Adenosine deaminase type 2 deficiency: From rare to common

Area of Science:

• Immunology
• Genetics
• Rare Diseases

Background:

• Deficiency of adenosine deaminase type 2 (DADA2) is an inborn error of immunity.
• It results from pathogenic variants in the ADA2 gene and presents with diverse clinical features like inflammation, vasculitis, hematological issues, and immunodeficiency.

Purpose of the Study:

• To explore the potential underdiagnosis of DADA2.
• To investigate emerging evidence suggesting heterozygous ADA2 variants can cause DADA2 via negative dominance.
• To re-evaluate the prevalence and clinical impact of ADA2-associated phenotypes.

Main Methods:

• Review of recent pathophysiological mechanisms.
• Analysis of data from PheWAS studies in large public databases.
• Examination of emerging genetic findings in ADA2 variants.

Main Results:

• A unifying pathomechanism for all DADA2 manifestations is still under investigation.
• Evidence supports that heterozygous ADA2 variants can cause DADA2 disease.
• PheWAS data corroborate the role of heterozygous variants.

Conclusions:

• The prevalence of ADA2-associated phenotypes may be significantly underestimated.
• The condition's complex phenotype and potential for heterozygous inheritance necessitate broader consideration across medical disciplines.
• Further research is needed to fully elucidate DADA2 pathogenesis and diagnostic criteria.