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14 results on '"Slegtenhorst, M. van"'

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

Author

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

Abstract

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

Published
2023

2. SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.

Author

Fasham, J., Huebner, A.K., Liebmann, L., Khalaf-Nazzal, R., Maroofian, R., Kryeziu, N., Wortmann, S.B., Leslie, J.S., Ubeyratna, N., Mancini, G.M.S., Slegtenhorst, M. van, Wilke, M., Haack, T.B., Shamseldin, H.E., Gleeson, J.G., Almuhaizea, M., Dweikat, I., Abu-Libdeh, B., Daana, M., Zaki, M.S., Wakeling, M.N., McGavin, L., Turnpenny, P.D., Alkuraya, F.S., Houlden, H., Schlattmann, P., Kaila, K., Crosby, A.H., Baple, E.L., Hübner, C.A., Fasham, J., Huebner, A.K., Liebmann, L., Khalaf-Nazzal, R., Maroofian, R., Kryeziu, N., Wortmann, S.B., Leslie, J.S., Ubeyratna, N., Mancini, G.M.S., Slegtenhorst, M. van, Wilke, M., Haack, T.B., Shamseldin, H.E., Gleeson, J.G., Almuhaizea, M., Dweikat, I., Abu-Libdeh, B., Daana, M., Zaki, M.S., Wakeling, M.N., McGavin, L., Turnpenny, P.D., Alkuraya, F.S., Houlden, H., Schlattmann, P., Kaila, K., Crosby, A.H., Baple, E.L., and Hübner, C.A.

Abstract

Item does not contain fulltext, SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that i

Published
2023

3. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development

Author

Woerden, G.M. van, Bos, M., Konink, C. de, Distel, B., Trezza, R. Avagliano, Shur, N.E., Barañano, K., Mahida, S., Chassevent, A., Schreiber, A., Erwin, A.L., Gripp, K.W., Rehman, F., Brulleman, S., McCormack, R., Geus, G. de, Kalsner, L., Sorlin, A., Bruel, A.L., Koolen, D.A., Gabriel, M.K., Rossi, M., Fitzpatrick, D.R., Wilkie, A.O.M., Calpena, E., Johnson, D., Brooks, A., Slegtenhorst, M. van, Fleischer, J., Groepper, D., Lindstrom, K., Innes, A. Micheil, Goodwin, A., Humberson, J., Noyes, A., Langley, K.G., Telegrafi, A., Blevins, A., Hoffman, J., Sacoto, M.J. Guillen, Juusola, J., Monaghan, K.G., Punj, S., Simon, M., Pfundt, R.P., Elgersma, Y., Kleefstra, T., Woerden, G.M. van, Bos, M., Konink, C. de, Distel, B., Trezza, R. Avagliano, Shur, N.E., Barañano, K., Mahida, S., Chassevent, A., Schreiber, A., Erwin, A.L., Gripp, K.W., Rehman, F., Brulleman, S., McCormack, R., Geus, G. de, Kalsner, L., Sorlin, A., Bruel, A.L., Koolen, D.A., Gabriel, M.K., Rossi, M., Fitzpatrick, D.R., Wilkie, A.O.M., Calpena, E., Johnson, D., Brooks, A., Slegtenhorst, M. van, Fleischer, J., Groepper, D., Lindstrom, K., Innes, A. Micheil, Goodwin, A., Humberson, J., Noyes, A., Langley, K.G., Telegrafi, A., Blevins, A., Hoffman, J., Sacoto, M.J. Guillen, Juusola, J., Monaghan, K.G., Punj, S., Simon, M., Pfundt, R.P., Elgersma, Y., and Kleefstra, T.

Abstract

Contains fulltext : 245113.pdf (Publisher’s version ) (Open Access), Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.

Published
2021

4. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Author

Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., Barakat, T.S., Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., and Barakat, T.S.

Abstract

Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access), PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Published
2021

5. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., Tartaglia, M., Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., and Tartaglia, M.

Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access), Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

6. 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

Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, 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, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, Koolen, D.A., Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, 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, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, and Koolen, D.A.

