ZAP70 was first reported in relation to autosomal recessive combined immunodeficiency in 1994 (Arpaia E, et al., 1994, PMID: 8124727). ZAP70 related combined immunodeficiency is caused by abnormal T-cell receptor signaling with low to absent CD8+ T cells and normal CD3+ and CD4+ T cells numbers. Symptoms include recurrent infections, including severe lower respiratory infections and oral candidiasis, chronic diarrhea, and failure to thrive. Combined immunodeficiencies such as ZAP-70 deficiency or major histocompatibility complex (MHC) class I and II gene expression deficiency may not be detected with the TREC assay as T-cell development is intact beyond the point of T-cell receptor (TCR) gene recombination (PMID: 32579701). Six variants (missense, nonsense, frameshift, and splicing substitutions) that have been reported in six probands in six publications (PMIDs: 8124727, 28124082, 21094993, 30778343, 8202713, 8202712) are included in this curation. Variants in this gene segregated with disease in two additional family members (PMIDs: 27448562). Heterozygous carriers in these families did not show evidence of pathogenicity.The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by animal models, expression studies, biochemical studies, and functional studies in patient cells (PMIDs: 27869819, 8176201, 25092893, 25092893, 8124727). ZAP70 is expressed exclusively in T and NK cell lines and is expressed in all murine and human thymocyte subpopulations (PMID: 8176201). ZAP70 null mice have no detectable ZAP70 expression and absent T cells and when null mice with a tetracycline inducible Zap70 transgene are induced with Zap70 protein, thymocyte generation is partially restored (PMID: 25092893). ZAP70 interacts with the T cell receptor complex via its SH2 domains and is activated by Lck (PMID: 27869819). In summary, ZAP70 is definitively associated with autosomal recessive combined immunodeficiency. 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 January 20, 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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