V-set immunoregulatory receptor gene mutation and neonatal combined immunodeficiency in a consanguineous family
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Abstract
Objective: To explore the potential association between a VSIR gene mutation and primary combined immunodeficiency (CID) in a patient from a consanguineous family.
Methods: This family-based genetic study was conducted after obtaining ethical approval from the Institutional Review Board of HBS Medical and Dental College, Islamabad (Ref: HBS/IRB/19/25). A 2-month-old female presenting with recurrent infections was clinically evaluated. Laboratory investigations included complete blood count, serum immunoglobulins, and lymphocyte subset analysis by flow cytometry. Whole exome sequencing (WES) was performed to identify potential genetic variants, followed by variant filtering, in-silico pathogenicity prediction, and segregation analysis using Sanger sequencing in available family members.
Results: The patient presented with recurrent infections, marked leukocytosis (WBC: 86.5 × 10⁹/L), thrombocytosis, and hypogammaglobulinemia (low IgA, IgM, and IgG). Flow cytometry demonstrated elevated CD3⁺, CD4⁺, and CD8⁺ T-cell counts with reduced NK cells. Whole-exome sequencing identified a rare homozygous missense variant in the VSIR gene (c.593C>T; p.Thr198Met), encoding VISTA, a negative immune checkpoint regulator. The variant lies in a conserved region, has a very low allele frequency (0.00008122), and was predicted to be deleterious (CADD score: 26.2). Segregation analysis confirmed autosomal recessive inheritance, and no other pathogenic variants were identified in known primary immunodeficiency genes.
Conclusion: This study highlights a potential role of VSIR mutations in immune dysregulation and combined immunodeficiency, particularly in consanguineous populations. The identified variant may contribute to abnormal T-cell regulation and hypogammaglobulinemia. Further functional studies are required to establish causality and clarify the role of VISTA in immune homeostasis.
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