Submission Details

PTPRC was first reported in relation to severe combined immunodeficiency, T cell-negative, B cell-positive, NK cell-positive disease in 2000 (Kung C et al., 2000, PMID:10700239). PTPRC deficiency is an autosomal recessive disease that is usually diagnosed at the time of newborn screening (where applicable) and otherwise the first 6 months of life. If untreated, PTPRC deficiency SCID leads to death usually within the first year. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms (including Candida albicans, Pneumocystis carinii, and cytomegalovirus). It is characterized by failure to thrive (linked to the recurrent infections), normal or elevated numbers of natural killer cells (NK) and peripheral blood B cells, absent or very low peripheral blood T cells (severe T cell lymphopenia) and low or absent immunoglobulins. Patients also present with pancytopenia and decreased T-cell proliferation in response to mitogen. The curation of PTPRC related to autosomal recessive severe combined immunodeficiency with MONDO:0012163 ID (T cell-negative, B cell-positive, NK cell-positive) includes both case-level and experimental evidence. Five variants (one missense, one in-frame indel, one nonsense, one frameshift and one large deletion (that spans over part of PTPRC gene but has unknown size and boundaries)) reported in four probands in four publications (PMIDs: 10700239, 11145714, 22689986 and 26915675) are included in this curation. A score of 6.2 points for genetic evidence has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease association is also supported by animal models, biochemical function and expression assays (PMIDs: 8334701, 8666928, 22724066, 2550143, 7428806, 8943569, 8428589, 1380033 and 28735895). Phenotypes of mice with PTPRC mutations were consistent with patients’ phenotypes, presenting normal or elevated numbers of B cells and low numbers or nearly absent mature T cells. Expression studies of CD45 in bone marrow and lymphoid tissues is consistent with the immunodeficiency associated with CD45 variation (PMID:7428806). Up-regulation of CD45 during positive selection is consistent with the stalling of T-cell maturation at the CD4+ CD8+ double-positive stage observed in patients with SCID due to CD45 variation (PMID: 8943569). CD45 is a phosphatase necessary for the activation of the kinase Lck (PMID: 8428589) that is critically needed to transduce signals downstream of T cell receptor triggering (PMID: 1380033). CD45 modulates Lck by dephosphorylating Tyrosine residues and it was observed that some of these residues and their phosphorylation status play an active part in the interaction between these two proteins (PMID: 28735895). CD45 has a large, heavily glycosylated extracellular domain, and this aspect plays important (and non-enzymatic) roles in activation of T cells and B cells by regulating the physical closeness of cell-surface molecules on antigen presenting cells with counter molecules on T cells. CD45 is alternately spliced upon activation of T cells, which regulates its physical size. A score of 6 points for experimental evidence has been reached, increasing the total score to 12.2 points. In summary, PTPRC is definitively associated with autosomal recessive severe combined immunodeficiency, T cell-negative, B cell-positive, NK cell-positive. 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 the meeting date December 16, 2021 (SOP Version 8).