Novel Genetic Etiologies of PIDs
Preliminary data from this work were accepted and presented as an oral communication at the 21st biennial ESID meeting (October 2024).
Epstein-Barr virus (EBV) is an oncogenic virus. Mostly asymptomatic, primary infection may be complicated by nonmalignant, malignant proliferations, and hemophagocytic lymphohistiocytosis. Infection resolution requires an appropriate cytotoxic T cell response, which depends on sustained T cell expansion. Several inherited EBV susceptibilities are associated with a high risk of complicated infection, which are often characterized by defective T cell expansion.
Four patients with EBV-related diseases and one with severe CMV were analyzed by whole-exome sequencing, in whom six deleterious biallelic compound heterozygous variants were identified in RECQL4. These mutations are predicted to be highly damaging and absent in exome public databases. RECQL4 is a DNA helicase involved in DNA replication initiation and DNA repair. Patients with RECQL4 variants have been previously reported with several autosomal recessive syndromes associated with poikiloderma and an increased risk of cancer. Few rare cases were also reported with immunodeficiency but no EBV-related diseases. An additional patient carrier of a homozygous null variant in RECQL4 presenting severe combined immunodeficiency and a severe RECQL4-related syndrome was studied.
We showed that RECQL4 is upregulated in activated control T cells upon TCR-CD3 activation. In HEK cells, transiently overexpressed RECQL4 variants of the patients result in a reduced or absent RECQL4 expression. In activated T cells from patients, RECQL4 expression is strongly reduced or absent, and T cells exhibit a proliferation defect and an increased activation-induced apoptosis. In Jurkat T cell line, 3 different shRNA-targeting RECQL4 decrease its expression and induce a cell cycle blockade, proliferation arrest, and an increased apoptosis. Similarly in control T cells, silencing RECQL4 results in an expansion disadvantage and an increased apoptosis in the infected cells.
RECQL4 deficiency is associated with impaired T cell expansion that may underlie EBV susceptibility in patients.
