Epidermodysplasia verruciformis

Summary

Epidermodysplasia verruciformis (MONDO:0009176) is a disease caused by TMC6 (GenCC Strong), with 7 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMC6 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 1,374
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001051	Seborrheic dermatitis	Very frequent (80-99%)
HP:0001581	Recurrent skin infections	Very frequent (80-99%)
HP:0002715	Abnormality of the immune system	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0200035	Skin plaque	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0200043	Verrucae	Very frequent (80-99%)
HP:0001053	Hypopigmented skin patches	Frequent (30-79%)
HP:0007565	Multiple cafe-au-lait spots	Frequent (30-79%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0100585	Telangiectasia of the skin	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	epidermodysplasia verruciformis
Mondo ID	MONDO:0009176
MeSH	D004819
Orphanet	302
DOID	DOID:13777
ICD-11	1191479808
NCIT	C126877
SNOMED CT	19138001
UMLS	C0014522
MedGen	41831
GARD	0006357
MedDRA	10052339
Is cancer (heuristic)	no

Also known as: epidermodysplasia verruciformis · EV · Lewandowsky-Lutz dysplasia · Lewandowsky-Lutz syndrome · Lutz-Lewandowsky epidermodysplasia verruciformis

Data availability: 1,374 ClinVar variants · 8 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › immune system disorder › epidermodysplasia verruciformis

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Subtypes (1): epidermodysplasia verruciformis, X-linked

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

600 retrieved; paginated sample, class counts are floors:

274 likely benign, 269 uncertain significance, 31 benign, 18 pathogenic, 5 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455103	NM_152468.5(TMC8):c.94dup (p.Ser32fs)	LOC130061792	Pathogenic	criteria provided, single submitter
1076199	NM_001127198.5(TMC6):c.1942_1943del (p.Met648fs)	TMC6	Pathogenic	criteria provided, single submitter
1437451	NM_001127198.5(TMC6):c.1177C>T (p.Gln393Ter)	TMC6	Pathogenic	criteria provided, single submitter
1452246	NM_001127198.5(TMC6):c.1146dup (p.Val383fs)	TMC6	Pathogenic	criteria provided, single submitter
1454263	NM_001127198.5(TMC6):c.711_715del (p.Ile237fs)	TMC6	Pathogenic	criteria provided, single submitter
1455852	NM_001127198.5(TMC6):c.190C>T (p.Gln64Ter)	TMC6	Pathogenic	criteria provided, single submitter
1456110	NM_001127198.5(TMC6):c.2033C>A (p.Ser678Ter)	TMC6	Pathogenic	criteria provided, single submitter
1460287	NM_001127198.5(TMC6):c.2211C>A (p.Tyr737Ter)	TMC6	Pathogenic	criteria provided, single submitter
1921332	NM_001127198.5(TMC6):c.1053_1056del (p.Phe351fs)	TMC6	Pathogenic	criteria provided, single submitter
2015434	NM_001127198.5(TMC6):c.1698del (p.Phe566fs)	TMC6	Pathogenic	criteria provided, single submitter
2027415	NM_001127198.5(TMC6):c.1354del (p.Val452fs)	TMC6	Pathogenic	criteria provided, single submitter
1068639	NM_152468.5(TMC8):c.568C>T (p.Arg190Ter)	TMC8	Pathogenic	criteria provided, single submitter
1072560	NM_152468.5(TMC8):c.661_662del (p.Leu221fs)	TMC8	Pathogenic	criteria provided, single submitter
1325196	NM_152468.5(TMC8):c.1729G>T (p.Glu577Ter)	TMC8	Pathogenic	criteria provided, single submitter
1349741	NM_152468.5(TMC8):c.1824-1G>C	TMC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1419566	NM_152468.5(TMC8):c.898del (p.Leu300fs)	TMC8	Pathogenic	criteria provided, single submitter
1954704	NM_152468.5(TMC8):c.1207_1208del (p.Lys403fs)	TMC8	Pathogenic	criteria provided, single submitter
1961021	NM_152468.5(TMC8):c.423del (p.Asp142fs)	TMC8	Pathogenic	criteria provided, single submitter
2029511	NM_152468.5(TMC8):c.871_883del (p.Gln291fs)	TMC8	Pathogenic	criteria provided, single submitter
1522815	NM_152468.5(TMC8):c.987+2T>A	TMC8	Likely pathogenic	criteria provided, single submitter
2001621	NM_152468.5(TMC8):c.1534-1G>C	TMC8	Likely pathogenic	criteria provided, single submitter
1008947	NM_001127198.5(TMC6):c.1333G>A (p.Ala445Thr)	TMC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1122634	NM_001127198.5(TMC6):c.526C>T (p.Arg176Cys)	TMC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1433646	NM_001127198.5(TMC6):c.170G>A (p.Arg57Gln)	TMC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1037004	NM_152468.5(TMC8):c.665G>A (p.Arg222Gln)	TMC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1037985	NM_152468.5(TMC8):c.1534-8G>A	TMC8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1347935	NM_001127198.5(TMC6):c.548G>T (p.Arg183Met)	LOC130061786	Uncertain significance	criteria provided, single submitter
1354570	NM_001127198.5(TMC6):c.607G>C (p.Gly203Arg)	LOC130061786	Uncertain significance	criteria provided, single submitter
1447000	NM_001127198.5(TMC6):c.551C>A (p.Thr184Asn)	LOC130061786	Uncertain significance	criteria provided, single submitter
1475963	NM_001127198.5(TMC6):c.628G>A (p.Val210Met)	LOC130061786	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 7 · 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
CIB1	Definitive	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 3	4
TMC6	Definitive	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 1	6
TMC8	Definitive	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 2	5
RHOH	Strong	Autosomal recessive	epidermodysplasia verruciformis, susceptibility to, 4	6
CORO1A	Moderate	Autosomal recessive	epidermodysplasia verruciformis	6
MST1	Moderate	Unknown	epidermodysplasia verruciformis	2
IL7	Supportive	Autosomal recessive	epidermodysplasia verruciformis	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMC6	Orphanet:302	Inherited epidermodysplasia verruciformis
TMC8	Orphanet:302	Inherited epidermodysplasia verruciformis
CIB1	Orphanet:302	Inherited epidermodysplasia verruciformis
CORO1A	Orphanet:228003	Severe combined immunodeficiency due to CORO1A deficiency
IL7	Orphanet:302	Inherited epidermodysplasia verruciformis
RHOH	Orphanet:324294	T-cell immunodeficiency with epidermodysplasia verruciformis
MST1	Orphanet:171	Primary sclerosing cholangitis

