Adenosine deaminase type 2 deficiency: From rare to common

Deficiency of adenosine deaminase type 2 (DADA2) is an inborn error of immunity caused by biallelic pathogenic variants in the ADA2 gene. DADA2 is characterized by a broad spectrum of clinical features, including inflammatory/vasculitic, hematological, and immunodeficient manifestations. Related to this complex clinical phenotype, which overlaps with other diseases, underdiagnosis of DADA2 can be suspected. Several pathophysiological mechanisms causing DADA2 have been described in recent years; however, a unifying pathomechanism explaining all DADA2 disease manifestations is still lacking. Although DADA2 is considered an autosomal recessive disorder, recently several variants in the ADA2 gene were described to cause DADA2 disease in a heterozygous state, via negative dominance. Data from PheWAS studies in large public databases support this observation. Based on these findings, the prevalence of ADA2-associated phenotypes might be much higher than the estimated 1 in 222,146 individuals. As a result, patients with these phenotypes are likely to be encountered by multiple medical disciplines.