Whole Exome Sequencing Identified a Pathogenic IL2RG Variant in Monozygotic Twins with Severe Combined Immunodeficiency

Abstract

Background: Severe combined immunodeficiency (SCID) is a life-threatening disorder of adaptive immunity, requiring rapid diagnosis and intervention. Objectives: This study aimed to determine the genetic cause of SCID in monozygotic twin male infants who presented with recurrent severe infections and disseminated Bacille Calmette-Guerin (BCG)-related complications. Methods: Whole exome sequencing (WES) was performed on one twin to identify candidate pathogenic variants. The detected IL2RG variant was validated through PCR and Sanger sequencing, and family segregation analysis was conducted. Comprehensive immunological assessments, including T-cell receptor excision circle (TREC) assays and lymphocyte profiling, were employed. High-resolution human leukocyte antigen (HLA) typing was also carried out to evaluate donor compatibility for hematopoietic stem cell transplantation (HSCT). Results: Whole exome sequencing revealed a hemizygous c.670C>T (p.Arg224Trp) variant in the IL2RG gene, a change absent from population databases and predicted to be deleterious by in silico tools. Sanger sequencing confirmed the variant in both twins, and maternal heterozygosity was identified. Clinically, the twins exhibited profound lymphopenia and undetectable TRECs, consistent with a T⁻B⁺NK⁻ immunophenotype [absent T and natural killer (NK) cells, with presence of non-functional B cells]. Human leukocyte antigen typing demonstrated only partial haplotype matches with the parents, highlighting the need for a haploidentical transplant approach. Conclusions: Integrating genomic analysis with immunological profiling effectively pinpointed a pathogenic IL2RG mutation as the cause of SCID in these twins. Early genetic diagnosis using WES is critical for guiding timely therapeutic interventions such as HSCT or gene therapy and underscores the need for implementing newborn screening and carrier testing programs, particularly in resource-limited settings.