Abstract

Contains fulltext : 218155.pdf (Publisher’s version ) (Closed access), 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

7. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., Linde, H.C. van der, Berg, P. van den, Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van, I.W.F., Valk, W.G. de, Herik, E. Medici-van den, Slegtenhorst, M. van, Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Futaisi, A. Al, Murshedi, F. Al, Mani, R., Azri, F. Al, Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., Ham, T.J. van, Barakat, T.S., Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., Linde, H.C. van der, Berg, P. van den, Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van, I.W.F., Valk, W.G. de, Herik, E. Medici-van den, Slegtenhorst, M. van, Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Futaisi, A. Al, Murshedi, F. Al, Mani, R., Azri, F. Al, Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., Ham, T.J. van, and Barakat, T.S.

Abstract

Contains fulltext : 218287.pdf (Publisher’s version ) (Open Access), Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

Published
2020

8. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Author

Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., Reversade, B., Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., and Reversade, B.

Abstract

Contains fulltext : 218288.pdf (publisher's version ) (Open Access), Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Published
2020

9. Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects

Author

Vrijenhoek, T., Kraaijeveld, K., Elferink, M., Ligt, J. de, Kranendonk, E., Santen, G., Nijman, IJ, Butler, D., Claes, G., Costessi, A., Dorlijn, W., Eyndhoven, W. van, Halley, D.J., Hout, M.C. van den, Hove, S. van, Johansson, L.F., Jongbloed, J.D., Kamps, R., Kockx, C.E., Koning, B. de, Kriek, M., Deprez, R.L., Lunstroo, H., Mannens, M., Mook, O.R., Nelen, M.R., Ploem, C., Rijnen, M., Saris, J.J., Sinke, R., Sistermans, E., Slegtenhorst, M. van, Sleutels, F., Stoep, N. van der, Tienhoven, M. van, Vermaat, M., Vogel, M., Waisfisz, Q., Weiss, J.M., Wijngaard, A. van den, Workum, W. van, IJntema, H., Zwaag, B. van der, van, I.W.F., Dunnen, J.T. den, Veltman, J.A., Hennekam, R., Cuppen, E., Vrijenhoek, T., Kraaijeveld, K., Elferink, M., Ligt, J. de, Kranendonk, E., Santen, G., Nijman, IJ, Butler, D., Claes, G., Costessi, A., Dorlijn, W., Eyndhoven, W. van, Halley, D.J., Hout, M.C. van den, Hove, S. van, Johansson, L.F., Jongbloed, J.D., Kamps, R., Kockx, C.E., Koning, B. de, Kriek, M., Deprez, R.L., Lunstroo, H., Mannens, M., Mook, O.R., Nelen, M.R., Ploem, C., Rijnen, M., Saris, J.J., Sinke, R., Sistermans, E., Slegtenhorst, M. van, Sleutels, F., Stoep, N. van der, Tienhoven, M. van, Vermaat, M., Vogel, M., Waisfisz, Q., Weiss, J.M., Wijngaard, A. van den, Workum, W. van, IJntema, H., Zwaag, B. van der, van, I.W.F., Dunnen, J.T. den, Veltman, J.A., Hennekam, R., and Cuppen, E.

Abstract

Item does not contain fulltext

Published
2015

13. Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation

Author

Halley, D., Slegtenhorst, M. van, Ouweland, A. van den, Verhoef, A., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., and Lindhout, D.

Abstract

Tuberous sclerosis complex is an inherited tumour suppressor syndrome, caused by a mutation in either the TSC1 or TSC2 gene. The disease is characterised by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction, and dermatological abnormalities. The TSC1 gene was recently identified and has 23 exons, spanning 45 kb of genomic DNA, and encoding an 8.6 kb mRNA. After screening all 21 coding exons in our collection of 225 unrelated patients, only 29 small mutations were detected, suggesting that TSC1 mutations are under-represented among TSC patients. Almost all TSC1 mutations were small changes leading to a truncated protein, except for a splice site mutation and two in frame deletions in exon 7 and exon 15. No clear difference was observed in the clinical phenotype of patients with an in frame deletion or a frameshift or nonsense mutation. We found the disease causing mutation in 13% of our unrelated set of TSC patients, with more than half of the mutations clustered in exons 15 and 17, and no obvious under-representation of mutations among sporadic cases. In conclusion, we find no support for a genotype-phenotype correlation for the group of TSC1 patients compared to the overall population of TSC patients.

Published
1999

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