Non-deletional hemoglobin H disease caused by rare α-globin gene mutations combined with Southeast Asian deletion

Objective To analyze the mutation types of non-deletional hemoglobin H (Hb H) disease, explore the correlation between distinct genotypes and clinical phenotypes, and identify rare α-globin gene mutations, so as to provide evidence for clinical diagnosis and treatment, genetic counseling, and prenatal diagnosis.

Methods Routine blood tests hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and Hb H analysis were performed on patients diagnosed and treated for α-thalassemia at the First Affiliated Hospital of Guangxi Medical University from January 2024 to January 2026. Gap-polymerase chain reaction (gap-PCR), fluorescence-based PCR melting curve assay (FCMA) and DNA sequencing were used for genetic analysis of thalassemia.

Results Among 217 patients with non-deletional Hb H disease, 187 patients were identified as Hb H-CS (--^SEA/α^CSα) and 27 patients as Hb H-QS(--^SEA/α^QSα), and 3 patients carried rare gene mutations causing Hb H disease, including one case each of --^SEA/α^ATG＞GTGα, --^SEA/α^{CD90-92(-AGCTTCGG)}α and --^SEA/α^CD30(-GAG)α. None of the patients were complicated with β-thalassemia. The results of routine blood tests showed that mild, moderate and severe anemia in the Hb H-CS group accounted for 22.99%, 64.71% and 12.30%, respectively; the corresponding proportions of mild, moderate and severe anemia in the Hb H-QS group accounted for 44.45%, 51.85% and 3.70%, respectively. The Hb levels were 107.30 g/L for the --^SEA/α^ATG＞GTGα genotype, 88.40 g/L for the --^SEA/α^{CD90-92(-AGCTTCGG)}α genotype, and 73.70 g/L for the --^SEA/α^CD30(-GAG)α genotype, all accompanied by decreased MCV and MCH. Hb analysis revealed that the Hb H level was 13.60% (10.45%–15.90%) in the Hb H-CS group and 23.20% (17.30%–25.00%) in the Hb H-QS group, with a statistically significant difference between the two groups (P＜0.05). The Hb H levels of the --^SEA/α^ATG＞GTGα, --^SEA/α^{CD90-92(-AGCTTCGG)}α and --^SEA/α^CD30(-GAG)α genotypes were 25.30%, 24.40% and 20.40%, respectively.

Conclusion The predominant genotype of non-deletional Hb H disease is --^SEA/α^CSα, followed by --^SEA/α^QSα. Moderate anemia is the main clinical manifestation of non-deletional Hb H disease. The Hb H level in the Hb H-QS group is higher than that in the Hb H-CS group. Three cases of Hb H disease with genotypes of --^SEA/α^ATG＞GTGα, --^SEA/α^{CD90-92(-AGCTTCGG)}α and --^SEA/α^CD30(-GAG)α are identified, presenting with mild to moderate anemia.