CD3E – Severe Combined Immunodeficiency

The association between CD3E and severe combined immunodeficiency (SCID) is supported by multiple lines of evidence, including case reports, multi‐patient studies, and functional assays. Overall, the clinical data consistently demonstrate that homozygous or compound heterozygous mutations in CD3E disrupt T‐cell receptor (TCR) signaling, leading to severe immunodeficiency (PMID:24515816).

Genetic evidence is robust. Several independent studies have reported pathogenic variants in CD3E, such as the recurrent splicing and frameshift mutations. One notable example is the variant c.490C>T (p.Arg164Ter), reported in multiple probands (PMID:28597365). Studies indicate that at least 23 probands from diverse families carry deleterious mutations with clear segregation, reinforcing the gene–disease relationship (PMID:15546002).

The inheritance mode is autosomal recessive, with affected individuals typically harboring biallelic loss‐of‐function mutations. Segregation analysis in the reported families has documented additional affected relatives who share the mutant alleles, further substantiating the genetic basis of SCID due to CD3E deficiency.

Functional assays corroborate the genetic findings. Experimental studies have demonstrated that loss of CD3E impairs TCR-mediated signal transduction and disrupts T-cell development, thereby compromising immune function (PMID:9759859). These functional data provide a mechanistic explanation that aligns with the clinical phenotype of SCID.

While some variability in clinical presentation is noted, the convergence of multiple independent case reports, familial segregation patterns, and experimental validations lead to a coherent narrative that supports the pathogenicity of CD3E mutations in SCID.

Key take‑home: The integration of compelling genetic and functional evidence firmly establishes CD3E as a causative gene for severe combined immunodeficiency, underscoring its value in diagnostic decision‑making, therapeutic targeting, and clinical management.

References

• Klinische Padiatrie • 2014 • Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3E deficiency: need for IgG‑substitution 6 years later PMID:24515816
• Immunogenetics • 2017 • A novel pathogenic frameshift variant of CD3E gene in two T‑B+ NK+ SCID patients from Turkey PMID:28597365
• The Journal of clinical investigation • 2004 • Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3 PMID:15546002
• Journal of immunology • 1998 • Impaired TCR-mediated apoptosis and Bcl-XL expression in T cells lacking the stress kinase activator SEK1/MKK4 PMID:9759859

Evidence Based Scoring (AI generated)