Submission Details

RAC2 was first reported in relation to autosomal dominant neutrophil immunodeficiency syndrome (i.e., immunodeficiency 73a with defective neutrophil chemotaxis and lymphopenia; OMIM: # 608203) in 2000 (Ambruso DR et al., PMID: 10758162). The phenotype associated with this disease is currently emerging in the literature and patients with this disease have been reported with infancy-onset recurrent infections and immunological defects, including neutrophilia, neutrophil functional defects (e.g., impaired chemotaxis and reactive oxygen species production), leukocytosis, and T-cell lymphopenia. 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 73b with defective neutrophil chemotaxis and lymphopenia and autosomal recessive immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia have been curated separately. One missense variant (RAC2 D57N) that has been reported as de novo in two unrelated probands in two publications (PMID: 10758162, 21167572) is included in this curation. Functional evidence supports that this variant causes a functional defect, where RAC2 levels are decreased in patient neutrophils compared to neutrophils from healthy donors and RAC2 D57N displays decreased GTP binding, where GTP-bound RAC2 is the active form, compared to wild-type RAC2 (PMID: 10758162). The mechanism of pathogenicity appears to be dominant negative loss of function. This gene-disease association is also supported by expression studies, functional studies, animal models, and functional alterations observed in patient cells. RAC2 expression is specific to hematopoietic cells and roles for RAC2 in neutrophil effector functions, including chemotaxis, reactive oxygen species production, and phagocytosis, have been demonstrated (PMID: 2189110, 14564009, 23875749). Purified RAC2 D57N protein displayed weaker binding to GTP and a lower rate of exchange of GDP for GTP by a guanine nucleotide-exchange factor compared to wild-type RAC2 (PMID: 11278678). A Zebrafish larva RAC2 knockout model displayed defects in neutrophil migration/chemotaxis and increased susceptibility to infection (PMID: 27837107). Impairment of NADPH oxidase activity and neutrophil differentiation and maturation observed in cells expressing RAC2 D57N was abrogated upon deletion of the TQQKRP motif near the RAC2 C-terminus (PMID: 12176888). Furthermore, neutrophils isolated from patients expressing RAC2 D57N had defects in chemotaxis, phagocytosis, granule release, and reactive oxygen species production compared to neutrophils from healthy donors (PMID: 10758162, 10961859). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.