From Variant of Uncertain Significance to Likely Pathogenic: Report of Two Siblings with Atypical RAG2 Deficiency

Abstract

Abstract Background: Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation. Case Presentation: The first case engaged a 1-year-old boy who had a history of recurring infections. Initial diagnosis of Bruton's agammaglobulinemia was revised to combined immunodeficiency (CID) after a comprehensive immunological workup. The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. Case 2, a four-month-old boy, presented with CMV chorioretinitis and a family history of primary immunodeficiency. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, along with the clinical phenotype, supports considering the mutation as likely pathogenic. Conclusions: This case report highlights a novel RAG2 gene mutation associated with SCID in siblings. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management.