CD8A

Inheritance Pattern: AR

Disease ID:MONDO:0012161

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012161

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012161

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012161

Submitter: ClinGen

*CD8A* was first reported in relation to an autosomal recessive CD8 deficiency in 2001 (de la Calle-Martin O, et al., 2001, PMID:11435463). The symptomatic cases presented with recurrent respiratory infections, bronchiolitis, recurrent otitis media and pneumonia. All cases had a complete absence of CD8-positive T cells and an increase in double-negative alpha-beta T cells. The curation of *CD8A* related to autosomal recessive susceptibility to respiratory infections associated with CD8alpha chain mutation (*CD8A* deficiency) with MONDO ID 0012161 includes both case-level and experimental evidence. To date, only five individuals from three families have been reported, all homozygous for the same mutation and all from consanguineous families of Spanish or Portuguese Gipsy community. The authors hypothesized that these families might be descendants of a common founder. One of the 25 year-old probands had two younger siblings that were homozygous for the same mutation but were asymptomatic. Four familial carriers of the mutation were reportedly asymptomatic but had a lower MFI of CD8 detected on T cells by flow cytometry. The same missense variant is reported in three probands in three publications (PMIDs:11435463, 17658607 and 26563160) and these are included in this curation. A score of 1.7 points for genetic evidence has been reached. This gene-disease association is also supported by animal model and functional alteration (PMIDs: 11435463, 1673361 and 21546492). Phenotypes of mice with CD8A mutations were consistent with patients’ phenotypes, presenting an absence of CD8 expression in the surface of T cells. Like in humans, CD8B expression on the surface of lymphocytes was also absent in homozygous mutants. T cells from the mutant mice also showed a lack of specific cytotoxic activities both to allogeneic cells and viruses. In proliferation assays, the mutant murineT cells responded well to MHC class II alloantigens but not to MHC class I alloantigens. Functional alterations were also observed in patient and non-patient cells. In patient cells (PMID: 21546492) there was complete absence of CD8 expression on the surface and a higher than normal proportion of double negative (DN) T cells. When analyzed, these DN T cells had effector T cells properties for one of the patients’ cells and effector memory T cells for the other. On proliferation assays with mitogens the patient’s DN T cells proliferated less than the CD4+ cells from the patient and less than the CD8+ T cells from control. TRECs in DN T Cells were also lower in number than the CD8+ from controls and the former also exhibited a skewed repertoire of TCR Vβ. On non-patient cells transfected with WT or CD8A bearing the patient mutation, CD8 expression was ablated whereas mutations in other areas did not produce the same effect. When producing single mutants in COS-7 cells via direct mutagenesis, it was observed that WT cells mutated to either CD8ser90 or CD8arg90 abolished expression, whereas CD8ser90 (mutation in patients) reverted to CD8gly90 (WT) re-established expression, showing the importance of that amino acid to protein expression on the surface. A score of 4 points for experimental evidence has been reached, increasing the total score to 5.7 points. In summary, this curation reached a level of Limited due to the small number of published patients, bearing the same mutation. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen SCID-CID Working Group on the meeting date August 18, 2022 (SOP Version 9). CD8A’s curation and existing evidence was re-examined in October 2025 (SOP version 11) and no new cases or contradictory evidence were reported since the last curation. The total score of 5.7 points and “Limited” classification remain unchanged.