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A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.
Palmer, Elizabeth E; Kumar, Raman; Gordon, Christopher T; Shaw, Marie; Hubert, Laurence; Carroll, Renee; Rio, Marlène; Murray, Lucinda; Leffler, Melanie; Dudding-Byth, Tracy; Oufadem, Myriam; Lalani, Seema R; Lewis, Andrea M; Xia, Fan; Tam, Allison; Webster, Richard; Brammah, Susan; Filippini, Francesca; Pollard, John; Spies, Judy; 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; de Saint Basile, Geneviève; Kivuva, Emma; Scott, Richard H; Rendon, Augusto; Munnich, Arnold; Newman, William; Kerr, Bronwyn; Besmond, Claude; Rosenfeld, Jill A; Amiel, Jeanne; Field, Michael; Gecz, Jozef.
Affiliation
  • Palmer EE; 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.
  • Kumar R; School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia.
  • Gordon CT; 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.
  • Shaw M; School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia.
  • Hubert L; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • Carroll R; School of Medicine, The Robinson Research Institute, The University of Adelaide, North Adelaide, SA 5005, Australia.
  • Rio M; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), 75015 Paris, France.
  • Murray L; Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
  • Leffler M; Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
  • Dudding-Byth T; Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; Grow Up Well Priority Research Centre, University of Newcastle, Callaghan NSW 2308, Australia.
  • Oufadem M; 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.
  • Lalani SR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Lewis AM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Tam A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Webster R; Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
  • Brammah S; Electron Microscope Unit, Anatomical Pathology, Concord Repatriation General Hospital, Sydney, NSW 2139, Australia.
  • Filippini F; 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.
  • Pollard J; Brain Mind Research Institute, The University of Sydney, Camperdown, NSW 2050, Australia.
  • Spies J; Department of Neurology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
  • Minoche AE; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
  • Cowley MJ; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
  • Risen S; Meyer Centre for Developmental Pediatrics, Texas Children's Hospital Autism Center, Houston, TX 77054, USA.
  • Powell-Hamilton NN; Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
  • Tusi JE; Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
  • Immken L; Dell Children's Medical Center of Central Texas, Austin, TX 78723, USA.
  • Nagakura H; Dell Children's Medical Center of Central Texas, Austin, TX 78723, USA.
  • Bole-Feysot C; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Genomic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • Nitschké P; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • Garrigue A; 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.
  • de Saint Basile G; 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, 7501
  • Kivuva E; Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK.
  • Scott RH; Genomics England, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
  • Rendon A; 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.
  • Munnich A; 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.
  • Newman W; 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
  • Kerr B; 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
  • Besmond C; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Translational Genetics, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Amiel J; 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 Necke
  • Field M; Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia. Electronic address: mike.field@health.nsw.gov.au.
  • Gecz J; 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.
Am J Hum Genet ; 101(6): 995-1005, 2017 Dec 07.
Article in En | MEDLINE | ID: mdl-29198722
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neurocognitive Disorders / DNA-Binding Proteins / Intellectual Disability Limits: Humans Language: En Journal: Am J Hum Genet Year: 2017 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neurocognitive Disorders / DNA-Binding Proteins / Intellectual Disability Limits: Humans Language: En Journal: Am J Hum Genet Year: 2017 Document type: Article Affiliation country: Australia