Expanding the clinical spectrum of CD3γ deficiency: comprehensive characterization of adult-onset disease and integrated reevaluation of all reported patients

Abstract

Objective CD3γ deficiency is an ultrarare autosomal recessive inborn error of immunity characterized by immune dysregulation and variable immunodeficiency. To date, only 16 predominantly pediatric cases have been reported. Here, we describe two additional adult patients with CD3γ deficiency and provide a comprehensive reevaluation of all previously published cases. Methods Clinical, immunological, and genetic investigations were performed in two adult patients presenting with immune dysregulation and hypogammaglobulinemia. Whole-genome sequencing was used to identify pathogenic CD3G variants, and protein expression was assessed by Western blot analysis. In addition, a literature review of all previously reported cases was conducted. Results Both patients presented with humoral immunodeficiency and Evans syndrome responsive to rituximab therapy. One patient, currently the oldest reported individual with CD3γ deficiency, harbored a novel homozygous frameshift variant in CD3G (c.213dupA, p.(Trp72Metfs*6)) resulting in complete loss of CD3γ expression. Reevaluation of all reported cases demonstrated marked phenotypic heterogeneity, ranging from isolated autoimmune manifestations to severe early-onset combined immunodeficiency requiring hematopoietic stem cell transplantation. Notably, patients carrying identical deleterious variants exhibited substantial variability in clinical presentation and outcomes, indicating that no obvious genotype-phenotype correlation could be established based on the currently available data. Conclusion CD3γ deficiency exhibits a broad and highly variable clinical spectrum extending into adulthood. Immune dysregulation, particularly autoimmune cytopenias, represents a prominent manifestation. Our findings expand the phenotypic spectrum of CD3γ deficiency and emphasize the importance of considering this disorder also in adult patients with hypogammaglobulinemia and autoimmune disease.