PDCD1

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0007179

Submitter: ClinGen

The *PDCD1* gene codes programmed cell death protein (PD-1), which is an immune-inhibitory receptor expressed in activated T cells. The PD1 protein is involved in the regulation of T-cell functions and the differentiation of CD4+ T cells into T regulatory cells. In 2021, Ogishi et al identified a homozygous frameshift variant of *PDCD1* c.105dup (p.Thr36HisfsTer) in a child born to consanguineous Turkish parents. The patient suffered from extrapulmonary tuberculosis and autoimmune manifestations including hypothyroidism, diabetes and juvenile idiopathic arthritis with autoimmune antibody positivity. The patient’s leukocytes did not express PD-1 and showed impaired production of IFN-γ and TNF upon mycobacterial stimulation, a similarity to inborn errors of IFN-γ production (PMID: 34183838). In addition to the expression evidence, several animal models recapitulated the phenotype observed in the reported proband and exhibited various degrees of lympho-proliferation and autoimmune disease (PMIDs: 10485649,12847137, 20410257, 27410049). Programmed death-1 (PD-1)-deficient mice showed sensitivity to tuberculosis demonstrated by increased bacterial loads and extensive focal necrotic areas after H37Rv aerosol infection, compared with wild-type mice (PMID: 20624978). It is worth mentioning that PD-1 and its ligand PD-L1, are used as drug targets to develop immune checkpoint blockade therapies for cancer. A series of immune-related adverse events (irAEs) which mimic the autoimmune phenotype reported are induced (PMIDs: 26176400, 35991054 , 37715029). Vulnerability to TB are also reported in cancer patients and macaques on PD-1 blockade (PMIDs: 30651320, 33452107). While there is multiple lines of evidence that fulfilled the experimental maximum score of 6 points, the genetic evidence stood at 2 points because there is a single proband reported at the time of this curation. Therefore, the evidence to support this gene-disease relationship is limited. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Inheritance Pattern: AR

Disease ID:MONDO:0975847

Submitter: PanelApp Australia