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2 results on '"Sacoto, M.J. Guillen"'

1. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author

Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., and Clinical Genetics

Subjects
Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Hypertelorism, Developmental Disabilities, speech impairment, Genetic Variation, ASXL3, BRPS, Young Adult, Phenotype, ASXL3-related syndrome, Bainbridge–Ropers syndrome, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Mutation, Humans, Muscle Hypotonia, Female, Genetic Predisposition to Disease, Child, Transcription Factors
Abstract

Item does not contain fulltext The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Published
2021
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2. 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

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