CD3D was first reported in relation to autosomal recessive immunodeficiency 19 in 2003 (Dadi et al., PMID: 14602880). Immunodeficiency 19 is a T-B+NK+ severe combined immunodeficiency (SCID). Six variants (nonsense, splice site, and intronic) that have been reported in 6 probands in 6 publications are included in this curation (PMID: 14602880, 15546002, 15729559, 28916186, 33628209, 21926461). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Affected individuals typically present in infancy with severe, recurrent infections and very low T cell counts. Hypomorphic phenotypes including Omenn syndrome and leaky SCID with a selective block in alpha beta but not in gamma delta T cell development have also been reported (PMID: 33628209, 21926461). The mechanism of pathogenicity is loss of function.
This gene-disease association is supported by expression studies, protein interactions, functional assays, an animal model, and a rescue assay (PMIDs: 18853439, 31461748, 34249896, 15546002, 9135151). CD3D is expressed in lymphoid tissues and encodes the delta chain of the T-cell receptor (TCR) complex (PMID: 18853439). The TCR is made up of multiple other CD3 chains including epsilon (CD3E gene), gamma (CD3G gene), and zeta (CD247) (PMID: 31461748). We have previously established that these three genes; CD3E, CD3G, and CD247; are definitively associated with severe combined immunodeficiency. A Jurkat cell line with knocked down CD3D shows impaired cell surface expression of TCR complexes, and patient T cells with a CD3D homozygous loss of function variant have blocked T cell differentiation (PMID: 34249896, 15546002). CD3D knockout mice show abnormal alpha beta T cell development which is restored with a CD3D transgene (PMID: 9135151).
In summary, CD3D is definitively associated with autosomal recessive immunodeficiency 19. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on April 21, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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