Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants
Kayumi, Sayaka; Pérez-Jurado, Luis A; Palomares, María; Rangu, Sneha; Sheppard, Sarah E; Chung, Wendy K; Kruer, Michael C; Kharbanda, Mira; Amor, David J; McGillivray, George; Cohen, Julie S; García-Miñaúr, Sixto; van Eyk, Clare L; Harper, Kelly; Jolly, Lachlan A; Webber, Dani L; Barnett, Christopher P; Santos-Simarro, Fernando; Pacio-Míguez, Marta; Pozo, Angela Del; Bakhtiari, Somayeh; Deardorff, Matthew; Dubbs, Holly A; Izumi, Kosuke; Grand, Katheryn; Gray, Christopher; Mark, Paul R; Bhoj, Elizabeth J; Li, Dong; Ortiz-Gonzalez, Xilma R; Keena, Beth; Zackai, Elaine H; Goldberg, Ethan M; Perez de Nanclares, Guiomar; Pereda, Arrate; Llano-Rivas, Isabel; Arroyo, Ignacio; Fernández-Cuesta, María Ángeles; Thauvin-Robinet, Christel; Faivre, Laurence; Garde, Aurore; Mazel, Benoit; Bruel, Ange-Line; Tress, Michael L; Brilstra, Eva; Fine, Amena Smith; Crompton, Kylie E; Stegmann, Alexander P A; Sinnema, Margje; Stevens, Servi C J; Nicolai, Joost; Lesca, Gaetan; Lion-François, Laurence; Haye, Damien; Chatron, Nicolas; Piton, Amelie; Nizon, Mathilde; Cogne, Benjamin; Srivastava, Siddharth; Bassetti, Jennifer; Muss, Candace; Gripp, Karen W; Procopio, Rebecca A; Millan, Francisca; Morrow, Michelle M; Assaf, Melissa; Moreno-De-Luca, Andres; Joss, Shelagh; Hamilton, Mark J; Bertoli, Marta; Foulds, Nicola; McKee, Shane; MacLennan, Alastair H; Gecz, Jozef; Corbett, Mark A
(2022) Genetics in medicine : official journal of the American College of Medical Genetics, volume 24, issue 11, pp. 2351 - 2366
(Article)
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.
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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 From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information.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.
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Keywords: Autism, Cerebral palsy, Familial exudative vitreoretinopathy, Microcephaly, Wnt beta catenin signaling pathway, Genetics(clinical), Journal Article
ISSN: 1098-3600
Publisher: Lippincott Williams & Wilkins
Note: Funding Information: This work was supported by the National Health and Medical Research Council, Australia project grant: 1099163 (A.H.M., C.L.v.E., M.A.C.), National Health and Medical Research Council Senior Fellowship App1155224 (J.G.), The Tenix Foundation, and Commercial Motor Vehicles Association (J.G., A.H.M., C.L.v.E., M.A.C.). This work was partially funded by strategic action projects in health from the Instituto de Salud Carlos III, Spain awarded to M.P. reference number: PI19/01681. M.P.-M is supported by a grant of the RAREGenomics network, funded by the Dirección de General de Universidades e Investigación de la Comunidad de Madrid, Spain (S2017/BMD-3721). We wish to acknowledge the Victorian Cerebral Palsy Register. Funding Information: This work was supported by the National Health and Medical Research Council, Australia project grant: 1099163 (A.H.M. C.L.v.E. M.A.C.), National Health and Medical Research Council Senior Fellowship App1155224 (J.G.), The Tenix Foundation, and Commercial Motor Vehicles Association (J.G. A.H.M. C.L.v.E. M.A.C.). This work was partially funded by strategic action projects in health from the Instituto de Salud Carlos III, Spain awarded to M.P. reference number: PI19/01681. M.P.-M is supported by a grant of the RAREGenomics network, funded by the Dirección de General de Universidades e Investigación de la Comunidad de Madrid, Spain (S2017/BMD-3721). We wish to acknowledge the Victorian Cerebral Palsy Register. Conceptualization: S.K. L.A.P.-J. M.P. M.C.K. J.G. M.A.C.; Data Curation: S.K. M.A.C.; Formal Analysis: S.K. M.A.C.; Project Administration: A.H.M. J.G. M.A.C.; Resources: S.K. L.A.P.-J. M.P. S.R. S.E.S. W.K.C. M.C.K. M.K. D.J.A. G.M. J.S.C. S.G.-M. K.H. L.A.J. D.L.W. C.P.B. F.S.-S. M.P.-M. A.d.P. S.B. M.D. H.A.D. K.I. K.G. C.G. P.R.M. E.J.B. D.L. X.R.O.-G. B.K. E.H.Z. E.M.G. G.P.d.N. A.Pe. I.L.-R. I.A. M.Á.F.-C. C.T.-R. L.F. A.G. B.M. A.-L.B. M.L.T. E.B. A.S.F. K.E.C. A.P.A.S. M.S. S.C.J.S. J.N. G.L. L.L.-F. D.H. N.C. A.Pi. M.N. B.C. S.S. J.B. C.M. K.W.G. R.A.P. F.M. M.M.M. M.A. A.M.-D.-L. S.J. M.J.H. M.B. N.F. S.M.; Supervision: C.L.v.E. J.G. M.A.C.; Writing-original draft: S.K. M.A.C.; Writing-review and editing: S.K. L.A.P.-J. M.P. S.R. S.E.S. W.K.C. M.C.K. M.K. D.J.A. G.M. J.S.C. S.G.-M. C.L.v.E. K.H. L.A.J. D.L.W. C.P.B. F.S.-S. M.P.-M. A.d.P. S.B. M.D. H.A.D. K.I. K.G. C.G. P.R.M. E.J.B. D.L. X.R.O.-G. B.K. E.H.Z. E.M.G. G.P.d.N. A.Pe. I.L.-R. I.A. M.Á.F.-C. C.T.-R. L.F. A.G. B.M. A.-L.B. M.L.T. E.B. A.S.F. K.E.C. A.P.A.S. M.S. S.C.J.S. J.N. G.L. L.L.-F. D.H. N.C. A.Pi. M.N. B.C. S.S. J.B. C.M. K.W.G. R.A.P. F.M. M.M.M. M.A. A.M.-D.-L. S.J. M.J.H. M.B. N.F. S.M. A.H.M. J.G. M.A.C. This study was approved by the Women's and Children's Health Network Human Research Ethics Committee number 2020/HRE01273. Written informed consent was obtained for all individuals for whom new data are presented in this study. Individual level data in this study are de-identified. Copies of explicit informed written consent for patients providing photographs (Figure 1F) are archived with the corresponding author. Publisher Copyright: © 2022 The Authors
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