Author: "Sinnema, M." - Searchworks@Jio Institute Digital Library Search Results

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139 results on '"Sinnema, M."'

1. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Author: Koster, R., Brandão, R. D., Tserpelis, D., van Roozendaal, C. E. P., van Oosterhoud, C. N., Claes, K. B. M., Paulussen, A. D. C., Sinnema, M., Vreeburg, M., van der Schoot, V., Stumpel, C. T. R. M., Broen, M. P. G., Spruijt, L., Jongmans, M. C. J., Lesnik Oberstein, S. A. J., Plomp, A. S., Misra-Isrie, M., Duijkers, F. A., Louwers, M. J., Szklarczyk, R., Derks, K. W. J., Brunner, H. G., van den Wijngaard, A., van Geel, M., and Blok, M. J.
Published: 2021
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2. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders.

Author: Sanden, B. van der, Schobers, G.M.G., Corominas-Galbany, J., Koolen, D.A., Sinnema, M., Reeuwijk, J. van, Stumpel, C.T., Kleefstra, T., Vries, B.B. de, Ruiterkamp-Versteeg, M., Leijsten, N., Kwint, M.P., Derks, R.C., Swinkels, H.L., Ouden, A.P.M. den, Pfundt, R.P., Rinne, T.K., Leeuw, N. de, Stegmann, A.P.A., Stevens, S.J.C., Wijngaard, A. van den, Brunner, H.G., Yntema, H.G., Gilissen, C., Nelen, M.R., Vissers, L.E.L.M., Sanden, B. van der, Schobers, G.M.G., Corominas-Galbany, J., Koolen, D.A., Sinnema, M., Reeuwijk, J. van, Stumpel, C.T., Kleefstra, T., Vries, B.B. de, Ruiterkamp-Versteeg, M., Leijsten, N., Kwint, M.P., Derks, R.C., Swinkels, H.L., Ouden, A.P.M. den, Pfundt, R.P., Rinne, T.K., Leeuw, N. de, Stegmann, A.P.A., Stevens, S.J.C., Wijngaard, A. van den, Brunner, H.G., Yntema, H.G., Gilissen, C., Nelen, M.R., and Vissers, L.E.L.M.
Abstract: 01 januari 2023, Item does not contain fulltext, Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.
Published: 2023

3. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

Author: Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., Kleefstra, T., Rots, D., Jakub, T.E., Keung, C., Jackson, A., Banka, S., Pfundt, R.P., Vries, B.B.A. de, Jaarsveld, R.H. van, Hopman, S.M.J., Binsbergen, E. van, Valenzuela, I., Hempel, M., Bierhals, T., Kortüm, F., Lecoquierre, F., Goldenberg, A., Hertz, J.M., Andersen, C.B., Kibæk, M., Prijoles, E.J., Stevenson, R.E., Everman, D.B., Patterson, W.G., Meng, L., Gijavanekar, C., Dios, K. De, Lakhani, S., Levy, T., Wagner, M., Wieczorek, D., Benke, P.J., Lopez Garcia, M.S., Perrier, R., Sousa, S.B., Almeida, P.M., Simões, M.J., Isidor, B., Deb, W., Schmanski, A.A., Abdul-Rahman, O., Philippe, C., Bruel, A.L., Faivre, L., Vitobello, A., Thauvin, C., Smits, J.J., Garavelli, L., Caraffi, S.G., Peluso, F., Davis-Keppen, L., Platt, D., Royer, E., Leeuwen, L van, Sinnema, M., Stegmann, A.P.A., Stumpel, C.T., Tiller, G.E., Bosch, D.G.M., Potgieter, S.T., Joss, S., Splitt, M., Holden, S., Prapa, M., Foulds, N., Douzgou, S., Puura, K., Waltes, R., Chiocchetti, A.G., Freitag, C.M., Satterstrom, F.K., Rubeis, S. de, Buxbaum, J., Gelb, B.D., Branko, A., Kushima, I., Howe, J., Scherer, S.W., Arado, A., Baldo, C., Patat, O., Bénédicte, D., Lopergolo, D., Santorelli, F.M., Haack, T.B., Dufke, A., Bertrand, M., Falb, R.J., Rieß, A., Krieg, P., Spranger, S., Bedeschi, M.F., Iascone, M., Josephi-Taylor, S., Roscioli, T., Buckley, M.F., Liebelt, J., Dagli, A.I., Aten, E., Hurst, A.C.E., Hicks, A., Suri, M., Aliu, E., Naik, S., Sidlow, R., Coursimault, J., Nicolas, G., Küpper, H., Petit, F., Ibrahim, V., Top, D., Cara, F. Di, Louie, R.J., Stolerman, E., Brunner, H.G., Vissers, L.E.L.M., Kramer, J.M., and Kleefstra, T.
Abstract: Item does not contain fulltext, De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Published: 2023

4. De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

Author: Reijnders, M.R.F., Seibt, A., Brugger, M., Lamers, I.J.C., Ott, T., Klaas, O., Horváth, J., Rose, A.M.S., Craghill, I.M., Brunet, T., Graf, E., Mayerhanser, K., Hellebrekers, D., Pauck, D., Neuen-Jacob, E., Rodenburg, R.J.T., Wieczorek, D., Klee, D., Mayatepek, E., Driessen, G., Bindermann, R., Averdunk, L., Lohmeier, K., Sinnema, M., Stegmann, A.P.A., Roepman, R., Poulter, J.A., Distelmaier, F., Reijnders, M.R.F., Seibt, A., Brugger, M., Lamers, I.J.C., Ott, T., Klaas, O., Horváth, J., Rose, A.M.S., Craghill, I.M., Brunet, T., Graf, E., Mayerhanser, K., Hellebrekers, D., Pauck, D., Neuen-Jacob, E., Rodenburg, R.J.T., Wieczorek, D., Klee, D., Mayatepek, E., Driessen, G., Bindermann, R., Averdunk, L., Lohmeier, K., Sinnema, M., Stegmann, A.P.A., Roepman, R., Poulter, J.A., and Distelmaier, F.
Abstract: 01 juli 2023, Contains fulltext : 294778.pdf (Publisher’s version ) (Open Access), PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. METHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. RESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model. CONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.
Published: 2023

