Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers.

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. We investigated the effect of these and additional reported ADA2 missense variants on ADA2 protein expression, secretion, and enzymatic activity. Our studies indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.