EBV-lymphoproliferative diseases (EBV-LPD) are either non-malignant or malignant disorders but overlap may exist between both entities.
We investigated 2 sisters from a consanguineous family. P2.1 presented a combined immune deficiency with recurrent lower respiratory tract infections, epidermodysplasia verruciformis and high chronic EBV viremia (>5 log). P2.2 developed an EBV-LPD at the age of 10 that was considered as an isolated Burkitt leukemia without c-myc rearrangement.
Targeted-sequencing in P2.1 then exome sequencing was performed in both, floowed by T-cell assays.
P2.1 was found to be carrier of a novel hypomorphic homozygous private variation (c.252C>G; p.84C>W) associated with a decreased ZAP70 expression and defects in TCR signaling and activation (total tyrosine phosphorylation, calcium flux, proliferation, degranulation, AICD). Unexpectedly, P2.2 was not carrier of the ZAP70 mutation and did not present any TCR functional defects.
Hence, both patients underwent exome sequencing which revealed a homozygous FAAP24 variation (c.635C>T; p.212T>M) segregating with the disease. The exact same mutation has been previously reported in 2 patients who died from EBV-LPD. Thus, we hypothesized that this mutation was involved in the EBV-LPD of P2.2. FAAP24 is involved in DNA damage response by recruiting Fanconi proteins and regulating cell cycle. Experiments are ongoing to assess these pathways and to test the stimulation between EBV-infected B cells and EBV-specific T cells.
This study highlights the genetic complexity underlying immunological phenotypes within a single family. Additional studies are warranted to characterize the interactions between the ZAP70 and FAAP24 mutations in P2.1 and to understand the function of FAAP24 in EBV immunity.