5. A novel distal 22q11.21 microduplication in a 43-year-old male patient with mild intellectual disability, social cognitive dysfunctions, and anxiety

Author: Egger, J.I.M., Verhoeven, W.M.A., Verbeeck, W.J.C., Sinnema, M., Stegmann, A., Stuurop, K., Leeuw, N. de, Egger, J.I.M., Verhoeven, W.M.A., Verbeeck, W.J.C., Sinnema, M., Stegmann, A., Stuurop, K., and Leeuw, N. de
Abstract: Contains fulltext : 299357.pdf (Publisher’s version ) (Open Access), 5 p.
Published: 2023

6. Sleep Disturbances and Behavioural Problems in Adults with Prader-Willi Syndrome

Author: Maas, A. P. H. M., Sinnema, M., and Didden, R.
Abstract: Background: Individuals with Prader-Willi syndrome (PWS) are at risk of sleep disturbances, such as excessive daytime sleepiness (EDS) and sleep apnoea, and behavioural problems. Sleep disturbances and their relationship with other variables had not been researched extensively in adults with PWS. Method: Sleep disturbances and behavioural problems were investigated in adults with genetically confirmed PWS using standardised questionnaires. Results of adults with paternal deletion (n = 45) were compared with those of adults with maternal uniparental disomy (n = 33). Results: Eleven adults with PWS (i.e. 15%) had a current sleep problem, mostly night waking problems. Twenty-six adults with PWS (i.e. 33%) suffered from severe EDS. No differences in prevalence of sleep disturbances between genetic subtypes were found. Seventeen adults with deletion (i.e. 38%) and 17 adults with maternal uniparental disomy (i.e. 52%) had behavioural problems. No significant relationships were found between sleep disturbances and behavioural problems. Conclusions: In adults with PWS, EDS is the most common type of sleep disturbance. Men and individuals with relative high body mass index are at increased risk for EDS. More research, aimed at developing a suitable screening instrument for sleep apnoea in adults with PWS, is necessary. Clinical implications of the findings are discussed.
Published: 2010
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7. Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON

Author: Dingemans, A.J.M., Truijen, K.M.G., Kim, J.H., Alaçam, Z., Faivre, L., Collins, K.M., Gerkes, E.H., Haelst, M. van, Laar, I. van de, Lindstrom, K., Nizon, M., Pauling, J., Heropolitańska-Pliszka, E., Plomp, A.S., Racine, C., Sachdev, R., Sinnema, M., Skranes, J., Veenstra-Knol, Hermine E., Verberne, E.A., Vulto-van Silfhout, A.T., Wilsterman, M.E., Ahn, E.E., Vries, B.B.A. de, Vissers, L.E.L.M., Dingemans, A.J.M., Truijen, K.M.G., Kim, J.H., Alaçam, Z., Faivre, L., Collins, K.M., Gerkes, E.H., Haelst, M. van, Laar, I. van de, Lindstrom, K., Nizon, M., Pauling, J., Heropolitańska-Pliszka, E., Plomp, A.S., Racine, C., Sachdev, R., Sinnema, M., Skranes, J., Veenstra-Knol, Hermine E., Verberne, E.A., Vulto-van Silfhout, A.T., Wilsterman, M.E., Ahn, E.E., Vries, B.B.A. de, and Vissers, L.E.L.M.
Abstract: Contains fulltext : 248367.pdf (Publisher’s version ) (Closed access), Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.
Published: 2022

8. Loss-of-function variants in SRRM2 cause a neurodevelopmental disorder

Author: Cuinat, S., Nizon, M., Isidor, B., Stegmann, Alexander, Jaarsveld, R.H. van, Gassen, K.L.I. van, Smagt, J.J. van der, Volker-Touw, C.M., Holwerda, S.J.B., Terhal, P.A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A.A., Yasaei, H., Ousager, L.B., Brasch-Andersen, C., Deb, W., Besnard, T., Simon, M.E., Amsterdam, K.H., Verbeek, N.E., Matalon, D., Dykzeul, N., White, S., Spiteri, E., Devriendt, K., Boogaerts, A., Willemsen, M.H., Brunner, H.G., Sinnema, M., Vries, B.B. de, Gerkes, E.H., Pfundt, R.P., Izumi, K., Krantz, I.D., Xu, Z.L., Murrell, J.R., Valenzuela, I., Cusco, I., Rovira-Moreno, E., Yang, Y., Bizaoui, V., Patat, O., Faivre, L., Tran-Mau-Them, F., Vitobello, A., Denommé-Pichon, A.S., Philippe, C., Bezieau, S., Cogné, B., Cuinat, S., Nizon, M., Isidor, B., Stegmann, Alexander, Jaarsveld, R.H. van, Gassen, K.L.I. van, Smagt, J.J. van der, Volker-Touw, C.M., Holwerda, S.J.B., Terhal, P.A., Schuhmann, S., Vasileiou, G., Khalifa, M., Nugud, A.A., Yasaei, H., Ousager, L.B., Brasch-Andersen, C., Deb, W., Besnard, T., Simon, M.E., Amsterdam, K.H., Verbeek, N.E., Matalon, D., Dykzeul, N., White, S., Spiteri, E., Devriendt, K., Boogaerts, A., Willemsen, M.H., Brunner, H.G., Sinnema, M., Vries, B.B. de, Gerkes, E.H., Pfundt, R.P., Izumi, K., Krantz, I.D., Xu, Z.L., Murrell, J.R., Valenzuela, I., Cusco, I., Rovira-Moreno, E., Yang, Y., Bizaoui, V., Patat, O., Faivre, L., Tran-Mau-Them, F., Vitobello, A., Denommé-Pichon, A.S., Philippe, C., Bezieau, S., and Cogné, B.
Abstract: Contains fulltext : 282702.pdf (Publisher’s version ) (Closed access), PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.
Published: 2022

9. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author: Kayumi, S, Perez-Jurado, LA, Palomares, M, Rangu, S, Sheppard, SE, Chung, WK, Kruer, MC, Kharbanda, M, Amor, DJ, McGillivray, G, Cohen, JS, Garcia-Minaur, S, van Eyk, CL, Harper, K, Jolly, LA, Webber, DL, Barnett, CP, Santos-Simarro, F, Pacio-Miguez, M, del Pozo, A, Bakhtiari, S, Deardorff, M, Dubbs, HA, Izumi, K, Grand, K, Gray, C, Mark, PR, Bhoj, EJ, Li, D, Ortiz-Gonzalez, XR, Keena, B, Zackai, EH, Goldberg, EM, de Nanclares, GP, Pereda, A, Llano-Rivas, I, Arroyo, I, Fernandez-Cuesta, MA, Thauvin-Robinet, C, Faivre, L, Garde, A, Mazel, B, Bruel, A-L, Tress, ML, Brilstra, E, Fine, AS, Crompton, KE, Stegmann, APA, Sinnema, M, Stevens, SCJ, Nicolai, J, Lesca, G, Lion-Francois, L, Haye, D, Chatron, N, Piton, A, Nizon, M, Cogne, B, Srivastava, S, Bassetti, J, Muss, C, Gripp, KW, Procopio, RA, Millan, F, Morrow, MM, Assaf, M, Moreno-De-Luca, A, Joss, S, Hamilton, MJ, Bertoli, M, Foulds, N, McKee, S, MacLennan, AH, Gecz, J, Corbett, MA, Kayumi, S, Perez-Jurado, LA, Palomares, M, Rangu, S, Sheppard, SE, Chung, WK, Kruer, MC, Kharbanda, M, Amor, DJ, McGillivray, G, Cohen, JS, Garcia-Minaur, S, van Eyk, CL, Harper, K, Jolly, LA, Webber, DL, Barnett, CP, Santos-Simarro, F, Pacio-Miguez, M, del Pozo, A, Bakhtiari, S, Deardorff, M, Dubbs, HA, Izumi, K, Grand, K, Gray, C, Mark, PR, Bhoj, EJ, Li, D, Ortiz-Gonzalez, XR, Keena, B, Zackai, EH, Goldberg, EM, de Nanclares, GP, Pereda, A, Llano-Rivas, I, Arroyo, I, Fernandez-Cuesta, MA, Thauvin-Robinet, C, Faivre, L, Garde, A, Mazel, B, Bruel, A-L, Tress, ML, Brilstra, E, Fine, AS, Crompton, KE, Stegmann, APA, Sinnema, M, Stevens, SCJ, Nicolai, J, Lesca, G, Lion-Francois, L, Haye, D, Chatron, N, Piton, A, Nizon, M, Cogne, B, Srivastava, S, Bassetti, J, Muss, C, Gripp, KW, Procopio, RA, Millan, F, Morrow, MM, Assaf, M, Moreno-De-Luca, A, Joss, S, Hamilton, MJ, Bertoli, M, Foulds, N, McKee, S, MacLennan, AH, Gecz, J, and Corbett, MA
Abstract: PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
Published: 2022

10. Verstandelijke handicap: definitie, classificaties en kenmerken

Author: Maaskant, M. A., van Kerkhof-Willemsen, G. H. P. M., and Sinnema, M.
Published: 2010
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11. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author: Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, 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.F., 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.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier 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., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, 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.F., 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.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier 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: Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), 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.
Published: 2021

12. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author: Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., Kleefstra, T., Kummeling, J., Stremmelaar, D.E., Raun, N., Reijnders, M.R., Willemsen, M.H., Ruiterkamp-Versteeg, M., Schepens, M.T.M., Man, C.C.O., Gilissen, C.F.H.A., Cho, M.T., McWalter, K., Sinnema, M., Wheless, J.W., Simon, M.E., Genetti, C.A., Casey, A.M., Terhal, P.A., Smagt, J.J. van der, Gassen, K.L.I. van, Joset, P., Bahr, A., Steindl, K., Rauch, A., Keller, E., Raas-Rothschild, A., Koolen, D.A., Agrawal, P.B., Hoffman, T.L., Powell-Hamilton, N.N., Thiffault, I., Engleman, K., Zhou, D., Bodamer, O., Hoefele, J., Riedhammer, K.M., Schwaibold, E.M.C., Tasic, V., Schubert, D., Top, D., Pfundt, R.P., Higgs, M.R., Kramer, J.M., and Kleefstra, T.
Abstract: Item does not contain fulltext, Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
Published: 2021

13. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Author: CMM Groep Cuppen, MS Urologische Oncologie, Cancer, Genetica, Genetica Klinische Genetica, Child Health, Psychosociale zorg patientenzorg, Other research (not in main researchprogram), Koster, R., Brandão, R. D., Tserpelis, D., van Roozendaal, C. E.P., van Oosterhoud, C. N., Claes, K. B.M., Paulussen, A. D.C., Sinnema, M., Vreeburg, M., van der Schoot, V., Stumpel, C. T.R.M., Broen, M. P.G., Spruijt, L., Jongmans, M. C.J., Lesnik Oberstein, S. A.J., Plomp, A. S., Misra-Isrie, M., Duijkers, F. A., Louwers, M. J., Szklarczyk, R., Derks, K. W.J., Brunner, H. G., van den Wijngaard, A., van Geel, M., Blok, M. J., CMM Groep Cuppen, MS Urologische Oncologie, Cancer, Genetica, Genetica Klinische Genetica, Child Health, Psychosociale zorg patientenzorg, Other research (not in main researchprogram), Koster, R., Brandão, R. D., Tserpelis, D., van Roozendaal, C. E.P., van Oosterhoud, C. N., Claes, K. B.M., Paulussen, A. D.C., Sinnema, M., Vreeburg, M., van der Schoot, V., Stumpel, C. T.R.M., Broen, M. P.G., Spruijt, L., Jongmans, M. C.J., Lesnik Oberstein, S. A.J., Plomp, A. S., Misra-Isrie, M., Duijkers, F. A., Louwers, M. J., Szklarczyk, R., Derks, K. W.J., Brunner, H. G., van den Wijngaard, A., van Geel, M., and Blok, M. J.
Published: 2021

14. Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

Author: Koster, R., primary, Brandão, R.D., additional, Tserpelis, D., additional, van Roozendaal, C.E.P., additional, van Oosterhoud, C.N., additional, Claes, K.B.M., additional, Paulussen, A.D.C., additional, Sinnema, M., additional, Vreeburg, M., additional, van der Schoot, V., additional, Stumpel, C.T.R.M., additional, Broen, M.P.G., additional, Spruijt, L., additional, Jongmans, M.C.J., additional, Oberstein, S.A.J. Lesnik, additional, Plomp, A.S., additional, Misra-Isrie, M., additional, Duijkers, F.A., additional, Louwers, M.J., additional, Szklarczyk, R., additional, Derks, K.W.J., additional, Brunner, H.G., additional, van den Wijngaard, A., additional, van Geel, M., additional, and Blok, M.J., additional
Published: 2021
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15. The GH/IGF-I Axis and Pituitary Function and Size in Adults with Prader-Willi Syndrome.

Author: van Nieuwpoort, IC, primary, Sinnema, M, additional, Castelijns, JA, additional, Twisk, JWR, additional, Curfs, LMG, additional, and Drent, ML, additional
Published: 2010
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16. Ageing in Prader-Willi syndrome: Twelve persons over the age of 50 years

Author: Maaskant, M. A., Sinnema, M., Schrander-Stumpel, C. T. R. M., Boer, H., and Curfs, L. M. G.
Published: 2012

17. Ageing in Prader-Willi syndrome

Author: Sinnema, M., Maaskant, M., Van Schrojenstein Lantman-de Valk, H., Schrander-Stumpel, C., and Curfs, L.
Published: 2010

18. Dementia in a woman with Prader-Willi syndrome

Author: Sinnema, M., Schrander-Stumpel, C. T., Verheij, H. E., Meeuwsen, M., Maaskant, M. A., and Curfs, L. M.
Published: 2010

19. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder

Author: den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

20. Ageing in Prader-Willi syndrome

Author: Sinnema, M., Maaskant, M. A., van Schrojenstein Lantman-de Valk, H. M. J., Schrander-Stumpel, C. T. R. M., and Curfs, L. M. G.
Published: 2008

21. Assessment, diagnosis and management

Author: Strydom, A., Maaskant, M., Lee, L., Torr, J., Tsiouris, J., Jokinen, N., Courtenay, K., Sinnema, M., and Shoostari, S.
Published: 2008

22. Epidemiology, risk factors and clinical features

Author: Maaskant, M., Lee, L., Torr, J., Tsiouris, J., Jokinen, N., Shoostari, S., Sinnema, M., Courtenay, K., and Strydom, A.
Published: 2008

23. A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism and cerebellar dysgenesis

Author: Jean-Marcais, N., Olson, H. E., Yang, E., Heron, D., Tatton-Brown, K., van der Zwaag, P. A., Bijlsma, E. K., Krock, B. L., Backer, E., Kamsteeg, E., Sinnema, M., Reijnders, M. R. F., Bearden, D., Lunsing, R. J., Burglen, L., Lesca, G., Smith, L. A., Sheidley, B., Pearl, P. L., El Achkar, C. Moufawad, Poduri, A., Skraban, C. M., Nesbitt, A. I., van de Putte, D. E. Fransen, Ruivenkamp, C. A. L., Rump, P., Sabatier, I., Sweetser, D. A., Waxler, J. L., Tarpinian, J., Wierenga, K. J., Donadieu, J., Narayanan, V., Ramsey, K. M., Nava, C., Lelieveld, S. H., Schuurs-Hoeijmakers, J., Brunner, H. G., Keren, B., Mau-Them, F. Tran, Thevenon, J., Faivre, L., Thomas, G., and Thauvin-Robinet, C.
Published: 2019

