{"id":59785,"date":"2026-03-26T11:00:00","date_gmt":"2026-03-26T10:00:00","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/03\/26\/a-novel-pathogenic-variant-in-trac-gene-associated-with-scid-phenotype-expanding-the-genetic-and-clinical-spectrum\/"},"modified":"2026-03-26T11:00:00","modified_gmt":"2026-03-26T10:00:00","slug":"a-novel-pathogenic-variant-in-trac-gene-associated-with-scid-phenotype-expanding-the-genetic-and-clinical-spectrum","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/03\/26\/a-novel-pathogenic-variant-in-trac-gene-associated-with-scid-phenotype-expanding-the-genetic-and-clinical-spectrum\/","title":{"rendered":"A Novel Pathogenic Variant in TRAC Gene Associated with SCID Phenotype: Expanding the Genetic and Clinical Spectrum"},"content":{"rendered":"<div>\n<p><b>J Clin Immunol<\/b>. 2026 Mar 26. doi: 10.1007\/s10875-026-02003-3. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>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.<\/p>\n<p>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&#8217;s structural and functional consequences.<\/p>\n<p>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 TCR\u03b1\u03b2\u207a T cells, skewed Th polarization, and elevated proinflammatory cytokine levelsfindings consistent with a SCID phenotype.<\/p>\n<p>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.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/41882383\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_campaign=journals&amp;utm_content=8102137&amp;ff=20260326071628&amp;v=2.19.0.post6+133c1fe\">41882383<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1007\/s10875-026-02003-3\">10.1007\/s10875-026-02003-3<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>J Clin Immunol. 2026 Mar 26. doi: 10.1007\/s10875-026-02003-3. Online ahead of print. ABSTRACT 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 &#8230; <a title=\"A Novel Pathogenic Variant in TRAC Gene Associated with SCID Phenotype: Expanding the Genetic and Clinical Spectrum\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/03\/26\/a-novel-pathogenic-variant-in-trac-gene-associated-with-scid-phenotype-expanding-the-genetic-and-clinical-spectrum\/\" aria-label=\"Read more about A Novel Pathogenic Variant in TRAC Gene Associated with SCID Phenotype: Expanding the Genetic and Clinical Spectrum\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[69,42],"tags":[],"class_list":["post-59785","post","type-post","status-publish","format-standard","hentry","category-journal-of-clinical-immunology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/59785","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=59785"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/59785\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=59785"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=59785"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=59785"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}