ARHGEF1

Inheritance Pattern: AR

Disease ID:MONDO:0032763

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0032763

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0032763

Submitter: ClinGen

ARHGEF1 - Autosomal Recessive, Immunodeficiency 62 ARHGEF1 (Rho Guanine Nucleotide Exchange Factor 1) was first reported in relation to Autosomal Recessive, Immunodeficiency 62 in 2019 (Bouafia et al, PMID: 30521495) . At least 2 unique variants (nonsense and splice acceptor site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data (3 Points): Variants in this gene have been reported in 2 probands in 1 publication (PMID:30521495). Phenotypes described in these probands include recurrent upper and lower respiratory tract infections, recurrent pneumonia, and bronchiectasis. Probands show defective antibody production (including T cell–dependent and –independent vaccine responses to poliovirus, tetanus, diphtheria toxoids, and pneumococcal immunizations). Patients may also have increased susceptibility to varicella zoster virus and herpes simplex virus. There is possibility for T cell defects due to the nature of these viral infections. Experimental Evidence This gene-disease association is supported by animal models, expression studies, protein interaction studies, and functional alteration experiments. The ARHGEF1 gene encodes a member of the guanine nucleotide exchange factor family, which modulates the activities of the RAS superfamily (PMID: 8810315). ARHGEF1 is predominantly expressed in hematopoietic cells and lymphoid tissue (PMID: 9135076) and is specific for the GTPase RhoA (PMID: 30521495, PMID: 8810315). ARHGEF1 is involved in the signaling of G protein-coupled receptors associated with G-alpha 12/13-containing heterotrimeric G proteins (PMID: 11526402, PMID: 30521495). Experimental evidence indicates that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling (PMID: 30521495), and localizing and confining B lymphocytes and myelocytes within their dedicated functional environment. Data suggest that immune deficiency primarily results in intrinsic defects in the trafficking and localization of B lymphocytes, causing a secondary defect in T-cell function. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. The clinical validity classification for this gene-disease relationship has been modified from a moderate classification to limited. The Gene-Disease Clinical Validity SOP requires at least 3 unrelated probands from at least 2 independent reports to get above the Limited classification. This classification was approved by the ClinGen Humoral Defects GCEP Working Group on January 19, 2021(SOP Version 8).