Novel HK1 Variant Identified as Cause of Hereditary Hemolytic Anemia via Whole-Exome Sequencing
Targeted analysis of whole-exome sequencing using a hereditary anemia gene panel identified a novel homozygous HK1 variant (c.2714C>A, p.Thr905Lys) in a child with congenital hemolytic anemia and developmental delay after common enzymopathies were excluded. The pathogenic nature was confirmed by biochemical studies and in silico structural modeling, illustrating the diagnostic value of WES with curated virtual panels for rare red cell enzymopathies.
The original study
Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the
- Authors
- Dongerdiye R, Jagadeesh S, Suresh B, Rajendran A, Devendra R, Warang P, et al.
- Journal
- Journal of clinical pathology
- Type
- Journal Article, Review
- PMID
- 33361148
Original 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.