Immunodeficiency and Autoimmunity as a Result of CD40LG Copy Number Gains

X-linked CD40LG encodes CD40L (CD154), a transmembrane protein transiently expressed primarily on activated CD4+ T cells. By binding CD40 on B cells and antigen-presenting cells (APCs), CD40L delivers a co-stimulatory signal that enhances antigen presentation, T cell priming, and activation, as well as class-switch recombination (CSR) in B cells. Inherited deficiency of CD40L in males leads to X-linked hyper-IgM syndrome (XHIGM), a combined immunodeficiency (CID) marked by CSR defects, recurrent infections, and significant morbidity and mortality. However, CD40LG copy number gains (CNGs) are much less recognized: only two male patients with either duplications or triplications have been previously described. Here, we expand the clinical and immunological understanding of this entity by presenting a case series of five male patients, including the two previously reported. We describe the clinical progression, immunological characteristics, and treatment responses of five patients with CD40LG CNGs, comprising three duplications and two triplications. The clinical phenotypes ranged from recurrent infections to early-onset, treatment-refractory autoimmunity. Thus, X-linked CD40LG CNG represents a variable spectrum of immunological phenotypes, including recurrent infections and autoimmunity, underscoring the importance of considering these genetic alterations in patients with immune dysregulation.