Submission Details

LAT was first reported in relation to autosomal recessive severe combined immunodeficiency due to LAT deficiency in 2016 (Keller et al., PMID: 27242165). Affected individuals have T-B+NK+ severe combined immunodeficiency (SCID), lymphadenopathy, hypogammaglobulinemia, and autoimmune hematologic conditions leading to failure to thrive, severe recurrent infections and splenomegaly. Most affected individuals require bone marrow transplant for survival. Two frameshift variants that have been reported in two probands in two publications (PMIDs: 27242165, 27522155) are included in this curation. Variants in this gene segregated with disease in 4 additional family members. Heterozygous family members did not have symptoms and had normal LAT function, indicating that there is no dominant-negative effect. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by mouse model, protein interactions, expression studies, biochemical function, functional alteration, and rescue studies in cell culture models (PMIDs: 9489702, 10204488, 27522155, 9846483, 10360968). LAT is expressed in T cells, NK cells, and mast cells, but not in B cells or monocytes. When LAT was co-expressed with Lck, Fyn, Syk and ZAP-70 in COS cells, Syc and ZAP-70 showed increased activity toward LAT where Lck and Fyn showed negligible activity. In addition, LAT binds to PLC-γ1, Grb2, and PI3K. Overexpression of LAT mutants blocked TCR-mediated AP-1 and NF-AT transcriptional activity (PMID: 9489702). In vitro expression studies showed disrupted downstream signaling, failure of CD69 upregulation and absence of calcium flux induction upon stimulation, as well as absence of downstream tyrosine phosphorylation (PMID: 27522155). LAT -/- mice had absent T cells, normal B cells. Thymocyte numbers were 10-20 fold lower than in LAT het and LAT WT mice. LAT -/- thymocytes fail to develop beyond the DN CD25+CD44- stage, and there were no mature alpha beta T cells in the lymph nodes and spleens of these mice (PMID: 10204488). Two cell culture models with significantly reduced LAT expression (ANJ3 and J.CaM2) showed rescue of TCR signaling after re-expression of LAT (PMID: 9846483, 10360968). In summary, there is strong evidence to support the relationship between LAT and autosomal recessive severe combined immunodeficiency due to LAT deficiency. Three years must elapse from the first proposal of the association to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen SCID/CID GCEP on April 21, 2022 (SOP Version 8).