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|Title:||A recurrent de novo nonsense variant in ZSWIM6 results in severe intellectual disability without frontonasal or limb malformations|
|Citation:||American Journal of Human Genetics, 2017; 101(6):995-1005|
|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.|
|Rights:||© 2017 American Society of Human Genetics.|
|Appears in Collections:||Genetics publications|
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