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
  • 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.