Thalassemia, highly prevalent in Indian subcontinent, is a heterogeneous group of inherited hemoglobinopathy that presents as microcytic hypochromic anemia, requiring frequent blood transfusions. Amongst all variants of thalassemia, beta-thalassemia major requires routine blood transfusions which are associated with complications viz. iron overload (20-70%), transfusion reactions (~50%), alloimmunization (10-20%), transfusion transmitted infections, pain (25%-69%), psychiatric disorders (25%-30%), and reduced health-related quality of life. In many centres, except for ABD group matching and compatibility testing, there is no further technical provisions of extended antigen phenotyping for common red cell antigens such as Rh antigens (CE/ce) and Kell. Many of the centres lack the facilities to ascertain the red cell antigenic constitution of the multiply transfused thalassemia patients because of lack of serological methods to differentiate the antigenic phenotype of patient from that of the allogenic transfused red cells. This may be overcome by DNA-based blood group genotyping methods which can determine the correct antigenic constitution of thalassemia patients which in turn, will facilitate better chances of getting antigen-matched packed RBC (PRBC) units. More precisely, exome sequencing defines blood group genotypes as well as resolve problematic serology based immune-hematological challenges. The exome sequencing strategy can be accurately and economically utilized to verify and resolve extended range of blood group genotypes or complex immune-hematological interactions leading to development of complications. Though blood group genotyping techniques are generally expensive; given the vast volume of blood group genotype–phenotype correlations, a large-scale genotyping program could offer some cost savings compared to a serologic matching program, providing an insight to complex immunogenetic interactions and enhancing the cost-effectiveness of the precision medicine approach. 

The exact path of development of alloimmunization is not well understood in multi-transfused thalassemia patients, and this endeavor aims to reduce the incidence of alloimmunization by establishing the genotypic approach to find any specific association of allelic polymorphism in such patients.