Biallelic GTF3A mutations underline a novel human combined immunodeficiency

<jats:p>Ribosome biogenesis defects are increasingly recognized in hematologic disorders, yet their contribution to human combined immunodeficiency (CID) remains largely unexplored. Here, we identify compound heterozygous mutations in GTF3A, encoding transcription factor IIIA (TFIIIA), in a patient with CID presenting with profound T-cell lymphopenia, diminished thymic output, and humoral failure. The patient-derived TFIIIA variants, I267S and L364Yfs*37, disrupted 5S rRNA transcription, impaired RNA-binding capacity, and compromised protein stability. Patient T and B lymphocytes exhibited intrinsic proliferative and differentiation defects, as well as increased apoptotic susceptibility in T cells, recapitulating the clinical phenotype. To model TFIIIA dosage, we generated heterozygous and progressively depleted Jurkat cell clones via sequential CRISPR editing; complete TFIIIA loss was lethal, whereas graded reduction impaired proliferation in a dose-dependent manner, fully rescued by wild-type GTF3A reconstitution. Collectively, these findings establish deficiency of GTF3A resulting in combined immunodeficiency (DoGCID) within the spectrum of ribosomopathies, highlighting the exquisite sensitivity of lymphocyte fitness to disruptions in ribosome biogenesis.</jats:p>