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Eur J Hum Genet. 2019 Feb 18. doi: 10.1038/s41431-019-0366-9. [Epub ahead of print]

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

Author information

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. wkc15@columbia.edu.
10
Department of Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@columbia.edu.

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.

PMID:
30778173
DOI:
10.1038/s41431-019-0366-9

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