- Title
- A recurrent De Novo nonsense variant in ZSWIM6 results in severe intellectual disability without frontonasal or limb malformations
- Creator
- Palmer, Elizabeth E.; Kumar, Raman; Oufadem, Myriam; Lalani, Seema R.; Lewis, Andrea M.; Xia, Fan; Tam, Allison; Webster, Richard; Brammah, Susan; Filippini, Francesca; Pollard, John; Spies, Judy; Gordon, Christopher T.; Minoche, Andre E.; Cowley, Mark J.; Risen, Sarah; Powell-Hamilton, Nina N.; Tusi, Jessica E.; Immken, LaDonna; Nagakura, Honey; Bole-Feysot, Christine; Nitschké, Patrick; Garrigue, Alexandrine; Shaw, Marie; de Saint Basile, Geneviève; Kivuva, Emma; Scott, Richard H.; Rendon, Augusto; Munnich, Arnold; Newman, William; Kerr, Bronwyn; Besmond, Claude; Rosenfeld, Jill A.; Amiel, Jeanne; Hubert, Laurence; Field, Michael; Gecz, Jozef; Carroll, Renee; Rio, Marlène; Murray, Lucinda; Leffler, Melanie; Dudding-Byth, Tracy
- Relation
- American Journal of Human Genetics Vol. 101, Issue 6, p. 995-1005
- Publisher Link
- http://dx.doi.org/10.1016/j.ajhg.2017.10.009
- Publisher
- Cell Press
- Resource Type
- journal article
- Date
- 2017
- Description
- 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.
- Subject
- de novo; intellectual disabilities; limb malformations; acromelic frontonasal dysostosis (AFND)
- Identifier
- http://hdl.handle.net/1959.13/1387118
- Identifier
- uon:32529
- Identifier
- ISSN:0002-9297
- Language
- eng
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