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
  • 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.