RHOH – Epidermodysplasia Verruciformis

This comprehensive summary delineates the association between RHOH and epidermodysplasia verruciformis. Multiple independent studies provide robust evidence that biallelic loss‑of‑function variants in RHOH underlie a distinct immunodeficiency characterized by T cell defects and susceptibility to EV‑HPV infections. The clinical phenotype includes persistent viral warts and an increased risk for skin carcinomas in affected individuals. Such findings are of paramount importance for diagnostic evaluation and personalized therapeutic decisions. In these studies, the identified gene defects were found to be inherited in an autosomal recessive manner. This relationship is clinically significant as it directs targeted genetic testing in patients with unexplained EV‑HPV infection (PMID:22850876).

Genetic investigations have revealed at least two distinct homozygous variants in independent families. One study reported a stop‐gain variant, c.114C>G (p.Tyr38Ter), observed in two young adult siblings, while another identified a germline homozygous missense variant, c.245G>A (p.Cys82Tyr), in a 21‑year‑old male with recurrent infections. Both variants are consistent with a loss‑of‑function mechanism, supporting the assertion of an autosomal recessive mode of inheritance. The presence of the recurrent c.114C>G (p.Tyr38Ter) variant adds considerable weight to the association. Moreover, additional affected relatives in these families demonstrated co‐segregation of the genotype with the clinical phenotype. These findings provide solid genetic evidence that underpins the association (PMID:22850876, PMID:38775840).

Functional studies have further corroborated the role of RHOH in immune regulation. In vivo murine models, as well as in vitro cellular assays, have demonstrated that RHOH deficiency leads to marked T cell dysfunction, including impaired T cell receptor signaling and abnormal expression of key integrins. Rescue experiments in Rhoh‑null mice showed that expression of the wild‑type allele corrected the lymphopenia and associated immunologic defects. These experimental data solidify the mechanism by which RHOH dysfunction predisposes individuals to chronic EV‑HPV infections. The consistency between the cellular findings and the clinical manifestations reinforces the functional evidence for this gene–disease relationship. As such, these studies lend moderate experimental support to the association (PMID:22850876, PMID:38775840).

Segregation data from the reported families further validate the association. In the study featuring the c.114C>G (p.Tyr38Ter) variant, the affected siblings provided evidence for intrafamilial co‑segregation, with one affected relative observed in a family with an index case. Similarly, the case involving the c.245G>A (p.Cys82Tyr) variant documented an affected sibling who succumbed to lung infection, reinforcing the autosomal recessive pattern. This pattern of segregation across independent families attests to the clinical relevance of RHOH mutations in the pathogenesis of epidermodysplasia verruciformis. The combined segregation data, though modest in numeric count, contributes significantly to the overall evidence when integrated with genetic and functional findings. These convergent lines of evidence enhance confidence in the clinical interpretability of the genetic findings (PMID:22850876, PMID:38775840).

By integrating the case‐report, segregation, and functional data, the association between RHOH mutations and epidermodysplasia verruciformis emerges as robust and clinically meaningful. The consistency of the autosomal recessive inheritance pattern, the identification of definitive loss‑of‑function variants, and the experimental demonstration of impaired T cell function collectively support a strong gene–disease relationship. Although the total number of probands is modest, the convergent evidence from independent studies exceeds the minimum threshold for a strong association under the ClinGen framework. The reported data not only inform diagnostic decision‑making but also guide risk stratification and future therapeutic research.

Key take‑home: The strong association between biallelic RHOH loss‑of‑function variants and epidermodysplasia verruciformis provides a powerful rationale for including RHOH in genetic testing panels for patients presenting with persistent EV‑HPV infections and T cell deficiencies.

References

• The Journal of clinical investigation • 2012 • Human RHOH deficiency causes T cell defects and susceptibility to EV‑HPV infections PMID:22850876
• Journal of clinical immunology • 2024 • A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections PMID:38775840

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