Biallelic germline variants in LCP2 (SLP76) were first reported in relation to combined T and B cell immunodeficiency in 2020 (PMID: 33231617). Patients with LCP2-related combined immunodeficiency demonstrate recurrent fungal infections with T cell dysfunction and associations with EBV-related infection and lymphoproliferation, platelet dysfunction and neutrophil dysfunction. Four variants were identified in the literature and are composed of missense, splice site and frameshift mutations (PMID: 33231617,36474126, 37211057). Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have not been reported to have a clinical phenotype.
LCP2 encodes for the protein SLP76, an important intermediate of T cell receptor signaling. Following T cell activation, SLP76 is recruited to membrane bound phosphorylated LAT by Gads and mediates the phosphorylation of ITK, resulting in the phosphorylation and PLC-gamma1. Activation of PLC-gamma1 is required for the initiation of the NFAT and MAPK signaling pathways, both of which are required for the generation of functional T cell signaling. A combination of cell lines and animal models have helped to identify the role SLP76 plays in the immune system. Studies in cell lines have identified interacting partners of SLP76, as well as important domains of the protein required for supporting T cell receptor signaling (PMID:7706237, 17420479, 10556826, 9665884, 16354835, 9257823). Mouse models of total SLP76 deficiency replicate peripheral T cell deficiency and platelet defect identified in patients (PMID: 9695951, 9884330). In these models, SLP76 deficient cells demonstrate a developmental block during double negative thymocyte development, leading to an absence of peripheral T cells (PMID: 9695951). Mouse models studying the impact of individual domains of SLP76 have shown different severity of thymocyte development block and resulting peripheral T cell survival, suggesting genotype-phenotype correlations (PMID: 11792851). This may be evident in the identified patients, as the age and presenting symptoms of the patients are varied.
In summary, there is definitive evidence to support this gene-disease relationship. This association 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 Working Group on 2/15/2024 (SOP Version 9).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.