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Your search keyword '"Au, P. Y. B."' showing total 2 results
Start Over Author "Au, P. Y. B." Topic intellectual disability
2 results on '"Au, P. Y. B."'

1. Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.

Author

Au PYB, Huang L, Broley S, Gallagher L, Creede E, Lahey D, Ordorica S, Mina K, Boycott KM, Baynam G, and Dyment DA

Subjects
5' Untranslated Regions, Abnormalities, Multiple diagnosis, Adult, Child, Preschool, Chromosomes, Human, X genetics, Female, Haploinsufficiency, Humans, Infant, Intellectual Disability diagnosis, Syndrome, Abnormalities, Multiple genetics, Chromosome Deletion, Frameshift Mutation, Intellectual Disability genetics, Phenotype, Ubiquitin Thiolesterase genetics
Abstract

The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Published
2017
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2. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author

Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael A. Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana E. Alhuzaimi, James J. Dowling, Susan Walker, Kimberly Amburgey, Robin Z. Hayeems, Lance H. Rodan, Marc A. Schwartz, Jonathan Picker, Sally A. Lynch, Aditi Gupta, Kristen J. Rasmussen, Lisa A. Schimmenti, Eric W. Klee, Zhiyv Niu, Katherine E. Agre, Ilana Chilton, Wendy K. Chung, Anya Revah-Politi, P.Y. Billie Au, Christopher Griffith, Melissa Racobaldo, Annick Raas-Rothschild, Bruria Ben Zeev, Ortal Barel, Sebastien Moutton, Fanny Morice-Picard, Virginie Carmignac, Jenny Cornaton, Nathalie Marle, Orrin Devinsky, Chandler Stimach, Stephanie Burns Wechsler, Bryan E. Hainline, Katie Sapp, Marjolaine Willems, Ange-line Bruel, Kerith-Rae Dias, Carey-Anne Evans, Tony Roscioli, Rani Sachdev, Suzanna E.L. Temple, Ying Zhu, Joshua J. Baker, Ingrid E. Scheffer, Fiona J. Gardiner, Amy L. Schneider, Alison M. Muir, Heather C. Mefford, Amy Crunk, Elizabeth M. Heise, Francisca Millan, Kristin G. Monaghan, Richard Person, Lindsay Rhodes, Sarah Richards, Ingrid M. Wentzensen, Benjamin Cogné, Bertrand Isidor, Mathilde Nizon, Marie Vincent, Thomas Besnard, Amelie Piton, Carlo Marcelis, Kohji Kato, Norihisa Koyama, Tomoo Ogi, Elaine Suk-Ying Goh, Christopher Richmond, David J. Amor, Jessica O. Boyce, Angela T. Morgan, Michael S. Hildebrand, Antony Kaspi, Melanie Bahlo, Rún Friðriksdóttir, Hildigunnur Katrínardóttir, Patrick Sulem, Kári Stefánsson, Hans Tómas Björnsson, Simone Mandelstam, Manuela Morleo, Milena Mariani, Marcello Scala, Andrea Accogli, Annalaura Torella, Valeria Capra, Mathew Wallis, Sandra Jansen, Quinten Waisfisz, Hugoline de Haan, Simon Sadedin, Sze Chern Lim, Susan M. White, David B. Ascher, Annette Schenck, Paul J. Lockhart, John Christodoulou, Tiong Yang Tan, Stephenson, S. E. M., Costain, G., Blok, L. E. R., Silk, M. A., Nguyen, T. B., Dong, X., Alhuzaimi, D. E., Dowling, J. J., Walker, S., Amburgey, K., Hayeems, R. Z., Rodan, L. H., Schwartz, M. A., Picker, J., Lynch, S. A., Gupta, A., Rasmussen, K. J., Schimmenti, L. A., Klee, E. W., Niu, Z., Agre, K. E., Chilton, I., Chung, W. K., Revah-Politi, A., Au, P. Y. B., Griffith, C., Racobaldo, M., Raas-Rothschild, A., Ben Zeev, B., Barel, O., Moutton, S., Morice-Picard, F., Carmignac, V., Cornaton, J., Marle, N., Devinsky, O., Stimach, C., Wechsler, S. B., Hainline, B. E., Sapp, K., Willems, M., Bruel, A. -L., Dias, K. -R., Evans, C. -A., Roscioli, T., Sachdev, R., Temple, S. E. L., Zhu, Y., Baker, J. J., Scheffer, I. E., Gardiner, F. J., Schneider, A. L., Muir, A. M., Mefford, H. C., Crunk, A., Heise, E. M., Millan, F., Monaghan, K. G., Person, R., Rhodes, L., Richards, S., Wentzensen, I. M., Cogne, B., Isidor, B., Nizon, M., Vincent, M., Besnard, T., Piton, A., Marcelis, C., Kato, K., Koyama, N., Ogi, T., Goh, E. S. -Y., Richmond, C., Amor, D. J., Boyce, J. O., Morgan, A. T., Hildebrand, M. S., Kaspi, A., Bahlo, M., Fridriksdottir, R., Katrinardottir, H., Sulem, P., Stefansson, K., Bjornsson, H. T., Mandelstam, S., Morleo, M., Mariani, M., Scala, M., Accogli, A., Torella, A., Capra, V., Wallis, M., Jansen, S., Weisfisz, Q., de Haan, H., Sadedin, S., Lim, S. C., White, S. M., Ascher, D. B., Schenck, A., Lockhart, P. J., Christodoulou, J., Tan, T. Y., and Human genetics

Subjects
F-box protein, Ubiquitin-Protein Ligase, Proteasome Endopeptidase Complex, F-Box-WD Repeat-Containing Protein 7, Ubiquitin-Protein Ligases, Neurodevelopment, global developmental delay, macrocephaly, Germ Cell, Article, All institutes and research themes of the Radboud University Medical Center, FBXW7, Neurodevelopmental Disorder, Genetics, Humans, hypotonia, Germ-Line Mutation, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], brain malformation, Ubiquitination, gastrointestinal issue, Germ Cells, intellectual disability, Neurodevelopmental Disorders, epilepsy, Human
Abstract

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Published
2022

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