PTCRA

Inheritance Pattern: AR

Disease ID:MONDO:0975761

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0975761

Submitter: ClinGen

*PTCRA* was first reported in relation to autosomal recessive Combined Immunodeficiency due to autosomal recessive pre-TCR alpha deficiency (previously IMD26) in 2024 (Materna et al., PMID: 38422122). Combined Immunodeficiency due to autosomal recessive pre-TCR alpha deficiency presents with a highly variable phenotype. Patients have increased susceptibility to recurrent infections, which may be mild or severe and can occur at any age, but often in 20s or 30s, a small or absent thymus, newborn screening positive for decreased TRECs (though may not develop clinical features), and T-cell abnormalities with impaired development of alpha/beta T cells. 7 variants (missense, nonsense, frameshift, large deletion) that have been reported in 7 probands in 2 publications (PMIDs: 38422122, 39805825) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models and in vitro functional assays (PMIDs: 38422122, 10570293, 9208843). Knockout of *Ptcra* in mice result in decreased CD4+ and CD8+ T cells. This can be rescued with the expression of *Ptcra* lacking its cytoplasmic tail. Additionally, CD34+ patient cells with loss of function variants do not differentiate into alpha beta T cells at the same rate as control cells do. In summary, there is definitive evidence supporting the relationship between *PTCRA* and AR Combined Immunodeficiency due to autosomal recessive pre-TCR alpha deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date December 18th 2025 (SOP Version 11).