Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach

J Allergy Clin Immunol. 2022 Jan;149(1):379-387. doi: 10.1016/j.jaci.2021.04.034. Epub 2021 May 15.


Background: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown.

Objective: We aimed to characterize the functional impact and carrier frequency of ADA2 variants.

Methods: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants.

Results: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals.

Conclusions: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.

Keywords: ADA2 variants; Adenosine deaminase 2; DADA2; carrier frequency; disease prevalence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / blood
  • Adenosine Deaminase / deficiency
  • Adenosine Deaminase / genetics*
  • Algorithms
  • Genetic Predisposition to Disease
  • Genetic Variation
  • HEK293 Cells
  • Humans
  • Immune System Diseases / genetics
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics*


  • Intercellular Signaling Peptides and Proteins
  • ADA2 protein, human
  • Adenosine Deaminase