Hyper IgM Syndrome (HIGM) is a primary immunodeficiency disorder characterized by symptoms such as recurrent respiratory infections, opportunistic infections, and autoimmune disorders. This disease is caused by the decreased, absent, or altered expression of genes involved in antibody isotype switching, including CD40LG, AID, UNG, and CD40. Mutations in the CD40LG gene are the most common form of this disease.

Currently, HIGM diagnosis is based on identifying genetic mutations in the genes involved in isotype switching mechanisms along with clinical symptoms. Although genetic diagnosis of this disease is performed using techniques like Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), these techniques are expensive and time-consuming. Additionally, these tests are not universally available, with only specific centers in the country capable of performing them. Therefore, there is a need for an affordable and accessible test that provides a quicker diagnosis of the disease.

Timely diagnosis of primary immunodeficiency diseases is crucial because delays in diagnosis or misdiagnosis and lack of appropriate and effective treatment can lead to complications and permanent damage to various organs, increasing mortality in patients. Conversely, timely diagnosis and treatment result in fewer infections, longer life expectancy, and better quality of life for patients. The significant role of flow cytometry in the diagnosis and monitoring of primary immunodeficiency diseases has been well demonstrated. Flow cytometry can be used to assess the expression of the CD40L protein in suspected HIGM patients, providing a quicker and more affordable diagnosis compared to genetic techniques.

Considering that Iranian HIGM patients with genetic mutations have not been assessed for protein expression and function, the findings of this study could aid in the genetic confirmation and definitive diagnosis of patients. Additionally, flow cytometry findings can be used to evaluate the phenotype-genotype relationship and its correlation with clinical symptoms. Determining the genotype-phenotype correlation can play a crucial role in diagnosing and categorizing these patients. This study will be conducted for the first time in Iranian patients, and it is hoped that the results will be used to achieve faster disease diagnosis, which is key to early treatment for these patients.