De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia

  • J Med Genet. 2017 Feb;54(2):84-86. doi: 10.1136/jmedgenet-2016-103943.
Esther R Berko  1 ,  Megan T Cho  2 ,  Christine Eng  3 ,  Yunru Shao  3  4 ,  David A Sweetser  5 ,  Jessica Waxler  5 ,  Nathaniel H Robin  6 ,  Fallon Brewer  6 ,  Sandra Donkervoort  7 ,  Payam Mohassel  7 ,  Carsten G Bönnemann  7 ,  Martin Bialer  8 ,  Christine Moore  8 ,  Lynne A Wolfe  9  10 ,  Cynthia J Tifft  9  10 ,  Yufeng Shen  11 ,  Kyle Retterer  2 ,  Francisca Millan  2 ,  Wendy K Chung  1  12
Affiliations
  • 1. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
  • 2. GeneDx, Gaithersburg, Maryland, USA.
  • 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 4. Texas Children's Hospital, Houston, Texas, USA.
  • 5. Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 6. University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • 7. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
  • 8. Cohen Children's Medical Center of NY, New Hyde Park, New York, USA.
  • 9. Office of the Clinical Director, National Institutes of Health, Bethesda, Maryland, USA.
  • 10. Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA.
  • 11. Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.
  • 12. Department of Medicine, Columbia University Medical Center, New York, New York, USA.
PMID: 27389779 DOI: 10.1136/jmedgenet-2016-103943
Abstract

Background: The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID.

Methods and results: In this study, we performed whole exome Sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin Ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis.

Conclusion: This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.

Keywords
HECW2; de novo; intellectual disability; neurodevelopmental delay; whole exome sequencing.