24. Germline AGO2 mutations impair RNA interference and human neurological development

Author: Lessel, D., Zeitler, D.M., Reijnders, M.R.F., Kazantsev, A., Nia, F. Hassani, Bartholomäus, A., Martens, V., Bruckmann, A., Graus, V., McConkie-Rosell, A., McDonald, M., Lozic, B., Tan, E.S., Gerkes, E., Johannsen, J., Denecke, J., Telegrafi, A., Zonneveld-Huijssoon, E., Lemmink, H.H., Cham, B.W.M., Kovacevic, T., Ramsdell, L., Foss, K., Duc, D. Le, Mitter, D., Syrbe, S., Merkenschlager, A., Sinnema, M., Panis, B., Lazier, J., Osmond, M., Hartley, T., Mortreux, J., Busa, T., Missirian, C., Prasun, P., Lüttgen, S., Mannucci, I., Lessel, I., Schob, C., Kindler, S., Pappas, J., Rabin, R., Willemsen, M.H., Gardeitchik, T., Löhner, K., Rump, P., Dias, K.R., Evans, C.A., Andrews, P.I., Roscioli, T., Brunner, H.G., Chijiwa, C., Lewis, M.E.S., Jamra, R.A., Dyment, D.A., Boycott, K.M., Stegmann, A.P.A., Kubisch, C., Tan, Ene-Choo, Mirzaa, G.M., McWalter, K., Kleefstra, T., Pfundt, R.P., Ignatova, Z., Meister, G., Kreienkamp, H.J., Lessel, D., Zeitler, D.M., Reijnders, M.R.F., Kazantsev, A., Nia, F. Hassani, Bartholomäus, A., Martens, V., Bruckmann, A., Graus, V., McConkie-Rosell, A., McDonald, M., Lozic, B., Tan, E.S., Gerkes, E., Johannsen, J., Denecke, J., Telegrafi, A., Zonneveld-Huijssoon, E., Lemmink, H.H., Cham, B.W.M., Kovacevic, T., Ramsdell, L., Foss, K., Duc, D. Le, Mitter, D., Syrbe, S., Merkenschlager, A., Sinnema, M., Panis, B., Lazier, J., Osmond, M., Hartley, T., Mortreux, J., Busa, T., Missirian, C., Prasun, P., Lüttgen, S., Mannucci, I., Lessel, I., Schob, C., Kindler, S., Pappas, J., Rabin, R., Willemsen, M.H., Gardeitchik, T., Löhner, K., Rump, P., Dias, K.R., Evans, C.A., Andrews, P.I., Roscioli, T., Brunner, H.G., Chijiwa, C., Lewis, M.E.S., Jamra, R.A., Dyment, D.A., Boycott, K.M., Stegmann, A.P.A., Kubisch, C., Tan, Ene-Choo, Mirzaa, G.M., McWalter, K., Kleefstra, T., Pfundt, R.P., Ignatova, Z., Meister, G., and Kreienkamp, H.J.
Abstract: Contains fulltext : 229431.pdf (publisher's version ) (Open Access), ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
Published: 2020

25. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, MRF, Miller, KA, Alvi, M, Goos, JAC, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Deciphering Developmental Disorders Study, Baralle, D, Blair, EM, Engels, H, Lüdecke, H-J, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, MF, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, PJ, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, SMA, Douzgou, S, Wall, SA, Küry, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, IMJ, Nellaker, C, Brunner, HG, and Wilkie, AOM
Subjects: Adult, Male, Adolescent, kinase, Messenger, Inheritance Patterns, Translocation, Medical and Health Sciences, Cell Line, Young Adult, Genetic, Clinical Research, Loss of Function Mutation, Genetics, 2.1 Biological and endogenous factors, Humans, Aetiology, Child, Preschool, Genetic Association Studies, Genetics & Heredity, Tousled-like, Base Sequence, Human Genome, Neurosciences, Facies, Infant, Deciphering Developmental Disorders Study, Biological Sciences, Brain Disorders, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, RNA, Female, Protein Kinases, facial averaging, Biotechnology
Abstract: Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
Published: 2018

26. SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes

Author: Kim, J.H., Park, E.Y., Chitayat, D., Stachura, D.L., Schaper, J., Lindstrom, K., Jewett, T., Wieczorek, D., Draaisma, J.M., Sinnema, M., Hoeberigs, C., Hempel, M., Bachman, K.K., Seeley, A.H., Stone, J.K., Kong, H.K., Vukadin, L., Richard, A., Shinde, D.N., McWalter, K., Si, Y.C., Douglas, G., Lim, S.T., Vissers, L.E.L.M., Lemaire, M., Ahn, E.E., Kim, J.H., Park, E.Y., Chitayat, D., Stachura, D.L., Schaper, J., Lindstrom, K., Jewett, T., Wieczorek, D., Draaisma, J.M., Sinnema, M., Hoeberigs, C., Hempel, M., Bachman, K.K., Seeley, A.H., Stone, J.K., Kong, H.K., Vukadin, L., Richard, A., Shinde, D.N., McWalter, K., Si, Y.C., Douglas, G., Lim, S.T., Vissers, L.E.L.M., Lemaire, M., and Ahn, E.E.
Abstract: Contains fulltext : 204239.pdf (Publisher’s version ) (Closed access), Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.
Published: 2019

27. De Novo and Inherited Loss-of-Function Variants in TLK2 : Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, M.R.F., Miller, K.A., Alvi, M., Goos, J.A.C., Lees, M.M., Burca, A. de, Henderson, A., Kraus, A., Mikat, B., Vries, B.B.A. de, Isidor, B., Kerr, B., Marcelis, C.L.M., Schluth-Bolard, C., Deshpande, C., Ruivenkamp, C.A.L., Wieczorek, D., Baralle, D., Blair, E.M., Engels, H., Ludecke, H.J., Eason, J., Santen, G.W.E., Clayton-Smith, J., Chandler, K., Tatton-Brown, K., Payne, K., Helbig, K., Radtke, K., Nugent, K.M., Cremer, K., Strom, T.M., Bird, L.M., Sinnema, M., Bitner-Glindzicz, M., Dooren, M.F. van, Alders, M., Koopmans, M., Brick, L., Kozenko, M., Harline, M.L., Klaassens, M., Steinraths, M., Cooper, N.S., Edery, P., Yap, P., Terhal, P.A., Spek, P.J. van der, Lakeman, P., Taylor, R.L., Littlejohn, R.O., Pfundt, R.P., Mercimek-Andrews, S., Stegmann, A.P.A., Kant, S.G., McLean, S., Joss, S., Swagemakers, S.M.A., Douzgou, S., Wall, S.A., Kury, S., Calpena, E., Koelling, N., McGowan, S.J., Twigg, S.R.F., Mathijssen, I.M.J., Nellaker, C., Brunner, H.G., Wilkie, A.O.M., Plastic and Reconstructive Surgery and Hand Surgery, Clinical Genetics, and Pathology
Subjects: Tousled-like, Facial Averaging, Haploinsufficiency, Intellectual Disability, Kinase, Adult, Male, Adolescent, kinase, viruses, Inheritance Patterns, Medizin, Translocation, Genetic, Cell Line, Young Adult, Loss of Function Mutation, Report, Humans, RNA, Messenger, Child, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Facies, Infant, haploinsufficiency, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Female, Protein Kinases, facial averaging, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOy lated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB-associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4-and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention.
Published: 2018

28. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Author: Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D, UK10K Consortium, Deciphering Developmental Disorders Study, NIHR BioResource Rare Diseases Consortium, Pittman A, Carr LJ, Pérez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA, and Apollo - University of Cambridge Repository
Subjects: DNA-Binding Proteins, Histones, Male, Dystonia, Adolescent, Lysine, Mutation, Histone Methyltransferases, Humans, Nuclear Proteins, Female, Histone-Lysine N-Methyltransferase, Methylation
Abstract: Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
Published: 2017

29. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Author: Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, Wilkie, AOM, Reijnders, M R F, Miller, KA, Alvi, M, Goos, Jacqueline, Lees, MM, de Burca, A, Henderson, A, Kraus, A, Mikat, B, de Vries, BBA, Isidor, B, Kerr, B, Marcelis, C, Schluth-Bolard, C, Deshpande, C, Ruivenkamp, CAL, Wieczorek, D, Baralle, D, Blair, EM, Engels, H, Ludecke, HJ, Eason, J, Santen, GWE, Clayton-Smith, J, Chandler, K, Tatton-Brown, K, Payne, K, Helbig, K, Radtke, K, Nugent, KM, Cremer, K, Strom, TM, Bird, LM, Sinnema, M, Bitner-Glindzicz, M, van Dooren, Marieke, Alders, M, Koopmans, M, Brick, L, Kozenko, M, Harline, ML, Klaassens, M, Steinraths, M, Cooper, NS, Edery, P, Yap, P, Terhal, PA, van der Spek, Peter, Lakeman, P, Taylor, RL, Littlejohn, RO, Pfundt, R, Mercimek-Andrews, S, Stegmann, APA, Kant, SG, McLean, S, Joss, S, Swagemakers, Sigrid, Douzgou, S, Wall, SA, Kury, S, Calpena, E, Koelling, N, McGowan, SJ, Twigg, SRF, Mathijssen, Irene, Nellaker, C, Brunner, HG, and Wilkie, AOM
Published: 2018

30. Prader-Willi syndrome : genotype and phenotype at adult age

Author: Sinnema, M., Sinnema, M., Sinnema, M., and Sinnema, M.
Published: 2011

31. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Author: Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., Kurian, M.A., Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., and Kurian, M.A.
Abstract: Item does not contain fulltext, Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
Published: 2017

32. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author: Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., Ahn, E.Y., Kim, J.H., Shinde, D.N., Reijnders, M.R.F., Hauser, N.S., Belmonte, R.L., Wilson, G.R., Bosch, D.G.M., Bubulya, P.A., Shashi, V., Petrovski, S., Stone, J.K., Park, E.Y., Veltman, J.A., Sinnema, M., Stumpel, C.T., Draaisma, J.M., Nicolai, J., Yntema, H.G., Lindstrom, K., Vries, B.B. de, Jewett, T., Santoro, S.L., Vogt, J., Bachman, K.K., Seeley, A.H., Krokosky, A., Turner, C., Rohena, L., Hempel, M., Kortum, F., Lessel, D., Neu, A., Strom, T.M., Wieczorek, D., Bramswig, N., Laccone, F.A., Behunova, J., Rehder, H., Gordon, C.T., Rio, M. del, Romana, S., Tang, S., El-Khechen, D., Cho, M.T., McWalter, K., Douglas, G., Baskin, B., Begtrup, A., Funari, T., Schoch, K., Stegmann, A.P., Stevens, S.J., Zhang, D.E., Traver, D., Yao, X., MacArthur, D.G., Brunner, H.G., Mancini, G.M., Myers, R.M., Owen, L.B., Lim, S.T., Stachura, D.L., Vissers, L.E.L.M., and Ahn, E.Y.
Abstract: Item does not contain fulltext, The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
Published: 2016

33. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author: Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., Ahn, E.-Y.E. (Eun-Young Erin), Kim, J.-H. (Jung-Hyun), Shinde, D.N. (Deepali N.), Reijnders, M.R.F. (Margot R.F.), Hauser, N.S. (Natalie S.), Belmonte, R.L. (Rebecca L.), Wilson, G.R. (Gregory R.), Bosch, D.G.M. (Daniëlle G.M.), Bubulya, P.A. (Paula A.), Shashi, V. (Vandana), Petrovski, S. (Slavé), Stone, J.K. (Joshua K.), Park, E.Y. (Eun Young), Veltman, J.A. (Joris), Sinnema, M. (Margje), Stumpel, C. (Connie), Draaisma, J. (Jos), Nicolai, J. (Joost), Yntema, H.G., Lindstrom, K. (Kristin), Vries, B. (Boukje) de, Jewett, T. (Tamison), Santoro, S.L. (Stephanie L.), Vogt, J. (Julie), Bachman, K.K. (Kristine K.), Seeley, A.H. (Andrea ), Krokosky, A. (Alyson), Turner, C. (Clesson), Rohena, L. (Luis), Hempel, M. (Maja), Kortüm, F. (Fanny), Lessel, D. (Davor), Neu, A. (Axel), Strom, T.M. (Tim), Wieczorek, D. (Dagmar), Bramswig, N. (Nuria), Laccone, F.A. (Franco A.), Behunova, J. (Jana), Rehder, H. (Helga), Gordon, C.T. (Christopher T.), Rio, M. (Marlène), Romana, S. (Serge), Tang, S. (Sha), El-Khechen, D. (Dima), Cho, M.T. (Megan T.), McWalter, K. (Kirsty), Douglas, G. (Ganka), Baskin, B. (Berivan), Begtrup, A. (Amber), Funari, T. (Tara), Schoch, K. (Kelly), Stegmann, A.P.A. (Alexander P.A.), Stevens, S.J., Zhang, D.-E. (Dong-Er), Traver, D. (David), Yao, X. (Xu), MacArthur, D.G. (Daniel G.), Brunner, H.G., Mancini, G.M.S. (Grazia), Myers, R.H. (Richard), Owen, L.B. (Laurie B.), Lim, S.-T. (Ssang-Taek), Stachura, D.L. (David L.), Vissers, L.E.L.M., and Ahn, E.-Y.E. (Eun-Young Erin)
Abstract: The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses c
Published: 2016
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34. Dementia in Older Adults With Intellectual Disabilities—Epidemiology, Presentation, and Diagnosis

