Biallelic BRF2 mutations disrupt redox homeostasis as etiological factors in syndromic immunodeficiency and developmental disorders.
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TFIIB-related factor 2 (BRF2) is a critical component in the recruitment of RNA polymerase III (RNA Pol III) to type III promoters containing a TATA box. These promoters regulate the expression of key elements such as U6 spliceosomal RNA, the tRNA processing enzyme RNase P, and selenocysteine tRNA. Despite the essential role of BRF2, the genetic disorders associated with BRF2 mutations and their molecular pathogenesis remain poorly defined. In this study, we identified and characterized novel biallelic BRF2 variants with impaired RNA Pol III activity in a familial case presenting with multisystem anomalies, malignancy, and primary immunodeficiency. Whole-exome sequencing revealed compound heterozygous BRF2 variants predicted to disrupt interaction with the TATA box-binding protein. Subsequent gene expression profiling of the patient's whole blood cells using single-cell RNA sequencing was conducted. Clinically, the patient exhibited recurrent infections and hypogammaglobulinemia in early childhood, which improved over time but was followed by the development of low-grade B cell lymphoma during adolescence, necessitating chemotherapy. Functional analyses in human cells expressing the BRF2 variants demonstrated defective BRF2-dependent RNA Pol III transcription of redox-regulating genes, specifically GPX1 and GPX4. These findings establish a pathogenic link between BRF2 dysfunction and disrupted redox homeostasis, offering mechanistic insights into the hemato-immunological and developmental abnormalities observed in affected individuals and highlighting potential implications for clinical management.