PTPRJ

Inheritance Pattern: AD

Disease ID:MONDO:0018630

Submitter: ClinGen

In addition to experimental evidence, there has been 1 report in the literature with an individual harboring a PTPRJ variant (Venkatachalam, 2010; PMID: 21036128). This individual has a 5' duplication of exons 1-11 of PTPRJ, located directly upstream of the wild-type gene. This was assigned 0.5 points for genetic evidence, bringing the total points to 2.0 with a classification of "Limited." The relationship between PTPRJ and Hereditary Nonpolyposis Colon Cancer (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10-9-2018 (SOP Version 6.0). Variants in PTPRJ were first reported in humans with this disease as early as 2010 (Venkatachalam et al). At least 1 variant (multi exon duplication) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 0.5 Points. A multi-exon duplication in this gene has been reported in at least 1 proband. Experimental Evidence: 1.5 Points. This gene-disease association is supported by biochemical function. In summary, there is limited evidence to support this gene-disease relationship. 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:0957578

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0957578

Submitter: ClinGen

The PTPRJ gene encodes a protein tyrosine phosphatase that is a master positive regulator of the activity of SFKs in platelets and megakaryocytes, and, as such, has a central role in controlling the transmission of signals in these cells. PTPRJ was first reported in relation to thrombocytopenia-10 (Marconi et al., PMID:30591527) in a family with thrombocytopenia and small platelet volume inherited in an autosomal-recessive manner. 2 different variants (c.97-2A>G and c.1875del, both leading to frameshifts and premature stop) were identified in 2 members of the family. These are the only patients and the only variants described so far in thrombocytopenia-10. The mechanism of disorder is loss of function. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (expression; functional alteration in patient cells and non-patient cells, non-human model organism). Summary of Case Level Data: 3 POINTS Variants in this gene have been reported in 2 probands in 1 publication (PMID 30591527). Affected patients show thrombocytopenia, small platelet volume, bleeding, defective platelet activation in response to convulxin and TRAP-6, defective aggregation in response to collagen, convulxin and TRAP-6. Summary of Experimental Data: 6.5 POINTS Senis et al. showed that PTPRJ is expressed in platelets by flow cytometry and Western blotting (PMID: 20345711) (Expression A). Marconi et al. showed that PTPRJ is less expressed on platelets of patients with variants in PTPRJ (PMID:30591527) (Expression B). They also showed evidence that megakaryocytes cultured from patients with PTPRJ variants show defective proplatelet formation and migration (functional alteration - Patient cells). DAMI cells knocked down for PTPRJ showed impaired migration as well (functional alteration - Patient cells). Finally, they knockdown ptprj in zebrafish and observe thrombocytopenia (Non-human model organism). Senis et al studied a murine model KO for ptprj, the mouse showed prolonged tail bleeding time, compatible with patients bleeding diathesis (PMID: 20345711) (Non-human model organism). In another mouse model, from Ellison et al, the same platelet aggregation defect of patients is shown (PMID: 20345711). In summary, we obtained moderate association of PTPRJ with thrombocytopenia-10. However, due to the limited genetic data (only one family described), we will maintain the final classification as limited until more genetic evidence becomes available. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 11-04-2024 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0957578

Submitter: Ambry Genetics

Inheritance Pattern: Unknown

Disease ID:MONDO:0005575

Submitter: Labcorp Genetics (formerly Invitae)