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@ARTICLE{Hengel:155888,
author = {Hengel, Holger and Hannan, Shabab B and Dyack, Sarah and
MacKay, Sara B and Schatz, Ulrich and Fleger, Martin and
Kurringer, Andreas and Balousha, Ghassan and Ghanim, Zaid
and Alkuraya, Fowzan S and Alzaidan, Hamad and Alsaif, Hessa
S and Mitani, Tadahiro and Bozdogan, Sevcan and Pehlivan,
Davut and Lupski, James R and Gleeson, Joseph J and
Dehghani, Mohammadreza and Mehrjardi, Mohammad Y V and
Sherr, Elliott H and Parks, Kendall C and Argilli, Emanuela
and Begtrup, Amber and Galehdari, Hamid and Balousha, Osama
and Shariati, Gholamreza and Mazaheri, Neda and Malamiri,
Reza A and Pagnamenta, Alistair T and Kingston, Helen and
Banka, Siddharth and Jackson, Adam and Osmond, Mathew and
Rieß, Angelika and Haack, Tobias B and Nägele, Thomas and
Schuster, Stefanie and Hauser, Stefan and Admard, Jakob and
Casadei, Nicolas and Velic, Ana and Macek, Boris and
Ossowski, Stephan and Houlden, Henry and Maroofian, Reza and
Schöls, Ludger},
collaboration = {Consortium, Care4Rare Canada and Consortium, Genomics
England Research},
title = {{B}i-allelic loss-of-function variants in {BCAS}3 cause a
syndromic neurodevelopmental disorder.},
journal = {The American journal of human genetics},
volume = {108},
number = {6},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DZNE-2021-01048},
pages = {1069 - 1082},
year = {2021},
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.},
keywords = {Adolescent / Adult / Animals / Cell Movement / Child /
Child, Preschool / Drosophila / Female / Fibroblasts:
metabolism / Fibroblasts: pathology / Humans / Infant / Loss
of Function Mutation / Loss of Heterozygosity / Male / Mice
/ Mice, Knockout / Neoplasm Proteins: genetics / Neoplasm
Proteins: metabolism / Neurodevelopmental Disorders:
etiology / Neurodevelopmental Disorders: metabolism /
Neurodevelopmental Disorders: pathology / Pedigree /
Proteome: analysis / Young Adult / BCAS3 (Other) / UAS-Gal4
(Other) / fibroblasts (Other) / global developmental delay
(Other) / microcephaly (Other) / neurodevelopmental disorder
(Other) / proteomics (Other) / pyramidal tract involvement
(Other) / thin corpus callosum (Other) / transcriptomics
(Other) / BCAS3 protein, human (NLM Chemicals) / Neoplasm
Proteins (NLM Chemicals) / Proteome (NLM Chemicals)},
cin = {AG Gasser / AG Schöls},
ddc = {570},
cid = {I:(DE-2719)1210000 / I:(DE-2719)5000005},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34022130},
pmc = {pmc:PMC8206390},
doi = {10.1016/j.ajhg.2021.04.024},
url = {https://pub.dzne.de/record/155888},
}