Hexokinase (EC 22.214.171.124, Adenosine Tri Phosphate (ATP): D-hexose-6-phosphotransferase) is a crucial regulatory enzyme of the glycolytic pathway (Embden-Meyerhof pathway). Hexokinase deficiency is associated with chronic non-spherocytic haemolytic anaemia (HA) with some exceptional cases showing psychomotor/mental retardation and fetus death. The proband is a four-and-half-year-old female child born of a four-degree consanguineous marriage hailing from South India with autosomal recessive congenital HA associated with developmental delay. She was well till 3 months of her age post an episode of diarrhoea when she was noted to be severely anaemic and requiring regular transfusions. The common causes of HA, haemoglobinopathies, red cell membranopathies and common red cell enzymopathies (G6PD, GPI, PK and P5N) were ruled out. Targeted analysis of whole exome sequencing (WES) using an insilico gene panel for hereditary anaemia was performed to identify pathogenic variants in the patient. Next-generation sequencing revealed a novel homozygous variant in hexokinase gene c.2714C>A (p. Thr905Lys) in exon-18. The pathogenic nature of the variant p. Thr905Lys in the HK1 gene was confirmed collectively by biochemical and molecular studies. Insilico analysis (PolyPhen-2, Provean, Mutation Taster) predicted the variant to be severe disease causing. Multiple sequence alignment demonstrated the conservation of p. Thr905 across the species. The impact of the mutation on the protein structure was studied by PyMOL and Swiss Protein databank viewer.
- central nervous system
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Handling editor Mary Frances McMullin.
Contributors PSK, PW, RD and RD participated in the design of the study, extracted DNA from blood and performed PCR, gene sequencing, bioinformatics study and manuscript writing. SJ, AR and BS participated in clinical management and studied family. PSK collected funds and supervised for the study. All authors read and approved the final manuscript.
Funding This study was funded by the Indian Council of Medical Research, New Delhi, and Department of Biotechnology, Ministry of Science and Technology, New Delhi, (Grant no. BT/PR20782/MED/12/737/16).
Competing interests Authors BS and SJ are employed by the company Mediscan Systems, No. 197, Dr. Natesan Road, Mylapore, Chennai-600004.
Provenance and peer review Not commissioned; externally peer reviewed.
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