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CD3D – Immunodeficiency 19

CD3D-related immunodeficiency 19 is an autosomal recessive disorder characterized by severe susceptibility to live-attenuated vaccines. To date, a single infant was reported with disseminated Bacillus Calmette-Guérin and rotavirus infections following standard immunization. Genetic testing identified a homozygous nonsense variant, c.128G>A (p.Trp43Ter), causing CD3δ loss-of-function and clinical immunodeficiency. No additional unrelated probands or segregation beyond this index case have been documented (PMID:33354374).

Functional assays have established that CD3δ is essential for T cell receptor (TCR)/CD3 complex assembly and signaling. In a CD3δ- and CD3γ-deficient CTL clone, reconstitution with truncated CD3δ restored surface TCR/CD3 expression and effector functions but impaired ligand-induced down-modulation (PMID:9126976). Moreover, human CD3δ/ε heterodimers rescued pre-TCR function in CD3-deficient mice, confirming CD3δ’s critical role in thymocyte maturation (PMID:16412509). These concordant in vitro and in vivo models support a Moderate level of functional evidence for CD3D haploinsufficiency.

Integrating these data, the single documented case provides Limited genetic evidence for CD3D association with immunodeficiency 19, while mechanistic studies yield Moderate functional support. Additional unrelated cases and segregation analyses are needed to strengthen clinical validity. Key Take-home: Homozygous truncating CD3D variants cause autosomal recessive immunodeficiency 19, warranting CD3D sequencing in infants with severe vaccine-associated infections.

References

  • Case Reports in Immunology • 2020 • Adverse Events of the BCG (Bacillus Calmette-Guérin) and Rotavirus Vaccines in a Young Infant with Inborn Error of Immunity PMID:33354374
  • Journal of Immunology • 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 (preTCR) function: human CD3delta/epsilon heterodimer restores the defective preTCR function in CD3gamma- and CD3gammadelta-deficient mice PMID:16412509

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single proband with homozygous CD3D truncating variant; no additional unrelated cases or segregation

Genetic Evidence

Limited

One homozygous loss-of-function variant in a single family ([PMID:33354374])

Functional Evidence

Moderate

In vitro reconstitution and mouse transgenic models demonstrate essential role of CD3δ in TCR assembly and thymocyte maturation ([PMID:9126976]; [PMID:16412509])