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

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

  • Am J Hum Genet. 2017 Dec 7;101(6):995-1005. doi: 10.1016/j.ajhg.2017.10.009.
Elizabeth E Palmer 1,  Raman Kumar 2,  Christopher T Gordon 3,  Marie Shaw 2,  Laurence Hubert 4,  Renee Carroll 2,  Marlène Rio 5,  Lucinda Murray 6,  Melanie Leffler 6,  Tracy Dudding-Byth 7,  Myriam Oufadem 3,  Seema R Lalani 8,  Andrea M Lewis 8,  Fan Xia 8,  Allison Tam 8,  Richard Webster 9,  Susan Brammah 10,  Francesca Filippini 3,  John Pollard 11,  Judy Spies 12,  Andre E Minoche 13,  Mark J Cowley 13,  Sarah Risen 14,  Nina N Powell-Hamilton 15,  Jessica E Tusi 15,  LaDonna Immken 16,  Honey Nagakura 16,  Christine Bole-Feysot 17,  Patrick Nitschké 18,  Alexandrine Garrigue 19,  Geneviève de Saint Basile 20,  Emma Kivuva 21,  DDD Study 22,  Richard H Scott 23,  Augusto Rendon 24,  Arnold Munnich 25,  William Newman 26,  Bronwyn Kerr 26,  Claude Besmond 4,  Jill A Rosenfeld 8,  Jeanne Amiel 27,  Michael Field 28,  Jozef Gecz 29
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
PMID: 29198722 DOI: 10.1016/j.ajhg.2017.10.009
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.

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