![]() The first pregnancy from this family resulted in a labor induction due to hydrocephalus at 6 months gestation and the second in a spontaneous abortion. The proband was a 2-month-24-days-old infant who was admitted to the hospital with repeated fever for 8 days with no evident cause. The 3D protein structure was affected by the mutation, and the variant gene expression was investigated. Whole-exome sequencing (WES) identified a variation in RAG1 that may lead to immunodeficiency. In this study, we report the case of a 2-month-old infant with SCID. Different RAG1 variants cause variable clinical penetrance and immunophenotypes. Only 24 variations were experimentally validated in SCID patients (Supplemental Table 1) and many RAG1 variants still require clinical and experimental verification of their pathogenicity. Currently, 345 variants of RAG1 are listed in the ClinVar Database ( ) of these, only 92 are reported as Pathogenic or Likely Pathogenic and the majority is missense. Approximately 50 % of patients with SCID lack B/T lymphocytes (T-, B- SCID) as a result of RAG1 and RAG2 mutations. All these changes in biological processes lead to primary immune deficiency and inheritance patterns are usually autosomal recessive. Mutations in RAG1 result in the complete or partial loss of recombinant enzyme activity, in unbalanced variable-diversity-joining (V(D)J) recombination, and in the impairment of T and B lymphocyte development at the early stages. Recombination-activating gene (RAG) proteins include RAG1 and RAG2, which are crucial for Ig and T lymphocyte receptor (TCR) fragment rearrangement and are responsible for DNA recognition and cleavage at specific sequences. The SCID criteria reference the Shearer et al 2014 criteria. Approximately 23 % – 30 % of patients with SCID present with detectable levels of natural killer (NK) cells, but not B and T lymphocytes (B-, T-, NK+ SCID). The overall prevalence of SCID is estimated to be 1/100000-2/100000. Patients diagnosed with SCID suffer recurrent and persistent infections during infancy, severe lymphopenia, and low or absent immunoglobulin (Ig) levels. Severe combined immunodeficiency (SCID) is an immune deficiency disorder presenting with heterogeneous genetic and clinical features. This finding expands the variant spectrum of RAG1 in SCID and provides further evidence for the clinical diagnosis of SCID. Our study identified a novel homozygous variant in RAG1 gene that causes SCID. Additionally, decreased expression of variant RAG1 gene was detected at both the mRNA and protein levels. The predicted 3D structure of variant RAG1 indicated altered protein stability. A homozygous variation c.2147G>A (NM_000448.2: exonme2: c.2147G>A (p.Arg716Gln)) was identified in the RAG1 gene using whole-exome sequencing and Sanger sequencing. ![]() The infant was diagnosed with severe combined immunodeficiency (SCID). In this study, a 2-month-24-days-old infant with recurrent fever was admitted to our hospital with multiple infections and absence of T and B lymphocytes. Typical clinical features driven by RAG1 variants include persistent infections, severe lymphopenia, and decreased immunoglobulin levels. Mutations in RAG1 have been reported to be associated with several types of immune disorders. The recombination-activating gene 1 (RAG1) protein is essential for the V (variable)-D (diversity)-J (joining) recombination process.
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