Phenotypes of patients with more than one autoinflammatory disease-associated gene variant: overlapping and mixed...

Genetic screening for systemic autoinflammatory disorders (SAIDs) often does not yield a definite diagnosis based on pathogenic variants. Instead, many patients are found to carry combinations of variants of uncertain significance (VUS), either in isolation or alongside pathogenic or likely pathogenic variants. We herein aimed to investigate the relationship between clinical phenotypes and genotypes in patients identified as carriers of variants in ≥2 autoinflammatory genes.

We conducted a retrospective analysis of patients who underwent genetic screening for SAIDs. Inclusion criteria were the presence of variants in ≥2 autoinflammatory genes, including both VUS and pathogenic/likely pathogenic variants. Clinical features were reviewed and compared across genetic profiles.

Forty-four (29.5%) of 149 referred patients were identified as having ≥2 gene variants. Fifteen (36.3%) were classified as familial Mediterranean fever (FMF), and some had non-FMF findings in association with additional variants. An additional five patients were diagnosed with VEXAS syndrome (n = 1), deficiency of adenosine deaminase 2 (DADA2, n = 2), A20 haploinsufficiency (HA20, n = 1), DADA2 and HA20 overlap (n = 1). The remaining patients were grouped as having NLRP1-AID (n = 1), NLRC4-AID (n = 1), NLRP1 and NLRC4-AID (n = 1) overlap, PFAPA-like (n = 2), and Behçet disease-like (n = 7) disorder according to their dominant phenotype. Twelve (27.2%) patients could not be classified into any groups.

The presence of multiple variants in autoinflammatory genes is a common finding in patients with SAID-like symptoms but does not always correlate with a known diagnosis. Follow-up of this group of patients with so-called 'mixed autoinflammatory disorder' (MAID) is necessary for the evaluation of their clinical course and long-term prognosis.