Author: Strydom, A., Shooshtari, S., Lee, L., Raykar, V., Torr, J., Tsiouris, J., Jokinen, N., Courtenay, K., Bass, N., Sinnema, M., and Maaskant, M.
Subjects: mental disorders, aging, Alzheimer's disease, comprehensive review, dementia, Down syndrome, intellectual disabilities, Prader-Willi syndrome, Downs syndrome, Alzheimers disease, Rett syndrome, follow-up, mental retardation, natural history, sudden death, learning disabilities, Klinefelter syndrome
Abstract: As life expectancy of people with intellectual disabilities (ID) extends into older age, dementia is an increasing cause of morbidity and mortality. To update and summarize current knowledge on dementia in older adults with ID, the authors conducted a comprehensive review of the published literature from 1997-2008 with a specific focus on: (1) epidemiology of dementia in ID in general as well as in specific genetic syndromes; (2) presentation; and (3) diagnostic criteria for dementia. The review drew upon a combination of searches in electronic databases Medline, EMBASE, and PsycINFO for original research papers in English, Dutch, or German. The authors report that varied methodologies and inherent challenges in diagnosis yield a wide range of reported prevalence rates of dementia. Rates of dementia in the population with intellectual disability not because of Down syndrome (DS) are comparable with or higher than the general population. Alzheimer's disease onset in DS appears earlier and the prevalence increases from under 10% in the 40s to more than 30% in the 50s, with varying prevalence reported for those 60 and older. Incidence rates increase with age. Few studies of dementia in other genetic syndromes were identified. Presentation differs in the ID population compared with the general population; those with DS present with prominent behavioral changes believed to be because of frontal lobe deficits. Authors recommend large-scale collaborative studies of high quality to further knowledge on the epidemiology and clinical presentation of dementia in this population.
Published: 2010

35. Sleep disturbances and behavioural problems in adults with Prader-Willi syndrome

Author: Maas, A.P.H.M., Sinnema, M., Didden, H.C.M., Maaskant, M.A., Schrander-Stumpel, C.T.R.M., and Curfs, L.M.G.
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Learning and Plasticity, nutritional and metabolic diseases, nervous system diseases
Abstract: Contains fulltext : 89221.pdf (Publisher’s version ) (Closed access) Background Individuals with Prader-Willi syndrome (PWS) are at risk of sleep disturbances, such as excessive daytime sleepiness (EDS) and sleep apnoea, and behavioural problems. Sleep disturbances and their relationship with other variables had not been researched extensively in adults with PWS. Method Sleep disturbances and behavioural problems were investigated in adults with genetically confirmed PWS using standardised questionnaires. Results of adults with paternal deletion (n = 45) were compared with those of adults with maternal uniparental disomy (n = 33). Results Eleven adults with PWS (i.e. 15%) had a current sleep problem, mostly night waking problems. Twenty-six adults with PWS (i.e. 33%) suffered from severe EDS. No differences in prevalence of sleep disturbances between genetic subtypes were found. Seventeen adults with deletion (i.e. 38%) and 17 adults with maternal uniparental disomy (i.e. 52%) had behavioural problems. No significant relationships were found between sleep disturbances and behavioural problems. Conclusions In adults with PWS, EDS is the most common type of sleep disturbance. Men and individuals with relative high body mass index are at increased risk for EDS. More research, aimed at developing a suitable screening instrument for sleep apnoea in adults with PWS, is necessary. Clinical implications of the findings are discussed.
Published: 2010

36. De talloze gezichten van de dualisering

Author: Denters, Sebastianus A.H. and Sinnema, M.
Subjects: METIS-238935
Published: 2007

37. Configuration in Industrial Product Families - The ConIPF Methodology

Author: Nijhuis, J.A G, Sinnema, M, MacGregor, J, and Faculty of Science and Engineering
Published: 2006

38. A product derivation framework for software product families

Author: Deelstra, S, Sinnema, M, Bosch, J, and VanDerLinden, F
Abstract: From our experience with several organizations that employ software product families, we have learned that deriving individual products from shared software artifacts is a time-consuming and expensive activity. In the research community, product derivation methodologies are rather scarce, however. By studying product derivation, we believe we will be better able to provide and validate industrially practicable solutions for application engineering. In this paper, we present a framework of terminology and concepts regarding product derivation that serves as basis for further discussion. We exemplify this framework with two industrial case studies, i.e. Thales Nederland B.V. and Robert Bosch GmbH.
Published: 2004

