RAC2

Inheritance Pattern: AD

Disease ID:MONDO:0011988

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0033555

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011988

Submitter: ClinGen

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.

Inheritance Pattern: AR

Disease ID:MONDO:0033555

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0033555

Submitter: ClinGen

RAC2 was first reported in relation to autosomal recessive immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia in 2015 (Alkhairy OK et al., PMID: 25512081). The phenotype associated with this disease is currently emerging in the literature and patients with this disease have been reported with immunological defects, including B-cell lymphocytopenia, hypogammaglobulinemia, and neutrophil functional abnormalities, and increased susceptibility to infection. 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 leukocytosis and autosomal dominant immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia have been curated separately. Two variants (both nonsense) that have been reported in 2 unrelated probands in 2 publications (PMIDs: 25512081, 31130284) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by RAC2 expression being specific to hematopoietic cells and demonstrated roles for RAC2 in regulation of B cell survival and proliferation and neutrophil effector functions, including chemotaxis and phagocytosis (PMID: 2189110, 14564009, 14564011, 23875749). Neutrophils from a patient homozygous for a loss-of-function RAC2 variant displayed defects in chemotaxis and cytoplasmic granule abnormalities (PMID: 25512081). A RAC2-/- mouse model and Zebrafish larvae model recapitulated several aspects of human disease; specifically, the mouse model presented with hypogammaglobulinemia and increased susceptibility to infection and the Zebrafish model with defects in neutrophil migration/chemotaxis and increased susceptibility to infection (PMID: 11907095, 25512081, 29897791). In summary, there is moderate evidence to the relationship between RAC2 and autosomal recessive immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Inheritance Pattern: Unknown

Disease ID:MONDO:0011988

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0033554

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0011988

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0033555

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0033554

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011988

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0033554

Submitter: ClinGen

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.