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Molecules in pathogenesis
Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the HK1 gene causing severe haemolytic anaemia with developmental delay in an Indian family
  1. Rashmi Dongerdiye1,
  2. Sujatha Jagadeesh2,
  3. Beena Suresh2,
  4. Aruna Rajendran3,
  5. Rati Devendra1,
  6. Prashant Warang1,
  7. Prabhakar S Kedar1
  1. 1Hematogenetics, National Institute of Immunohaematology, Mumbai, Maharashtra, India
  2. 2Department of Clinical Genetics and Genetic Counseling Department, MediScan Systems, Chennai, Tamil Nadu, India
  3. 3Department of Hematology, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India
  1. Correspondence to Dr Prabhakar S Kedar, Hematogenetics, National Institute of Immunohaematology, Mumbai 400012, India; kedarps2002{at}yahoo.com

Abstract

Hexokinase (EC 2.7.1.1, 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
  • diagnosis
  • erythrocytes
  • genetics
  • anemia
  • hemolytic

https://doi.org/10.1136/jclinpath-2020-206960

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    Footnotes

    • 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.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by the Ethics Review Board of the National Institute of Immunohematology, Mumbai. Written informed consent was obtained from all patients before blood collection, and all samples were stored according to the principles of the Declaration of Helsinki.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.