A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620576
Title:
A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.
Authors:
Palmer, E. E. [et al]; Kivuva, Emma
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.
Citation:
A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations. 2017, 101 (6):995-1005 Am. J. Hum. Genet.
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
7-Dec-2017
URI:
http://hdl.handle.net/11287/620576
DOI:
10.1016/j.ajhg.2017.10.009
PubMed ID:
29198722
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii//S0002-9297(17)30430-5
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorPalmer, E. E. [et al]en
dc.contributor.authorKivuva, Emmaen
dc.date.accessioned2017-12-22T10:35:15Z-
dc.date.available2017-12-22T10:35:15Z-
dc.date.issued2017-12-07-
dc.identifier.citationA Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations. 2017, 101 (6):995-1005 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid29198722-
dc.identifier.doi10.1016/j.ajhg.2017.10.009-
dc.identifier.urihttp://hdl.handle.net/11287/620576-
dc.description.abstractA 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.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii//S0002-9297(17)30430-5en
dc.rightsArchived with thanks to American journal of human geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleA Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.type.versionPublisheden

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