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMC6	HGNC:18021	ENSG00000141524	Q7Z403	Transmembrane channel-like protein 6	gencc,clinvar
TMC8	HGNC:20474	ENSG00000167895	Q8IU68	Transmembrane channel-like protein 8	gencc,clinvar
CIB1	HGNC:16920	ENSG00000185043	Q99828	Calcium and integrin-binding protein 1	gencc
CORO1A	HGNC:2252	ENSG00000102879	P31146	Coronin-1A	gencc
IL7	HGNC:6023	ENSG00000104432	P13232	Interleukin-7	gencc
RHOH	HGNC:686	ENSG00000168421	Q15669	Rho-related GTP-binding protein RhoH	gencc
MST1	HGNC:7380	ENSG00000173531	P26927	Hepatocyte growth factor-like protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMC6	Transmembrane channel-like protein 6	Acts as a regulatory protein involved in the regulation of numerous cellular processes.
TMC8	Transmembrane channel-like protein 8	Acts as a regulatory protein involved in the regulation of numerous cellular processes.
CIB1	Calcium and integrin-binding protein 1	Calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis.
CORO1A	Coronin-1A	May be a crucial component of the cytoskeleton of highly motile cells, functioning both in the invagination of large pieces of plasma membrane, as well as in forming protrusions of the plasma membrane involved in cell locomotion.
IL7	Interleukin-7	Hematopoietic cytokine that plays an essential role in the development, expansion, and survival of naive and memory T-cells and B-cells thereby regulating the number of mature lymphocytes and maintaining lymphoid homeostasis.
RHOH	Rho-related GTP-binding protein RhoH	Negative regulator of hematopoietic progenitor cell proliferation, survival and migration.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.29

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
Protease	1	5.2×	0.609
Scaffold/PPI	1	2.5×	0.609
Enzyme (other)	1	1.7×	0.609
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMC6	Other/Unknown	no		TMC_dom, TMC
TMC8	Other/Unknown	no		TMC_dom, TMC
CIB1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CORO1A	Scaffold/PPI	no		WD40_rpt, DUF1899, Trimer_CC
IL7	Other/Unknown	no		IL-7, IL-7/IL-9_CS, IL7_sf
RHOH	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
MST1	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A

Expression context

Cohort genes with no expression data: 0.

