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Type: Journal article
Title: Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants
Author: Kayumi, S.
Pérez-Jurado, L.A.
Palomares, M.
Rangu, S.
Sheppard, S.E.
Chung, W.K.
Kruer, M.C.
Kharbanda, M.
Amor, D.J.
McGillivray, G.
Cohen, J.S.
García-Miñaúr, S.
van Eyk, C.L.
Harper, K.
Jolly, L.A.
Webber, D.L.
Barnett, C.P.
Santos-Simarro, F.
Pacio-Míguez, M.
Pozo, A.D.
et al.
Citation: Genetics in Medicine, 2022; 24(11):2351-2366
Publisher: Elsevier BV
Issue Date: 2022
ISSN: 1098-3600
Statement of
Sayaka Kayumi, Luis A. Perez-Jurado, María Palomares, Sneha Rangu, Sarah E. Sheppard, Wendy K. Chung, Michael C. Kruer, Mira Kharbanda, David J. Amor, George McGillivray, Julie S. Cohen, Sixto García-Minaúr, Clare L. van Eyk, Kelly Harper, Lachlan A. Jolly, Dani L. Webber, Christopher P. Barnett, Fernando Santos-Simarro, Marta Pacio-Míguez, Angela del Pozo, Somayeh Bakhtiari, Matthew Deardorff, Holly A. Dubbs, Kosuke Izumi, Katheryn Grand, Christopher Gray, Paul R. Mark, Elizabeth J. Bhoj, Dong Li, Xilma R. Ortiz-Gonzalez, Beth Keena, Elaine H. Zackai, Ethan M. Goldberg, Guiomar Perez de Nanclares, Arrate Pereda, Isabel Llano-Rivas, Ignacio Arroyo, María Angeles Fernandez-Cuesta, Christel Thauvin-Robinet, Laurence Faivre, Aurore Garde, Benoit Mazel, Ange-Line Bruel, Michael L. Tress, Eva Brilstra, Amena Smith Fine, Kylie E. Crompton, Alexander P.A. Stegmann, Margje Sinnema, Servi C.J. Stevens, Joost Nicolai, Gaetan Lesca, Laurence Lion-Francois, Damien Haye, Nicolas Chatron, Amelie Piton, Mathilde Nizon, Benjamin Cogne, Siddharth Srivastava, Jennifer Bassetti, Candace Muss, Karen W. Gripp, Rebecca A. Procopio, Francisca Millan, Michelle M. Morrow, Melissa Assaf, Andres Moreno-De-Luca, Shelagh Joss, Mark J. Hamilton, Marta Bertoli, Nicola Foulds, Shane McKee, Alastair H. MacLennan, Jozef Gecz, Mark A. Corbett
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 From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information.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.
Keywords: Autism; Cerebral palsy; Familial exudative vitreoretinopathy; Microcephaly; Wnt beta catenin signaling pathway
Rights: © 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (
DOI: 10.1016/j.gim.2022.08.006
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