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Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

Hengel, H; Hannan, SB; Dyack, S; MacKay, SB; Schatz, U; Fleger, M; Kurringer, A; Balousha, G; Ghanim, Z; Alkuraya, FS; et al. Hengel, H; Hannan, SB; Dyack, S; MacKay, SB; Schatz, U; Fleger, M; Kurringer, A; Balousha, G; Ghanim, Z; Alkuraya, FS; Alzaidan, H; Alsaif, HS; Mitani, T; Bozdogan, S; Pehlivan, D; Lupski, JR; Gleeson, JJ; Dehghani, M; Mehrjardi, MYV; Sherr, EH; Parks, KC; Argilli, E; Begtrup, A; Galehdari, H; Balousha, O; Shariati, G; Mazaheri, N; Malamiri, RA; Pagnamenta, AT; Kingston, H; Banka, S; Jackson, A; Osmond, M; Care4Rare Canada Consortium; Genomics England Research Consortium; Rieß, A; Haack, TB; Nägele, T; Schuster, S; Hauser, S; Admard, J; Casadei, N; Velic, A; Macek, B; Ossowski, S; Houlden, H; Maroofian, R; Schöls, L (2021) Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder. Am J Hum Genet, 108 (6). pp. 1069-1082. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2021.04.024
SGUL Authors: Maroofian, Reza

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Abstract

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Item Type: Article
Additional Information: © 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: BCAS3, UAS-Gal4, fibroblasts, global developmental delay, microcephaly, neurodevelopmental disorder, proteomics, pyramidal tract involvement, thin corpus callosum, transcriptomics, Care4Rare Canada Consortium, Genomics England Research Consortium, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
3 June 2021Published
21 May 2021Published Online
29 April 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UM1 HG006542NHGRI NIH HHSUNSPECIFIED
R35 NS105078NINDS NIH HHSUNSPECIFIED
R01 NS058721NINDS NIH HHSUNSPECIFIED
WT093205 MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
SCHO754/2-1Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
INST 37/1049-1NGS Competence Center TübingenUNSPECIFIED
779257Solve-RD projectUNSPECIFIED
OGI-147Ontario Genomics Institutehttp://dx.doi.org/10.13039/501100000092
2R01NS058721-07A1National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
2554-0-0University of TübingenUNSPECIFIED
739510European Reference Network for Rare Neurological DiseasesUNSPECIFIED
3701-1International Rett Syndrome Foundationhttp://dx.doi.org/10.13039/100001819
418081722Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
PubMed ID: 34022130
Web of Science ID: WOS:000658897400006
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113389
Publisher's version: https://doi.org/10.1016/j.ajhg.2021.04.024

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