Submission Details

RAC2 was first reported in relation to autosomal dominant immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia in 2019 (Hsu AP et al., PMID: 30723080). This phenotypically heterogeneous disease is characterized by immunological defects (e.g., decreased B and T lymphopenia, T-cell and neutrophil disfunction, and hypogammaglobulinemia, including reduced IgM, IgA, and IgG) and recurrent and/or severe infections (particularly respiratory infections, but other types of infection, such as cellulitis, meningitis, and sepsis, have been reported). This disease has an age of onset of infancy or early childhood and incomplete penetrance has not been reported to date. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance pattern, and/or phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant neutrophil immunodeficiency syndrome (i.e., autosomal dominant immunodeficiency 73a with defective neutrophil chemotaxis and lymphopenia; OMIM: # 608203), autosomal dominant immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia (OMIM: # 618986), and autosomal recessive immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia (OMIM: # 618987). The split curations for autosomal dominant immunodeficiency 73a with defective neutrophil chemotaxis and lymphopenia and autosomal recessive immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia have been curated separately. Four missense variants that have been reported in 8 probands in 5 publications (PMIDs: 30654050, 30723080, 31071452, 31382036, 31919089) are included in this curation. When family members were available to be genotyped, the variants were found to either be de novo (PMID: 30723080) or inherited from affected family members (PMID: 30654050, 31382036, 31919089). The mechanism of pathogenicity appears to be gain-of-function, as evidenced by an increased reactive oxygen species production and/or proportion of GTP-bound RAC2 (the active form) in the presence of these RAC2 variant, although there are concurrent defects in B-cell, T-cell, and neutrophil populations and/or functions. This gene-disease association is also supported by RAC2 expression being specific to hematopoietic cells and demonstrated roles for RAC2 in regulation of T cell proliferation, B cell survival and proliferation, and neutrophil effector functions, including reactive oxygen species production and chemotaxis (PMID: 2189110, 11581314, 14564009, 14564011). A mouse model expressing a gain-of-function variant reported in a patient was found to recapitulate the immunological features of the disease seen in humans (PMIDs: 30723080). Assessment of patient neutrophils carrying a RAC2 variant revealed significantly increased reactive oxygen species production and proportion of GTP-bound RAC2 and defects in chemotaxis and killing of Staphylococcus aureus compared to control neutrophils (PMID: 30723080, 31382036). In summary, there is strong evidence to support the relationship between RAC2 and autosomal dominant immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia. Three years must elapse from the first proposal of the association to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted.