDF

10. A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations

Author

Franzen, S. (Sanne), Berg, E. (Esther) van den, Goudsmit, M. (Miriam), Jurgens, C.K. (Caroline K.), Van De Wiel, L. (Lotte), Kalkisim, Y. (Yuled), Uysal-Bozkir, O. (Özgül), Ayhan, Y. (Yavuz), Nielsen, T.R. (T. Rune), Papma, J.M. (Janne), Franzen, S. (Sanne), Berg, E. (Esther) van den, Goudsmit, M. (Miriam), Jurgens, C.K. (Caroline K.), Van De Wiel, L. (Lotte), Kalkisim, Y. (Yuled), Uysal-Bozkir, O. (Özgül), Ayhan, Y. (Yavuz), Nielsen, T.R. (T. Rune), and Papma, J.M. (Janne)

Abstract

Objective:Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations.Method:A systematic review was performed using six databases, without restrictions on the year or language of publication.Results:Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer's disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n = 12, of which 10 were naming tests). Many studies did not report a thorough adaptation procedure (n = 39) or blinding procedures (n = 29).Conclusions:Various formats of memory tests seem suitable for low-educated, non-Western populations. Promising tasks in other cognitive domains are the Stick Design Test, Five Digit Test, and verbal fluency test. Further research is needed regarding cross-cultural instruments measuring executive functioning and language in low-educated people.

Published
2019
Full Text
View/download PDF

11. The Geodetic Signature of the Earthquake Cycle at Subduction Zones: Model Constraints on the Deep Processes

Author

Govers, R., Furlong, K.P., van de Wiel, L., Herman, M.W., Broerse, T., Govers, R., Furlong, K.P., van de Wiel, L., Herman, M.W., and Broerse, T.

Abstract

Recent megathrust events in Tohoku (Japan), Maule (Chile), and Sumatra (Indonesia) were well recorded. Much has been learned about the dominant physical processes in megathrust zones: (partial) locking of the plate interface, detailed coseismic slip, relocking, afterslip, viscoelastic mantle relaxation, and interseismic loading. These and older observations show complex spatial and temporal patterns in crustal deformation and displacement, and significant differences among different margins. A key question is whether these differences reflect variations in the underlying processes, like differences in locking, or the margin geometry, or whether they are a consequence of the stage in the earthquake cycle of the margin. Quantitative models can connect these plate boundary processes to surficial and far-field observations. We use relatively simple, cyclic geodynamic models to isolate the first-order geodetic signature of the megathrust cycle. Coseismic and subsequent slip on the subduction interface is dynamically (and consistently) driven. A review of global preseismic, coseismic, and postseismic geodetic observations, and of their fit to the model predictions, indicates that similar physical processes are active at different margins. Most of the observed variability between the individual margins appears to be controlled by their different stages in the earthquake cycle. The modeling results also provide a possible explanation for observations of tensile faulting aftershocks and tensile cracking of the overriding plate, which are puzzling in the context of convergence/compression. From the inversion of our synthetic GNSS velocities we find that geodetic observations may incorrectly suggest weak locking of some margins, for example, the west Aleutian margin.

Published
2018

13. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), Kremer, H. (Hannie), Wesdorp, M. (Mieke), de Koning Gans, P.A.M. (P. A M), Schraders, M. (Margit), Oostrik, J. (Jaap), Huynen, M. (Martijn), Venselaar, H. (Hanka), Beynon, A.J. (Andy J.), van Gaalen, J. (Judith), Piai, V. (Vitória), Voermans, N.C. (Nicol), Rossum, M.M. (Michelle) van, Hartel, B.P. (Bas P.), Lelieveld, S.H. (Stefan H.), Wiel, L. (Laurens), Verbist, B. (Berit), Rotteveel, L.J. (Liselotte J.), Dooren, M.F. (Marieke) van, Lichtner, P. (Peter), Kunst, H.P.M. (Henricus P. M.), Feenstra, I. (Ilse), Admiraal, R.J.C. (Ronald J. C.), van Dooren, M.F. (M. F.), de Gier, H.H.W. (H. H.W.), Hoefsloot, E.H. (Lies), Schroeff, M.P. (Marc) van der, Kant, S.G. (Sarina), Rotteveel, L.J.C. (L. J.C.), Frints, S.G.M. (Suzanna), Hof, J.R. (J. R.), Stokroos, R.J. (Robert Jan), Vanhoutte, E.K. (Els), Admiraal, R.J. (Ronald), Feenstra, I. (I.), Kremer, H. (H.), Kunst, H.P.M. (Henricus P.M.), Pennings, R.J.E. (Ronald J.E.), Yntema, H.G. (H. G.), Essen, J.A. (Anthonie) van, Free, R.H. (Rolien), Klein-Wassink, J.S. (J. S.), Yntema, H.G., Pennings, R.J.E. (Ronald J. E.), and Kremer, H. (Hannie)

