A New Variant in CTLA4 Highlights the Heterogeneous Phenotype of CTLA4 Haploinsufficiency

Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good's syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.