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Am J Hum Genet. 2017 Dec 7;101(6):995-1005. doi: 10.1016/j.ajhg.2017.10.009. Epub 2017 Nov 30.

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

Author information

1
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; School of Women and Children's Health, University of New South Wales, Randwick, NSW 2031, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2
School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia.
3
Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
4
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
5
Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), 75015 Paris, France.
6
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
7
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Grow Up Well Priority Research Centre, University of Newcastle, Callaghan NSW 2308, Australia.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
9
Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
10
Electron Microscope Unit, Anatomical Pathology, Concord Repatriation General Hospital, Sydney, NSW 2139, Australia.
11
Brain Mind Research Institute, The University of Sydney, Camperdown, NSW 2050, Australia.
12
Department of Neurology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
13
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
14
Meyer Centre for Developmental Pediatrics, Texas Children's Hospital Autism Center, Houston, TX 77054, USA.
15
Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
16
Dell Children's Medical Center of Central Texas, Austin, TX 78723, USA.
17
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Genomic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
18
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
19
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
20
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Centre d'Etudes des Déficits Immunitaires, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France.
21
Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK.
22
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
23
Genomics England, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
24
Genomics England, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 0PT, UK.
25
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), 75015 Paris, France.
26
Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK; Division of Evolution and Genomic Sciences School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK.
27
Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), 75015 Paris, France.
28
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia. Electronic address: mike.field@health.nsw.gov.au.
29
School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia; Healthy Mothers and Babies, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address: jozef.gecz@adelaide.edu.au.

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:

ZSWIM6; autism; de novo; epilepsy; exome sequencing; genomics; intellectual disability; nonsense-mediated decay; recurrent; ubiquitination

PMID:
29198722
PMCID:
PMC5812890
DOI:
10.1016/j.ajhg.2017.10.009
[Indexed for MEDLINE]
Free PMC Article

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