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

Pui Y. Lee, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address: pui.lee@childrens.harvard.edu.
Erinn S. Kellner, Division of Allergy/Immunology, Cincinnati Children's Hospital and University of Cincinnati, Cincinnati, Ohio.
Yuelong Huang, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Elissa Furutani, Dana Farber and Boston Children's Cancer and Blood Disorders Center, Boston, Mass.
Zhengping Huang, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China.
Wayne Bainter, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Mohammed F. Alosaimi, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia.
Kelsey Stafstrom, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Craig D. Platt, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Tali Stauber, Primary Immunodeficiency Clinic, Sheba Medical Center, Jeffrey Modell Foundation, Tel Hashomer, Israel.
Somech Raz, Primary Immunodeficiency Clinic, Sheba Medical Center, Jeffrey Modell Foundation, Tel Hashomer, Israel.
Irit Tirosh, Pediatric Rheumatology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Aaron Weiss, Department of Pediatrics, Maine Medical Center, Portland, Me.
Michael B. Jordan, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio.
Christa Krupski, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio.
Despina Eleftheriou, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom.
Paul Brogan, University College London, Great Ormond Street Institute of Child Health, London, United Kingdom.
Ali Sobh, Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Zeina Baz, Department of Pediatrics, St George Hospital University Medical Center, Beirut, Lebanon.
Gerard Lefranc, Institut de Génétique Humaine, UMR 9002 CNRS-Université de Montpellier, Montpellier, France.
Carla Irani, Internal Medicine & Clinical Immunology Department, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon.
Sara S. Kilic, Department of Pediatric Immunology and Rheumatology, Uludag University Medical Faculty, Bursa, Turkey.
Rasha El-Owaidy, Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt.
M R. Lokeshwar, Department of Pediatrics, Lilavati Hospital and Research Centre, Mumbai, India.
Pallavi Pimpale, SRCC Children's Hospital, Mumbai, India.
Raju Khubchandani, SRCC Children's Hospital, Mumbai, India.
Eugene P. Chambers, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tenn; DADA2 Foundation, Nashville, Tenn.
Janet Chou, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Raif S. Geha, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Peter A. Nigrovic, Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Qing Zhou, Life Sciences Institute, Zhejiang University, Zhejiang, China.

Abstract

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.