2. Academic Validation
  3. De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia

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

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.

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