Characterization of a Novel, Recurrent 40.6 kb α 0 ‐Thalassemia Deletion in Canadians of East Indian Descent

ABSTRACT Introduction Large α 0 ‐thalassemia deletions involving both HBA1 and HBA2 genes are rare in South Asian populations and remain under‐characterized. We describe a novel 40.6 kb α 0 ‐thalassemia deletion identified in multiple unrelated Canadians of East Indian descent and assess its molecular and clinical significance. Methods Individuals with suspected α‐thalassemia trait were identified by complete blood count and hemoglobin analysis. Samples with microcytosis and/or hypochromia and normal Hb A 2 underwent molecular testing, including gap‐PCR for common deletions, Sanger sequencing, and multiplex ligation‐dependent probe amplification. Deletion breakpoints were defined by targeted PCR and Sanger sequencing. A specific gap‐PCR assay was developed for rapid detection, and retrospective screening was performed. Results Twelve unrelated carriers of a 40.6 kb deletion removing HBZ , HBA2 , and HBA1 were identified. All showed hematologic features consistent with α‐thalassemia trait (MCV 65.4 ± 3.6 fL, MCH 20.2 ± 1.1 pg, normal Hb A 2 ). Breakpoint analysis demonstrated non‐homologous recombination between Alu elements. Recurrence among individuals of similar ancestry suggests a founder effect. We identified two couples at 25% risk for having children with Hb H disease due to compound heterozygosity for the 40.6 kb deletion and α + ‐thalassemia mutations, and diagnosed two Hb H disease patients with genotypes involving the 40.6 kb deletion. Conclusions This novel α 0 ‐thalassemia deletion is a recurrent and likely under‐recognized cause of α‐thalassemia and Hb H disease in individuals of East Indian ancestry, underscoring the need for population‐specific molecular testing strategies.