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Purpose <p>Pathogenic variants in the T-cell receptor alpha constant (<i>TRAC</i>) gene have been primarily associated with combined immunodeficiency (CID). To date, only five patients from three unrelated families harboring the same <i>TRAC</i> variant with a CID phenotype, and three patients carrying a distinct variant with severe combined immunodeficiency (SCID), have been described. We report a previously unreported homozygous <i>TRAC</i> variant causing a premature stop codon in three siblings with classical SCID phenotype.</p> Methods <p>Comprehensive immunological and molecular analyses were performed, including lymphocyte immunophenotyping, proliferation assays, qPCR for T helper (Th) subset–related gene expression, and cytokine secretion profiling. In silico analyses included conservation assessment, structural modeling using ChimeraX, and protein stability prediction via PremPS to evaluate the variant’s structural and functional consequences.</p> Results <p>All three siblings exhibited recurrent infections, refractory diarrhea, and elevated liver enzymes, accompanied by profound T-cell lymphopenia with preserved B-cell numbers. Whole-exome sequencing revealed a homozygous <i>TRAC</i> variant in the affected siblings and heterozygous carriage in their parents. The variant alters a highly conserved residue, disrupting hydrogen bonding and likely destabilizing the protein structure. Functional assays demonstrated a marked reduction in recent thymic emigrants (RTEs) cell ratio absence of TCRαβ⁺ T cells, skewed Th polarization, and elevated proinflammatory cytokine levelsfindings consistent with a SCID phenotype.</p> Conclusion <p>These findings expand the clinical and molecular spectrum of <i>TRAC</i>-related immunodeficiency and support its inclusion among genes primarily associated with SCID. The results further emphasize that specific mutation sites within immune-related genes critically influence disease severity and phenotype variability.</p>

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A Novel Pathogenic Variant in TRAC Gene Associated with SCID Phenotype: Expanding the Genetic and Clinical Spectrum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Mehmet Ali Karaselek,
  • Mehmet Yavuz Ozbey,
  • Vedat Uygun,
  • Serkan Kuccukturk,
  • Necdet Karabey,
  • Ugur Tokdemir,
  • Gokhan Ozel,
  • Zeynep Dilruba Demircioglu,
  • Serhat Yildirim,
  • Ali Sahin,
  • Tugce Duran,
  • Abdullah Akkus,
  • Selman Yildirim,
  • Sukru Guner,
  • İsmail Reisli,
  • Sevgi Keles

摘要

Purpose

Pathogenic variants in the T-cell receptor alpha constant (TRAC) gene have been primarily associated with combined immunodeficiency (CID). To date, only five patients from three unrelated families harboring the same TRAC variant with a CID phenotype, and three patients carrying a distinct variant with severe combined immunodeficiency (SCID), have been described. We report a previously unreported homozygous TRAC variant causing a premature stop codon in three siblings with classical SCID phenotype.

Methods

Comprehensive immunological and molecular analyses were performed, including lymphocyte immunophenotyping, proliferation assays, qPCR for T helper (Th) subset–related gene expression, and cytokine secretion profiling. In silico analyses included conservation assessment, structural modeling using ChimeraX, and protein stability prediction via PremPS to evaluate the variant’s structural and functional consequences.

Results

All three siblings exhibited recurrent infections, refractory diarrhea, and elevated liver enzymes, accompanied by profound T-cell lymphopenia with preserved B-cell numbers. Whole-exome sequencing revealed a homozygous TRAC variant in the affected siblings and heterozygous carriage in their parents. The variant alters a highly conserved residue, disrupting hydrogen bonding and likely destabilizing the protein structure. Functional assays demonstrated a marked reduction in recent thymic emigrants (RTEs) cell ratio absence of TCRαβ⁺ T cells, skewed Th polarization, and elevated proinflammatory cytokine levelsfindings consistent with a SCID phenotype.

Conclusion

These findings expand the clinical and molecular spectrum of TRAC-related immunodeficiency and support its inclusion among genes primarily associated with SCID. The results further emphasize that specific mutation sites within immune-related genes critically influence disease severity and phenotype variability.