RHOH

Inheritance Pattern: AR

Disease ID:MONDO:0009176

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0032666

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0032666

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0032666

Submitter: ClinGen

*RHOH* (Ras homolog family member H) was first identified in 1995 (Dallery et al., PMID: 7784061) and was reported in relation to autosomal recessive susceptibility to epidermodysplasia verruciformis 4 in 2012 (Crequer et al., PMID: 22850876). *RHOH* encodes an atypical Rho GTPase that is hematopoietic‑restricted and GTPase‑deficient, remaining constitutively in a GTP‑bound state. Unlike canonical Rho GTPases that function as molecular switches downstream of immune receptors, *RHOH* acts as an adaptor/regulatory protein essential for proper T‑cell receptor (TCR) signaling and T‑cell development. To date, two unique homozygous *RHOH* variants have been reported in two affected individuals from consanguineous families across two publications (Crequer et al., 2012, PMID: 22850876; Zhou et al., 2024, PMID: 38775840). Reported variants include a predicted loss‑of‑function nonsense variant (p.Tyr38Ter) and a missense variant (p.Cys82Tyr). Affected individuals presented in childhood with persistent EV‑HPV infections, verrucae, and combined immunodeficiency dominated by T‑cell lymphopenia. Functional studies in patient peripheral blood mononuclear cells demonstrated defective T‑cell activation, with failure to proliferate in response to anti‑CD3 stimulation and partial rescue with costimulation or bypass activation (anti‑CD3 plus anti‑CD28, PHA, or PMA/ionomycin), consistent with impaired proximal TCR signaling (PMID: 22850876; PMID: 38775840). Heterozygous parents of individuals with autosomal‑recessive *RHOH* deficiency are clinically unaffected carriers, showing preserved *RHOH* transcript levels, normal T‑cell viability and activation in anti‑CD3/CD28 stimulation assays, and no evidence of immune dysfunction (Zhou et al., 2024). Experimental evidence supports the biological plausibility of this gene–disease relationship. Expression studies demonstrate that *RHOH* is expressed exclusively in hematopoietic tissues and cell lines, with highest expression in thymus and T lymphocytes, supporting relevance to immune development (Li et al., 2002, PMID: 11809807). Protein interaction studies show that *RHOH* physically associates with key proximal TCR signaling proteins, including LCK and ZAP70, regulating their localization and activation at the plasma membrane (Wang et al., 2010, PMID: 20851766; Zhou et al., 2024, PMID: 38775840). Non‑human model organism studies demonstrate that Rhoh‑/‑ mice exhibit impaired thymocyte development, reduced peripheral CD4⁺ and CD8⁺ T‑cell numbers, and defective TCR signaling, closely paralleling the human phenotype (Gu et al., 2006, PMID: 17028588). Rescue experiments further show that transduction of wild‑type *RHOH* into Rhoh‑/‑ bone marrow cells partially restores T‑cell development, whereas patient‑derived mutant alleles fail to rescue, supporting a loss‑of‑function disease mechanism (PMID: 22850876). In summary, there is moderate evidence to support the relationship between RHOH and autosomal recessive epidermodysplasia verruciformis, susceptibility to, 4. While additional unrelated cases would further strengthen this association, no convincing contradictory evidence has emerged. This gene–disease pair was originally evaluated by the ClinGen SCID‑CID Gene Curation Expert Panel on February 17, 2023, at which time the classification was Limited. It was re‑evaluated on April 16, 2026, with consideration of newly published genetic and functional evidence, including an additional affected individual and supporting functional data (Zhou et al., 2024, PMID: 38775840). As a result of this reevaluation, the classification increased from Limited to Moderate.

Inheritance Pattern: AR

Disease ID:MONDO:0032666

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0017925

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0032666

Submitter: Labcorp Genetics (formerly Invitae)