Discovering patterns in the pathologic significance of non-missense deleterious variants in RELA

Monoallelic RELA variants resulting in haploinsufficiency (HI) have been linked to recurrent mucocutaneous ulcers and enteritis. Heterozygous RELA dominant-negative (DN) variants often exhibit autoinflammatory phenotypes associated with type I interferonopathy beyond those typically associated with RELA-HI variants. The vast majority of documented cases of autosomal dominant (AD) RelA deficiency are caused by non-missense deleterious variants introducing a premature stop codon.

We sought to characterize the clinical manifestations and pathologic significance of RELA variants and to establish the boundary separating RELA-HI and RELA-DN variants to facilitate position-based estimation of the nature of RELA variants.

RELA variants were characterized via a nuclear factor-κB reporter assay, immunoblotting, immunoprecipitation, and electrophoretic mobility shift assay in RELA and NFKB1 double knockout cells.

Eight patients from 5 families with AD RelA deficiency were identified, and all harbored novel RELA variants. A comprehensive functional study using RELA nonsense variants identified amino acid P290 as the boundary between RELA-HI and RELA-DN variants in non-missense deleterious variants. In patients with RELA-DN variants, corticosteroid preparations were relatively ineffective, leading to increased use of biological drugs, mainly anti-TNF agents. We also identified atypical additional variants, including a missense variant and an in-frame variant, and experimentally confirmed their pathogenicity.

The positions of non-missense deleterious variants in RELA allow the estimation of the associated functional changes, facilitating the precise diagnosis of AD RelA deficiency. Conversely, RELA missense variants require functional verification, as their impact cannot be predicted solely from their position.