CD28

Inheritance Pattern: AR

Disease ID:MONDO:0971177

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0971177

Submitter: ClinGen

CD28 was first reported in relation to autosomal recessive immunodeficiency 123 with HPV-related verrucosis in 2021 (Beziat et al., 34214472). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least one missense variant that affects mRNA splicing has been reported in a consanguineous family where it segregated with disease in three affected family members (PMID: 34214472). They had severe human papillomavirus (HPV)-driven skin papillomatosis ranging from HPV-4-associated skin warts in two patients to HPV-2- associated ‘‘tree man syndrome’’ in one patient. Additional symptoms include increased levels of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia, and a defect in mounting antibody responses to vaccines. Heterozygous carriers were unaffected. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is supported by animal models, expression studies, in vitro functional assays, and rescue in patient cells. CD28 deficient mice are susceptible to MmuPV1 (Mouse papillomavirus type 1). Keratinocytes from affected patients have absent CD28 expression and their T-cells have no detectable p65 phosphorylation in response to CD28 or CD3/CD28 cross-linking. A lentiviral vector expressing the WT CD28 cDNA restored p65 phosphorylation in response to CD28 or CD3/CD28 cross-linking in patient T cells (PMID: 34214472). In summary, there is moderate evidence to support this gene-disease relationship. 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 GCEP on the meeting date October 17, 2024 (SOP Version 11)].