Abstract

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

Published
2018
Full Text
View/download PDF

14. Performance optimization of solving methods in ELEFANT and development of simPyFEM: An efficient educational tool for geodynamic simulations using Python

Author

Mos, J., Thieulot, C. (Thesis Advisor), Wiel, L. van de, Mos, J., Thieulot, C. (Thesis Advisor), and Wiel, L. van de

Abstract

Numerical models are used to develop a better physical understanding of small and large scale geodynamic processes over geological time scales. Through continuous development of computational techniques and methods, the accuracy and resolution of the models increases each year. Simulating geodynamic processes such as mantle convection or subduction requires the solve of a linear system in which efficient solvers and preconditioners can be used to yield low computation times and thus optimal performance. Many state of the art codes are fully parallel but even then can require multiple days or weeks to run large simulations. Implementing an efficient solver and preconditioner into ELEFANT is the first step into optimizing its performance. A free and open source package for scientific computing (PETSc) is used to facilitate this process. The second part of this thesis consists of the development of an educational tool for geodynamics called simPyFEM. By translating and optimizing a pre-exisiting code (simpleFEM) from Fortran to Python, its usability and versatility are improved. This modernization is inviting to students who are new to geodynamic modelling and want to experience the effect, on an educational level, of changing parameter such as viscosity, density and gravity.

Published
2018

18. Performance optimization of solving methods in ELEFANT and development of simPyFEM: An efficient educational tool for geodynamic simulations using Python

Author

Mos, J., Thieulot, C. (Thesis Advisor), Wiel, L. van de, Mos, J., Thieulot, C. (Thesis Advisor), and Wiel, L. van de

Abstract

Numerical models are used to develop a better physical understanding of small and large scale geodynamic processes over geological time scales. Through continuous development of computational techniques and methods, the accuracy and resolution of the models increases each year. Simulating geodynamic processes such as mantle convection or subduction requires the solve of a linear system in which efficient solvers and preconditioners can be used to yield low computation times and thus optimal performance. Many state of the art codes are fully parallel but even then can require multiple days or weeks to run large simulations. Implementing an efficient solver and preconditioner into ELEFANT is the first step into optimizing its performance. A free and open source package for scientific computing (PETSc) is used to facilitate this process. The second part of this thesis consists of the development of an educational tool for geodynamics called simPyFEM. By translating and optimizing a pre-exisiting code (simpleFEM) from Fortran to Python, its usability and versatility are improved. This modernization is inviting to students who are new to geodynamic modelling and want to experience the effect, on an educational level, of changing parameter such as viscosity, density and gravity.

Published
2018

21. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., Levin, E., Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., and Levin, E.

Abstract

Contains fulltext : 147276.pdf (preprint version ) (Closed access)

Published
2015

22. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., Levin, E., Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., and Levin, E.

Abstract

Contains fulltext : 147276.pdf (preprint version ) (Closed access)

Published
2015

23. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., Levin, E., Japkowicz, N., Matwin, S., Wiel, L., Heskes, T., and Levin, E.

Abstract

Contains fulltext : 147276.pdf (Author’s version preprint ) (Closed access)

Published
2015

24. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., den Hoed, J., de Boer, E., Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L., Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.-L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.-S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P., Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S., Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A., Pfundt, R., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Blok, L.S., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-dos-Santos, J.H., Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

