PTGS1

Inheritance Pattern: AR

Disease ID:MONDO:0011588

Submitter: PanelApp Australia

Inheritance Pattern: SD

Disease ID:MONDO:0011588

Submitter: ClinGen

*PTGS1* was first reported in relation to platelet-type bleeding disorder 12 in 2018 (Bastida JM, et al., 2018, PMID: 28983057). *PTGS1* encodes a dual cyclooxygenase and peroxidase (COX-1), during platelet activation, arachidonic acid is released from membrane phospholipids and metabolized to thromboxane A2 (TXA2) through the actions of COX-1 and TXA2 synthase. An inherited defect in *PTGS1* is specifically linked to defective platelet aggregation with arachidonic acid and absence of the second wave response to epinephrine, ADP and collagen but normal response with TXA2 agonists. Several such patients with mild bleeding have been reported either with autosomal dominant or, more recently, autosomal recessive transmission of variants in *PTGS1* (reviewed in PMID: 33147934). Patients may lack protein or have a functionally defective, potentially dominant negative, but normally expressed enzyme. While the clinical and laboratory phenotype of COX-1 deficiency appear to be well established, the mode of inheritance for this pathology remains to be fully elucidated but is currently curated as semi-dominant to consider both dominant and recessive cases. Thus far, five unique variants (both missense and in-frame deletions) have been reported in five patients from three publications (PMIDs: 32299908, 28983057, 28748566). Additionally, another *PTGS1* missense variant (NM_000962:exon5:c.412T>C (p.W138R)) was identified in an affected mother and her affected son by an expert member of the Hemostasis/Thrombosis GCEP. Both individuals had normal platelet count and size and normal platelet surface glycoprotein expression. In addition, they presented with absent aggregation to AA and and reduced to low dose collagen with a normal response to endoperoxide analog suggesting a cyclooxygenase deficiency. This gene-disease relationship is supported by its biochemical function (PMID: 7947975) in platelet activation and preferential expression at high levels in selected cells, including endothelium, monocytes, platelets, renal collecting tubules, and seminal vesicles (PMID: 18657230). As well as altered function and expression in patients (PMID: 32299908). Additional functional alteration in non-patient cells showed the *PTGS1* N143S variant caused a dominant-negative effect of the COX-1 enzyme activity and reduced downstream TXB2 synthesis (PMID: 33326144) and homozygous mutant mice showed reduced platelet aggregation, which was similar to the patient phenotypes (PMID: 8521478). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.