Novel HBB:c.375_376delAC mutation in a Malay patient with HbE beta-thalassemia intermedia: A case report

Hemoglobin E beta-thalassemia (HbE-BT) is a prevalent and genetically diverse inherited hemoglobin disorder in Malaysia. While most cases are attributed to known genetic variants, discovering novel mutations is essential for understanding their wide-ranging clinical presentations and underlying genetic heterogeneity.

We present the case of a Malay male patient with an intermediate phenotype of HbE-BT whose clinical course was marked by a progression to a transfusion-dependent status, a change triggered by an acute febrile illness. The case highlights the complex challenges of long-term management, including a high risk of iron overload and the significant morbidity and mortality associated with postsplenectomy infections.

The patient was referred for a comprehensive DNA analysis of thalassemia syndromes. Full blood count showed hypochromic microcytic anemia (hemoglobin 7.90 g/dL, mean corpuscular volume 66.10 fL). Hemoglobin analysis via capillary electrophoresis revealed a characteristic pattern of HbA (49.1%), HbE (20.6%), and HbF (27.0%). Sanger sequencing subsequently confirmed a compound heterozygous state of HBB:c.79G>A (HbE) and a novel frameshift mutation at codon 124 of the beta-globin gene (HBB:c.375_376delAC). Predictive computational tools further supported the pathogenicity of this new variant, and its data have been submitted to the ITHANET database (IthaID: 4155).

Initially, the patient's condition was managed with nutritional supplements and intermittent blood transfusions. Following an acute febrile episode at age 26, his clinical condition worsened, necessitating regular monthly blood transfusions to manage severe anemia. He also received subcutaneous chelation therapy to address severe hepatic iron overload. At age 36, he underwent a splenectomy to reduce his transfusion requirements.

Despite these interventions, the patient passed away at the age of 37 from septic shock and multiorgan failure. This outcome occurred a year after his splenectomy and underscores the critical risk of overwhelming postsplenectomy infection, a significant complication in splenectomized thalassemia patients.

Identifying this novel compound heterozygosity contributes to our understanding of the genetic landscape of HbE-BT in Malaysia. This case reinforces the importance of comprehensive molecular analysis for accurate diagnosis, and it has important implications for improving long-term management and genetic counseling strategies for patients with thalassemia syndromes.