28. De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders

Author

Genetica, KTO Office, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Nabais Sá, Maria J., El Tekle, Geniver, de Brouwer, Arjan P.M., Sawyer, Sarah L., del Gaudio, Daniela, Parker, Michael J., Kanani, Farah, van den Boogaard, Marie José H., van Gassen, Koen, Van Allen, Margot I., Wierenga, Klaas, Purcarin, Gabriela, Elias, Ellen Roy, Begtrup, Amber, Keller-Ramey, Jennifer, Bernasocchi, Tiziano, van de Wiel, Laurens, Gilissen, Christian, Venselaar, Hanka, Pfundt, Rolph, Vissers, Lisenka E.L.M., Theurillat, Jean Philippe P., de Vries, Bert B.A., Genetica, KTO Office, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Nabais Sá, Maria J., El Tekle, Geniver, de Brouwer, Arjan P.M., Sawyer, Sarah L., del Gaudio, Daniela, Parker, Michael J., Kanani, Farah, van den Boogaard, Marie José H., van Gassen, Koen, Van Allen, Margot I., Wierenga, Klaas, Purcarin, Gabriela, Elias, Ellen Roy, Begtrup, Amber, Keller-Ramey, Jennifer, Bernasocchi, Tiziano, van de Wiel, Laurens, Gilissen, Christian, Venselaar, Hanka, Pfundt, Rolph, Vissers, Lisenka E.L.M., Theurillat, Jean Philippe P., and de Vries, Bert B.A.

Published
2020

29. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

30. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

31. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

32. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., Fisher, Simon E., Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Blok, Lot Snijders, Kleefstra, Tjitske, Venselaar, Hanka, Maas, Saskia, Kroes, Hester Y., Lachmeijer, Augusta M. A., van Gassen, Koen L., I, Firth, Helen, V, Tomkins, Susan, Bodek, Simon, Study, The D. D. D., Ounap, Katrin, Wojcik, Monica H., Cunniff, Christopher, Bergstrom, Katherine, Powis, Zoe, Tang, Sha, Shinde, Deepali N., Au, Catherine, Iglesias, Alejandro D., Izumi, Kosuke, Leonard, Jacqueline, Abou Tayoun, Ahmad, Baker, Samuel W., Tartaglia, Marco, Niceta, Marcello, Dentici, Maria Lisa, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Vitobello, Antonio, Faivre, Laurence, Philippe, Christophe, Gilissen, Christian, Wiel, Laurens, Pfundt, Rolph, Deriziotis, Pelagia, Brunner, Han G., and Fisher, Simon E.

Published
2019

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

Author

Genetica, UMC Utrecht, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cancer, Diets, Illja J., van der Donk, Roos, Baltrunaite, Kristina, Waanders, Esmé, Reijnders, Margot R.F., Dingemans, Alexander J.M., Pfundt, Rolph, Vulto-van Silfhout, Anneke T., Wiel, Laurens, Gilissen, Christian, Thevenon, Julien, Perrin, Laurence, Afenjar, Alexandra, Nava, Caroline, Keren, Boris, Bartz, Sarah, Peri, Bethany, Beunders, Gea, Verbeek, Nienke, van Gassen, Koen, Thiffault, Isabelle, Cadieux-Dion, Maxime, Huerta-Saenz, Lina, Wagner, Matias, Konstantopoulou, Vassiliki, Vodopiutz, Julia, Griese, Matthias, Boel, Annekatrien, Callewaert, Bert, Brunner, Han G., Kleefstra, Tjitske, Hoogerbrugge, Nicoline, de Vries, Bert B.A., Hwa, Vivian, Dauber, Andrew, Hehir-Kwa, Jayne Y., Kuiper, Roland P., Jongmans, Marjolijn C.J., Genetica, UMC Utrecht, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Cancer, Diets, Illja J., van der Donk, Roos, Baltrunaite, Kristina, Waanders, Esmé, Reijnders, Margot R.F., Dingemans, Alexander J.M., Pfundt, Rolph, Vulto-van Silfhout, Anneke T., Wiel, Laurens, Gilissen, Christian, Thevenon, Julien, Perrin, Laurence, Afenjar, Alexandra, Nava, Caroline, Keren, Boris, Bartz, Sarah, Peri, Bethany, Beunders, Gea, Verbeek, Nienke, van Gassen, Koen, Thiffault, Isabelle, Cadieux-Dion, Maxime, Huerta-Saenz, Lina, Wagner, Matias, Konstantopoulou, Vassiliki, Vodopiutz, Julia, Griese, Matthias, Boel, Annekatrien, Callewaert, Bert, Brunner, Han G., Kleefstra, Tjitske, Hoogerbrugge, Nicoline, de Vries, Bert B.A., Hwa, Vivian, Dauber, Andrew, Hehir-Kwa, Jayne Y., Kuiper, Roland P., and Jongmans, Marjolijn C.J.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results