Systemic review and meta-analysis of clinical characteristics and immunological phenotype in patients with CARMIL2 Deficiency

Background: Inborn errors of immunity (IEI) include a wide spectrum of inherited illnesses brought on by faulty components of the immune system that result in higher vulnerability to infections, immunological dysregulation, and malignancies. A rare kind of combined immunodeficiency, CARMIL2 deficiency results from biallelic mutations in the CARMIL2 gene. Recurrent infections, skin abnormalities, EBV-related illnesses, and compromised T-cell and B-cell activities define it. Although CARMIL2 deficiency has clinical relevance, the particular immunological phenotypes and the prevalence of different CARMIL2 isoforms are still largely unknown. Methodology: To assess the clinical and immunological characteristics in people with CARMIL2 deficiency, a methodical review and meta-analysis were done. Relevant research describing clinical outcomes and immunological findings including T-cell, B-cell, and NK-cell profiles were found using a complete search of PubMed, Embase, and Scopus. English-published case reports, cohort studies, and clinical trials were sources of the data. The prevalence of CARMIL2 isoforms and the frequency of main immunological abnormalities were evaluated using meta-analysis. Results: Although the clinical characteristics described across studies showed heterogeneity, recurring infections, skin condition (e.g., dermatitis, mucocutaneous inflammation), and EBV-related disorders (e.g., smooth muscle tumors) were consistently noted. Immunologically, patients showed diminished CD4+ and CD8+ memory T-cells, few regulatory T-cells, skewed activation of naïve T-cells, and impaired CD28 signaling. Also, common findings were decreased memory B-cells and damaged NK-cell function. Most mutations were missense, frameshift, and splice-site mutations influencing important structural domains including LRR and Pleckstrin Homology. Isoform 1 (1435 amino acids) turned out to be the most common isoform, at 79%, followed by Isoform 2 at 10% and Isoform 3 at 7%. Conclusion: CARMIL2 deficiency causes a broad spectrum of clinical symptoms, especially skin conditions, recurring infections, and EBV-related cancers. Immunologically, the deficit is characterized by major changes in T-cell and B-cell subsets as well as NK-cell dysfunction. The results highlight the need for CARMIL2 for immune regulation, where isoform 1 is the main form related to this disease.