CD3D – Severe Combined Immunodeficiency

CD3D has been implicated in severe combined immunodeficiency (SCID), a life‐threatening immunodeficiency characterized by the near absence of T lymphocytes, despite the presence of normal numbers of B and NK cells. Multiple independent studies, including case reports and multi‐patient cohorts, have reported homozygous loss‑of‑function mutations and splicing abnormalities in CD3D that segregate with SCID in affected families (PMID:15729559, PMID:15546002). In a Japanese family, for example, a novel homozygous splicing mutation disrupting the acceptor site of intron 2 was identified, leading to aberrant CD3delta transcript processing and subsequent T‑cell developmental arrest. Similarly, a study of Mexican Mennonite children revealed a homozygous CD3D mutation associated with a respiratory presentation of SCID, underscoring the gene’s role in T‑cell differentiation (PMID:24288697).

Genetic evidence further supports an autosomal recessive inheritance pattern. Segregation analysis in several families consistently indicates that affected individuals harbor biallelic CD3D mutations, with additional affected relatives exhibiting the variant in a homozygous state. For instance, multi‐patient studies have identified CD3D mutations in at least three independent families, reinforcing the causative link between CD3D loss‑of‑function and the SCID phenotype (PMID:15546002).

A representative variant reported in these studies is c.279C>A (p.Cys93Ter). This variant results in a premature termination codon leading to a truncated protein, which is consistent with the complete loss of CD3delta function observed in affected individuals. The recurrence of such loss‑of‑function mutations across unrelated families further bolsters the genetic etiology of CD3D‑linked SCID.

Functional assays have demonstrated that CD3D is critical for proper assembly and surface expression of the T‑cell receptor (TCR)/CD3 complex. In vitro studies and animal models show that loss of CD3delta disrupts TCR signaling and thymocyte maturation, processes that are essential for T‑cell development. These mechanistic studies provide important experimental confirmation of the clinical observations and further validate the role of CD3D in SCID pathogenesis (PMID:9126976, PMID:16412509).

It is noteworthy that despite some variability in the clinical phenotype, the convergence of genetic, segregation, and functional data across multiple studies firmly supports a strong association between CD3D mutations and SCID. No significant conflicting evidence has emerged to dispute this relationship. Additional experimental findings beyond the standard ClinGen scoring maximum further strengthen the utility of CD3D testing in the diagnostic evaluation of SCID.

Key Take‑home Sentence: CD3D genetic testing is a critical diagnostic tool for SCID, as loss‑of‑function mutations in this gene consistently disrupt T‑cell development and affirm its role in severe immune deficiency.

References

• European journal of pediatrics • 2005 • Severe combined immunodeficiency caused by a splicing abnormality of the CD3delta gene PMID:15729559
• The Journal of clinical investigation • 2004 • Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3 PMID:15546002
• Canadian respiratory journal • 2014 • The respiratory presentation of severe combined immunodeficiency in two Mennonite children PMID:24288697
• Journal of immunology (Baltimore, Md. : 1950) • 1997 • Role of CD3gamma and CD3delta cytoplasmic domains in cytolytic T lymphocyte functions and TCR/CD3 down-modulation PMID:9126976
• Molecular immunology • 2006 • Different role for mouse and human CD3delta/epsilon heterodimer in preT cell receptor function PMID:16412509

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