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https://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.E. Kumar, R. Gordon, C.T. Shaw, M. Hubert, L. Carroll, R. Rio, M. Murray, L. Leffler, M. Dudding-Byth, T. Oufadem, M. Lalani, S.R. Lewis, A.M. 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. |
DOI: | 10.1016/j.ajhg.2017.10.009 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1091593 |
Published version: | http://dx.doi.org/10.1016/j.ajhg.2017.10.009 |
Appears in Collections: | Aurora harvest 8 Genetics publications |
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