Hb H disease associated with compound heterozygosity for --SEA deletion and a novel alpha globin chain variant (HBA2:c.175C>A) on the distal histidine in a Chinese family

Objectives: In clinical practice, the majority of alpha-thalassaemia cases arise from deletions of the alpha-globin genes. However, a subset of cases is attributed to rare haemoglobin variants, which can manifest with borderline or normal screening results, potentially leading to missed diagnoses in clinical practice. Methods: Blood samples were collected from family members and underwent haematological, DNA and RNA analysis. Results: The five-month-old proband presented a haematological phenotype consistent with Hb H disease. The mother's haematology profile was consistent with an alpha-thalassaemia carrier, while the father exhibited a borderline reduction in MCV and MCH. MALDI-TOF identified an abnormal alpha-chain in the proband. DNA analysis revealed a novel alpha-globin variant (HBA2:c.175C>A, alpha 58His>Asn, Hb DG-Nancheng) affecting the distal histidine in the family. The father and the mother had alpha-genotype of --(SEA)/alpha alpha and alpha(DG-Nancheng)alpha/alpha alpha, respectively; while the proband inherited both mutant alleles (--(SEA)/alpha(DG-Nancheng)alpha). Sequencing of cDNA from HBA2 gene identified an equal ratio of normal and mutant alleles. Conclusion: This rare case highlighted the importance of identifying rare haemoglobin variant during prenatal screening. The clinical and genetic data provides useful information on the pathogenicity of this variant and further insight into the role of distal histidine residue of alpha-globin.