Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113335
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Type: Journal article
Title: A recurrent de novo nonsense variant in ZSWIM6 results in severe intellectual disability without frontonasal or limb malformations
Author: Palmer, E.
Kumar, R.
Gordon, C.
Shaw, M.
Hubert, L.
Carroll, R.
Rio, M.
Murray, L.
Leffler, M.
Dudding-Byth, T.
Oufadem, M.
Lalani, S.
Lewis, A.
Xia, F.
Tam, A.
Webster, R.
Brammah, S.
Filippini, F.
Pollard, J.
Spies, J.
et al.
Citation: American Journal of Human Genetics, 2017; 101(6):995-1005
Publisher: Cell Press
Issue Date: 2017
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Elizabeth E. Palmer, Raman Kumar, Christopher T. Gordon … Jozef Gecz … Raman K. Sharma … Marie A. Shaw … et al.
Abstract: A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.
Keywords: Mandibulofacial Dysostosis
Rights: © 2017 American Society of Human Genetics.
RMID: 0030078489
DOI: 10.1016/j.ajhg.2017.10.009
Grant ID: http://purl.org/au-research/grants/nhmrc/1091593
Appears in Collections:Genetics publications

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