2. Academic Validation
  3. De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

  • Eur J Hum Genet. 2019 Jul;27(7):1081-1089. doi: 10.1038/s41431-019-0366-9.
Volkan Okur 1,  Megan T Cho 2,  Richard van Wijk 3,  Brigitte van Oirschot 3,  Jonathan Picker 4,  Stephanie A Coury 4,  Dorothy Grange 5,  Linda Manwaring 5,  Ian Krantz 6,  Colleen Clark Muraresku 6,  Peter J Hulick 7,  Holley May 7,  Eric Pierce 8,  Emily Place 8,  Kinga Bujakowska 8,  Aida Telegrafi 2,  Ganka Douglas 2,  Kristin G Monaghan 2,  Amber Begtrup 2,  Ashley Wilson 1,  Kyle Retterer 2,  Kwame Anyane-Yeboa 1,  Wendy K Chung 9 10
Affiliations

Affiliations

  • 1 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
  • 2 GeneDx, Gaithersburg, MD, USA.
  • 3 Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 4 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • 5 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 6 Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 7 Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
  • 8 Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. [email protected].
  • 10 Department of Medicine, Columbia University Medical Center, New York, NY, USA. [email protected].
PMID: 30778173 DOI: 10.1038/s41431-019-0366-9
Abstract

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of Hexokinase enzymatic activity.

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