39. Experiences in software product families: Problems and issues during product derivation

Author: Deelstra, S, Sinnema, M, Bosch, J, and Nord, RL
Subjects: LINES
Abstract: A fundamental reason for investing in product families is to minimize the application engineering costs. Several organizations that employ product families, however, are becoming increasingly aware of the fact that, despite the efforts in domain engineering, deriving individual products from their shared software assets is a time- and effort-consuming activity. In this paper, we present a collection of product derivation problems that we identified during a case study at two large and mature industrial organizations. These problems are attributed to the lack of methodological support for application engineering, and to underlying causes of complexity and implicit properties. For each problem, we provide a description and an example, while for each cause we present a description, consequences, solutions, and research issues. The discussions in this paper are relevant outside the context of the two companies, as the challenges they face arise in, for example, comparable or less mature organizations.
Published: 2004

40. COVAMOF: A framework for modeling variability in software product families

Author: Sinnema, M, Deelstra, S, Nijhuis, J, Bosch, J, and Nord, RL
Abstract: A key aspect of variability management in software product families is the explicit representation of the variability. Experiences at several industrial software development companies have shown that a software variability model should do four things: (1) uniformly represent variation points as first-class entities in all abstraction layers (ranging from features to code), (2) allow for the hierarchical organization of the variability, (3) allow for the first-class representation of simple (i.e., one-to-one) and complex (i.e., n-to-m) dependencies, and (4) allow for modeling the relations between dependencies. Existing variability modeling approaches support the first two requirements, but lack support for the latter two. The contribution of this paper is a framework for variability modeling-COVAMOF-that provides support for all four requirements.
Published: 2004

41. The use of medical care and the prevalence of serious illness in an adult Prader-Willi syndrome cohort

Author: Sinnema, M., Maaskant, M.A., Schrojenstein Lantman-de Valk, H.M. van, Boer, H. de, Curfs, L.M.G., Schrander-Stumpel, C.T.R.M., Sinnema, M., Maaskant, M.A., Schrojenstein Lantman-de Valk, H.M. van, Boer, H. de, Curfs, L.M.G., and Schrander-Stumpel, C.T.R.M.
Abstract: Item does not contain fulltext, INTRODUCTION: Adults with Prader-Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness. METHOD: Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS. RESULTS: The need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions. DISCUSSION: People with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing con
Published: 2013

42. Physical health problems in adults with Prader-Willi syndrome

Author: Sinnema, M., Maaskant, M.A., Schrojenstein Lantman-de Valk, H.M.J. van, Nieuwpoort, I.C. van, Drent, M.L., Curfs, L.M.G., Schrander-Stumpel, C.T.R.M., Sinnema, M., Maaskant, M.A., Schrojenstein Lantman-de Valk, H.M.J. van, Nieuwpoort, I.C. van, Drent, M.L., Curfs, L.M.G., and Schrander-Stumpel, C.T.R.M.
Abstract: Contains fulltext : 98215.pdf (publisher's version ) (Closed access), Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage.
Published: 2011

43. Urinary incontinence in persons with Prader-Willi Syndrome

Author: Gontard, A. von, Didden, H.C.M., Sinnema, M., Curfs, L.M.G., Gontard, A. von, Didden, H.C.M., Sinnema, M., and Curfs, L.M.G.
Abstract: Item does not contain fulltext, OBJECTIVE To assess and identify the frequency and type of urinary incontinence (UI), as well as associated symptoms in persons with Prader-Willi syndrome (PWS). PWS is characterized by mental retardation, short stature, obesity and hypogonadism. The behavioural phenotype includes eating problems, temper outbursts, affective disorders, stereotypies and speech abnormalities. UI is common in children with mental retardation in general, but has not been reported systematically in children with PWS so far. MATERIALS AND METHODS The Dutch version of the ‘Parental Questionnaire: Enuresis/Urinary Incontinence’ was completed by 118 parents of children with PWS. This questionnaire includes items referring to day- and night-time wetting, toilet habits, observable voiding behaviours and reactions, urinary tract infections, stool habits and behavioural symptoms. RESULTS The rate of nocturnal enuresis in persons with PWS was 13.6% (16) at a mean age of 15.1 years. 3.8% (5) had additional daytime urinary incontinence, and 3.3% (4) had faecal incontinence. Lower urinary tract symptoms were commonly indicative of overactive bladder, dysfunctional voiding and postponement. Also, the rate of internalizing and externalizing behavioural problems was high. CONCLUSION Urinary incontinence is more common in persons with PWS than in typically developing children, adolescents and adults. As lower urinary tract symptoms are common, detailed assessment and specific treatment of UI should be part of the care of all persons with PWS.
Published: 2010

44. The GH/IGF-I Axis and Pituitary Function and Size in Adults with Prader-Willi Syndrome

Author: van Nieuwpoort, I.C., primary, Sinnema, M., additional, Castelijns, J.A., additional, Twisk, J.W.R., additional, Curfs, L.M.G., additional, and Drent, M.L., additional
Published: 2011
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45. Prader-Willi syndrome : genotype and phenotype at adult age

Author: Sinnema, M., primary
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46. Modeling dependencies in product families with COVAMOF

Author: Sinnema, M., primary, Deelstra, S., additional, Nijhuis, J., additional, and Bosch, J., additional
Published: 2006
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47. COSVAM: a technique for assessing software variability in software product families.

Author: Deelstra, S., Sinnema, M., Nijhuis, J., and Bosch, J.
Published: 2004
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48. Behavioral phenotype in adults with Prader-Willi syndrome.

Author: Sinnema M, Einfeld SL, Schrander-Stumpel CT, Maaskant MA, Boer H, and Curfs LM
Published: 2011
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49. Dementia in older adults with intellectual disabilities---epidemiology, presentation, and diagnosis.

Author: Strydom A, Shooshtari S, Lee L, Raykar V, Torr J, Tsiouris J, Jokinen N, Courtenay K, Bass N, Sinnema M, and Maaskant M
Published: 2010
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50. 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.

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