Case report and review of the literature: immune dysregulation in a large familial cohort due to a novel pathogenicRELAvariant

Abstract

Objective To explore and define the molecular cause(s) of a multi-generational kindred affected by Bechet’s-like mucocutaneous ulcerations and immune dysregulation. Methods Whole genome sequencing and confirmatory Sanger sequencing were performed. Components of the NFκB pathway were quantified by immunoblotting, and function was assessed by cytokine production [IL-6, TNF-α, IL-1β] after lipopolysaccharide (LPS) stimulation. Detailed immunophenotyping of T and B cell subsets was performed in four patients from this cohort. Results A novel variant in the RELA gene, p. Tyr349LeufsTer13, was identified. This variant results in premature truncation of the protein before the serine (S) 536 residue, a key phosphorylation site, resulting in enhanced degradation of the p65 protein. Immunoblotting revealed significantly decreased phosphorylated [p]p65 and pIκBα. The decrease in [p]p65 may suggest reduced heterodimer formation between p50/p65 [NFκB1/RelA]. Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T cell populations in one patient [P1]. P1 also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the other three patients. Conclusion Family members with this novel RELA variant have a clinical phenotype similar to other reported RELA cases with predominant chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet’s syndrome and inflammatory bowel disease (IBD). Here we describe the clinical, immunological, and genetic evaluation of a large kindred to further expand identification of patients with autosomal dominant RELA deficiency, facilitating earlier diagnosis and intervention. The functional impairment of the canonical NFκB pathway suggests that this variant is causal for the clinical phenotype in these patients.

Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity

“…The second report of RELA haploinsufficiency described a patient with autoimmune hematological disorders (neutropenia and thrombocytopenia), splenomegaly, and mild lymphadenopathy associated with RELA heterozygosity (c.736C>T, p.R246*; Comrie et al, 2018 ). In contrast, five cases from a three-generation family harbored a monoallelic single nucleotide deletion, c.1459delC (p.H487Tfs*7), and four cases presented with p.Y349Lfs*13 mutation in the 3′ portion of RELA , which was found to be a DN mutation in the present study ( Adeeb et al, 2021 ; Lecerf et al, 2022 ). Here, we stratified each case into a phenotypic category on the basis of DN or haploinsufficiency ( Table 1 ).…”

“…Using the NF-κB reporter assay, we assessed the impact of increasing the concentrations of the plasmids encoding various RelA mutants while maintaining the concentration of the plasmid encoding the WT RelA protein. Intriguingly, all five mutants, as well as the previously reported but uncharacterized mutants p.H487Tfs*7 and p.Y349Lfs*13 ( Adeeb et al, 2021 ; Lecerf et al, 2022 ), exerted a DN effect in a dose-dependent manner compared with the p.R246* mutant that was used as a control for RELA haploinsufficiency ( Fig. 3 B and Fig.…”

“…Here, we report a novel form of human AD RELA deficiency, with DN mutations in six patients from five unrelated families. Previously, 14 patients from four families with AD RELA haploinsufficiency have been described ( Badran et al, 2017 ; Comrie et al, 2018 ; Adeeb et al, 2021 ; Lecerf et al, 2022 ). The first study reported four cases from a two-generation family with a heterozygous mutation in RELA (c.599 + 1G>A) that caused RELA haploinsufficiency ( Badran et al, 2017 ).…”

“…Recently, four related patients with RELA haploinsufficiency were described with TNF-dependent mucocutaneous ulcerations treatable with infliximab therapy ( Badran et al, 2017 ). Subsequently, two additional affected families were reported: lymphoproliferation with autoimmune cytopenia due to RELA haploinsufficiency ( Comrie et al, 2018 ) or Behçet’s disease associated with heterozygous mutation in the 3′ portion of the RELA gene ( Adeeb et al, 2021 ; Lecerf et al, 2022 ). In the current study, we performed a multicenter survey investigating patients with heterozygous RELA variants.…”

Inborn errors of immunity underlying defective T-cell memory

“…Of note, patients with RELA deficiency have no defects in memory T cells and develop a 'classical' CID exhibiting decreased na€ ıve T cells associated with high proportions of TEMRA cells and senescent T cells [36,37].…”