7 cohort genes 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
lymph node	2
vermiform appendix	2
bronchial epithelial cell	2
C1 segment of cervical spinal cord	1
spleen	1
bronchus	1
epithelium of bronchus	1
leukocyte	1
monocyte	1
male germ cell	1
sperm	1
bone marrow cell	1
duodenum	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMC6	274	ubiquitous	marker	granulocyte, C1 segment of cervical spinal cord, lymph node
TMC8	209	broad	marker	granulocyte, spleen, vermiform appendix
CIB1	289	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
CORO1A	252	ubiquitous	marker	granulocyte, monocyte, leukocyte
IL7	217	broad	marker	sperm, male germ cell, bronchial epithelial cell
RHOH	174	broad	marker	bone marrow cell, lymph node, vermiform appendix
MST1	134	broad	marker	right lobe of liver, liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RHOH	4,044
CORO1A	3,620
CIB1	2,642
IL7	2,611
TMC6	2,052
TMC8	1,271
MST1	1,172

Intra-cohort edges

A	B	Sources
CIB1	TMC6	string_interaction
CIB1	TMC8	biogrid_interaction, string_interaction
CORO1A	TMC8	string_interaction
RHOH	TMC8	string_interaction
TMC6	TMC8	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CIB1	Q99828	9
IL7	P13232	2
MST1	P26927	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORO1A	P31146	93.25
RHOH	Q15669	92.81
TMC8	Q8IU68	76.77
TMC6	Q7Z403	72.56

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 7 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MST1	1	456.8×	0.010	MST1
Prevention of phagosomal-lysosomal fusion	1	253.8×	0.010	CORO1A
Interleukin-7 signaling	1	63.4×	0.020	IL7
RHOH GTPase cycle	1	61.7×	0.020	RHOH
Neutrophil degranulation	1	4.6×	0.199	TMC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intracellular zinc ion homeostasis	2	137.6×	0.004	TMC6, TMC8
positive regulation of T cell differentiation	2	130.1×	0.004	IL7, RHOH
homeostasis of number of cells within a tissue	2	126.7×	0.004	CORO1A, IL7
extrinsic apoptotic signaling pathway	2	87.5×	0.006	CIB1, IL7
positive regulation of male germ cell proliferation	1	2407.4×	0.007	CIB1
regulation of cAMP-dependent protein kinase activity	1	2407.4×	0.007	MST1
negative regulation of vesicle fusion	1	1203.7×	0.009	CORO1A
uropod organization	1	1203.7×	0.009	CORO1A
negative regulation of actin nucleation	1	1203.7×	0.009	CORO1A
negative regulation of canonical NF-kappaB signal transduction	2	49.1×	0.009	TMC8, RHOH
endomitotic cell cycle	1	802.5×	0.011	CIB1
thymocyte migration	1	802.5×	0.011	CORO1A
actin filament organization	2	33.9×	0.012	CORO1A, RHOH
phagolysosome assembly	1	481.5×	0.014	CORO1A
T cell lineage commitment	1	481.5×	0.014	IL7
obsolete early endosome to recycling endosome transport	1	481.5×	0.014	CORO1A
positive regulation of catalytic activity	1	343.9×	0.015	CIB1
natural killer cell degranulation	1	343.9×	0.015	CORO1A
mast cell activation	1	343.9×	0.015	RHOH
regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	343.9×	0.015	TMC8
interleukin-7-mediated signaling pathway	1	300.9×	0.016	IL7
thrombopoietin-mediated signaling pathway	1	300.9×	0.016	CIB1
positive regulation of cytokine-mediated signaling pathway	1	240.7×	0.019	IL7
protein stabilization	2	19.1×	0.019	TMC6, TMC8
regulation of receptor signaling pathway via JAK-STAT	1	200.6×	0.020	MST1
positive regulation of organ growth	1	200.6×	0.020	IL7
nerve growth factor signaling pathway	1	185.2×	0.020	CORO1A
positive regulation of protein serine/threonine kinase activity	1	185.2×	0.020	CIB1
positive regulation of B cell differentiation	1	160.5×	0.022	IL7
leukocyte chemotaxis	1	150.5×	0.022	CORO1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMC6	0	0
TMC8	0	0
CIB1	0	0
CORO1A	0	0
IL7	0	0
RHOH	0	0
MST1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MST1	91	Binding:91
CIB1	12	Binding:12
CORO1A	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RHOH	3.6.5.2	small monomeric GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	1	MST1
D	Druggable family + AlphaFold only, no drug	1	RHOH
E	Difficult family or no structure, no drug	5	TMC6, TMC8, CIB1, CORO1A, IL7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMC6	0	—
TMC8	0	—
CIB1	12	—
CORO1A	12	—
IL7	0	—
RHOH	0	—
MST1	91	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00973856	Not specified	COMPLETED	Evaluation of the Effectiveness of an Alcohol Based Hand Gel for the Reduction of Warts on the Hands