Mutations in the ADA2 gene (which encodes the ADA2 enzyme) cause deficiency of adenosine deaminase 2 (DADA2). DADA2 is described as a monogenic, autosomal recessive autoinflammatory disease, as individuals who carry a single pathogenic variant of ADA2 are generally defined as asymptomatic carriers. However, some individuals present with clinical symptoms of DADA2 despite being heterozygous carriers of pathogenic ADA2 variants, albeit with no clear disease mechanism.

A study now provides insights into how specific ADA2 variants might cause disease in heterozygous carriers. Corresponding author of the study, Isabelle Meyts, explains “we encountered ten patients from seven kindreds with a typical and often severe DADA2 phenotype, yet they all carried a single pathogenic variant in the ADA2 gene. More interestingly, in two pedigrees there was an autosomal dominant inheritance pattern, albeit with incomplete penetrance. This finding convinced us to pursue this study.”