Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)

Pui Y. Lee*, Erinn S. Kellner, Yuelong Huang, Elissa Furutani, Zhengping Huang, Wayne Bainter, Mohammed F. Alosaimi, Kelsey Stafstrom, Craig D. Platt, Tali Stauber, Somech Raz, Irit Tirosh, Aaron Weiss, Michael B. Jordan, Christa Krupski, Despina Eleftheriou, Paul Brogan, Ali Sobh, Zeina Baz, Gerard LefrancCarla Irani, Sara S. Kilic, Rasha El-Owaidy, M. R. Lokeshwar, Pallavi Pimpale, Raju Khubchandani, Eugene P. Chambers, Janet Chou, Raif S. Geha, Peter A. Nigrovic, Qing Zhou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. Objective: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. Methods: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. Results: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. Conclusions: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

Original languageEnglish
Pages (from-to)1664-1672.e10
JournalJournal of Allergy and Clinical Immunology
Issue number6
StatePublished - Jun 2020
Externally publishedYes


  • Adenosine deaminase 2
  • DADA2
  • bone marrow failure
  • pure red cell aplasia
  • vasculitis


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