T-cell immunodeficiency with epidermodysplasia verruciformis

Summary

T-cell immunodeficiency with epidermodysplasia verruciformis (MONDO:0017925) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 84

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	T-cell immunodeficiency with epidermodysplasia verruciformis
Mondo ID	MONDO:0017925
Orphanet	324294
UMLS	C4749500
MedGen	1648416
GARD	0017483
Is cancer (heuristic)	no

Also known as: T-cell immunodeficiency due to RHOH deficiency

Data availability: 84 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › T-cell immunodeficiency with epidermodysplasia verruciformis

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

84 retrieved; paginated sample, class counts are floors:

47 likely benign, 34 uncertain significance, 2 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1015888	NM_004310.5(RHOH):c.202A>G (p.Ile68Val)	RHOH	Uncertain significance	criteria provided, single submitter
1024903	NM_004310.5(RHOH):c.496G>A (p.Ala166Thr)	RHOH	Uncertain significance	criteria provided, single submitter
1056822	NM_004310.5(RHOH):c.530G>A (p.Arg177Gln)	RHOH	Uncertain significance	criteria provided, single submitter
1356356	NM_004310.5(RHOH):c.470G>A (p.Arg157Gln)	RHOH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1365400	NM_004310.5(RHOH):c.538A>T (p.Arg180Trp)	RHOH	Uncertain significance	criteria provided, single submitter
1380928	NM_004310.5(RHOH):c.226G>C (p.Ala76Pro)	RHOH	Uncertain significance	criteria provided, single submitter
1401164	NM_004310.5(RHOH):c.89C>T (p.Pro30Leu)	RHOH	Uncertain significance	criteria provided, single submitter
1406547	NM_004310.5(RHOH):c.329del (p.Pro110fs)	RHOH	Uncertain significance	criteria provided, single submitter
1437482	NM_004310.5(RHOH):c.436A>C (p.Lys146Gln)	RHOH	Uncertain significance	criteria provided, single submitter
1445989	NM_004310.5(RHOH):c.263A>G (p.His88Arg)	RHOH	Uncertain significance	criteria provided, single submitter
1482421	NM_004310.5(RHOH):c.422A>G (p.Gln141Arg)	RHOH	Uncertain significance	criteria provided, single submitter
1490780	NM_004310.5(RHOH):c.188A>T (p.Asp63Val)	RHOH	Uncertain significance	criteria provided, single submitter
1494921	NM_004310.5(RHOH):c.331G>C (p.Val111Leu)	RHOH	Uncertain significance	criteria provided, single submitter
1517425	NM_004310.5(RHOH):c.29T>C (p.Val10Ala)	RHOH	Uncertain significance	criteria provided, single submitter
1719148	NM_004310.5(RHOH):c.310A>G (p.Ser104Gly)	RHOH	Uncertain significance	criteria provided, multiple submitters, no conflicts
1914602	NM_004310.5(RHOH):c.401T>C (p.Met134Thr)	RHOH	Uncertain significance	criteria provided, single submitter
1994043	NM_004310.5(RHOH):c.101A>G (p.Lys34Arg)	RHOH	Uncertain significance	criteria provided, single submitter
1999983	NM_004310.5(RHOH):c.190G>T (p.Ala64Ser)	RHOH	Uncertain significance	criteria provided, single submitter
2098100	NM_004310.5(RHOH):c.503G>A (p.Arg168Gln)	RHOH	Uncertain significance	criteria provided, single submitter
2191555	NM_004310.5(RHOH):c.395A>G (p.Asn132Ser)	RHOH	Uncertain significance	criteria provided, single submitter
2816124	NM_004310.5(RHOH):c.415C>G (p.Leu139Val)	RHOH	Uncertain significance	criteria provided, single submitter
2870791	NM_004310.5(RHOH):c.515A>G (p.Asn172Ser)	RHOH	Uncertain significance	criteria provided, single submitter
3606424	NM_004310.5(RHOH):c.205C>T (p.Arg69Trp)	RHOH	Uncertain significance	criteria provided, single submitter
3618973	NM_004310.5(RHOH):c.95C>T (p.Ala32Val)	RHOH	Uncertain significance	criteria provided, single submitter
3648732	NM_004310.5(RHOH):c.224A>C (p.Gln75Pro)	RHOH	Uncertain significance	criteria provided, single submitter
3654266	NM_004310.5(RHOH):c.166C>T (p.Leu56Phe)	RHOH	Uncertain significance	criteria provided, single submitter
4715008	NM_004310.5(RHOH):c.464G>A (p.Ser155Asn)	RHOH	Uncertain significance	criteria provided, single submitter
477860	NM_004310.5(RHOH):c.537_539del (p.Arg181del)	RHOH	Uncertain significance	criteria provided, single submitter
4797587	NM_004310.5(RHOH):c.311G>A (p.Ser104Asn)	RHOH	Uncertain significance	criteria provided, single submitter
577507	NM_004310.5(RHOH):c.181G>A (p.Gly61Ser)	RHOH	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RHOH	Strong	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RHOH	Orphanet:324294	T-cell immunodeficiency with epidermodysplasia verruciformis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHOH	HGNC:686	ENSG00000168421	Q15669	Rho-related GTP-binding protein RhoH	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RHOH	Rho-related GTP-binding protein RhoH	Negative regulator of hematopoietic progenitor cell proliferation, survival and migration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RHOH	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
lymph node	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHOH	174	broad	marker	bone marrow cell, lymph node, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHOH	4,044

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOH	Q15669	92.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOH GTPase cycle	1	308.6×	0.003	RHOH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mast cell activation	1	2407.4×	0.003	RHOH
positive regulation of T cell differentiation	1	455.5×	0.007	RHOH
T cell differentiation	1	383.0×	0.007	RHOH
small GTPase-mediated signal transduction	1	183.2×	0.009	RHOH
negative regulation of canonical NF-kappaB signal transduction	1	172.0×	0.009	RHOH
actin filament organization	1	118.7×	0.011	RHOH
regulation of DNA-templated transcription	1	31.6×	0.036	RHOH
signal transduction	1	16.1×	0.062	RHOH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RHOH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RHOH	3.6.5.2	small monomeric GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	RHOH
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RHOH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.