Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections

Clin Immunol. 2019 Aug;205:1-5. doi: 10.1016/j.clim.2019.05.003. Epub 2019 May 7.


Here we describe a 10-year-old girl with combined immunodeficiency presenting as recurring chest infections, lung disease and herpetic skin infections. The patient experienced two hematopoietic stem cell transplantations and despite full chimerism, she developed bone marrow aplasia due to adenovirus infection and died at post-transplant day 86. Immunologic investigation revealed low numbers of TRECs/KRECs, a severe reduction of memory B cells, absence of isohemagglutinins, and low IgG levels. Whole exome sequencing (WES) identified a novel heterozygous mutation in RAC2(c.275A > C, p.N92 T). Flow cytometric investigation of neutrophil migration demonstrated an absence of chemotaxis to fMLP. Cell lines transfected with RAC2 [N92 T] displayed characteristics of active GTP-bound RAC2 including enhanced NADPH oxidase-derived superoxide production both at rest and in response to PMA. Our findings broaden the clinical picture of RAC2 dysfunction, showing that some individuals can present with a combined immunodeficiency later in childhood rather than a congenital neutrophil disease.

Keywords: Dominant activating RAC2 mutation; Infantile-onset humoral immunodeficiency; Viral infections.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenovirus Infections, Human
  • B-Lymphocytes
  • Bone Marrow Failure Disorders
  • Child
  • Fatal Outcome
  • Female
  • Hematopoietic Stem Cell Transplantation
  • Heterozygote
  • Humans
  • Immunoglobulins, Intravenous / therapeutic use
  • Immunologic Factors / therapeutic use
  • Immunologic Memory
  • Lymphopenia
  • Mutation
  • Recurrence
  • Severe Combined Immunodeficiency / genetics*
  • T-Lymphocytes
  • Virus Diseases
  • rac GTP-Binding Proteins / genetics*


  • Immunoglobulins, Intravenous
  • Immunologic Factors
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins