Familial multiple trichoepithelioma

Summary

Familial multiple trichoepithelioma (MONDO:0011114) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 114
• Phenotypes (HPO): 4

Clinical features

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Frequent (30-79%)
HP:0002671	Basal cell carcinoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial multiple trichoepithelioma
Mondo ID	MONDO:0011114
Orphanet	867
NCIT	C205364
SNOMED CT	403825008
UMLS	C1275122
MedGen	220890
GARD	0010867
Is cancer (heuristic)	no

Also known as: epithelioma adenoides cysticum · hereditary multiple benign cystic epithelioma · multiple familial trichoepithelioma · trichoepithelioma multiple familial

Data availability: 114 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Brooke-Spiegler syndrome › familial multiple trichoepithelioma

Related subtypes (1): familial cylindromatosis

Subtypes (2): trichoepithelioma, multiple familial, 2, trichoepithelioma, multiple familial, 1

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

114 retrieved; paginated sample, class counts are floors:

68 uncertain significance, 30 benign, 7 benign/likely benign, 5 conflicting classifications of pathogenicity, 3 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5256	NM_001378743.1(CYLD):c.2240_2241del (p.Glu747fs)	CYLD	Pathogenic	no assertion criteria provided
5257	NM_001378743.1(CYLD):c.1826+2T>G	CYLD	Pathogenic	no assertion criteria provided
5258	NM_001378743.1(CYLD):c.2240A>G (p.Glu747Gly)	CYLD	Pathogenic	no assertion criteria provided
5259	NM_001378743.1(CYLD):c.2806C>T (p.Arg936Ter)	CYLD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
319497	NM_001378743.1(CYLD):c.59T>G (p.Ile20Ser)	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319502	NM_001378743.1(CYLD):c.1172T>C (p.Ile391Thr)	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319506	NM_001378743.1(CYLD):c.2145T>C (p.Tyr715=)	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319515	NM_001378743.1(CYLD):c.*779G>A	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319549	NM_001378743.1(CYLD):c.*3148T>C	CYLD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133957	NM_001378743.1(CYLD):c.665C>A (p.Thr222Lys)	CYLD	Uncertain significance	criteria provided, single submitter
319494	NM_001378743.1(CYLD):c.-229G>C	CYLD	Uncertain significance	criteria provided, single submitter
319495	NM_001378743.1(CYLD):c.-124+1988A>G	CYLD	Uncertain significance	criteria provided, single submitter
319496	NM_001378743.1(CYLD):c.-23A>C	CYLD	Uncertain significance	criteria provided, single submitter
319499	NM_001378743.1(CYLD):c.543C>T (p.Tyr181=)	CYLD	Uncertain significance	criteria provided, single submitter
319501	NM_001378743.1(CYLD):c.1166C>G (p.Thr389Arg)	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts
319504	NM_001378743.1(CYLD):c.1503C>T (p.Leu501=)	CYLD	Uncertain significance	criteria provided, single submitter
319512	NM_001378743.1(CYLD):c.*403T>C	CYLD	Uncertain significance	criteria provided, single submitter
319513	NM_001378743.1(CYLD):c.*468A>C	CYLD	Uncertain significance	criteria provided, single submitter
319519	NM_001378743.1(CYLD):c.*1102G>A	CYLD	Uncertain significance	criteria provided, single submitter
319520	NM_001378743.1(CYLD):c.*1245T>C	CYLD	Uncertain significance	criteria provided, single submitter
319521	NM_001378743.1(CYLD):c.*1308A>G	CYLD	Uncertain significance	criteria provided, single submitter
319526	NM_001378743.1(CYLD):c.*1667G>T	CYLD	Uncertain significance	criteria provided, single submitter
319528	NM_001378743.1(CYLD):c.*1746C>T	CYLD	Uncertain significance	criteria provided, single submitter
319529	NM_001378743.1(CYLD):c.*1810A>T	CYLD	Uncertain significance	criteria provided, single submitter
319531	NM_001378743.1(CYLD):c.*1983T>C	CYLD	Uncertain significance	criteria provided, single submitter
319536	NM_001378743.1(CYLD):c.*2305A>T	CYLD	Uncertain significance	criteria provided, single submitter
319539	NM_001378743.1(CYLD):c.*2438G>A	CYLD	Uncertain significance	criteria provided, single submitter
319544	NM_001378743.1(CYLD):c.*2856T>C	CYLD	Uncertain significance	criteria provided, single submitter
319545	NM_001378743.1(CYLD):c.*2975C>T	CYLD	Uncertain significance	criteria provided, single submitter
319550	NM_001378743.1(CYLD):c.*3229C>T	CYLD	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
CYLD	Strong	Autosomal dominant	trichoepithelioma, multiple familial, 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYLD	Orphanet:211	Familial cylindromatosis
CYLD	Orphanet:867	Familial multiple trichoepithelioma

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYLD	HGNC:2584	ENSG00000083799	Q9NQC7	Ubiquitin carboxyl-terminal hydrolase CYLD	gencc,clinvar
CYLD-AS2	HGNC:56848	ENSG00000260616		CYLD antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYLD	Ubiquitin carboxyl-terminal hydrolase CYLD	Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYLD	Protease	yes		CAP-Gly_domain, Peptidase_C19_UCH, USP_CS
CYLD-AS2	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
lateral nuclear group of thalamus	1
lymph node	1
bone marrow	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYLD	294	ubiquitous	marker	lateral nuclear group of thalamus, calcaneal tendon, lymph node
CYLD-AS2	112		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYLD	3,507
CYLD-AS2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYLD	Q9NQC7	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
TNFR1-induced proapoptotic signaling	1	439.2×	0.005	CYLD
TNFR1-induced NF-kappa-B signaling pathway	1	335.9×	0.005	CYLD
Negative regulators of DDX58/IFIH1 signaling	1	326.3×	0.005	CYLD
NOD1/2 Signaling Pathway	1	317.2×	0.005	CYLD
Regulation of TNFR1 signaling	1	223.9×	0.005	CYLD
Ub-specific processing proteases	1	53.1×	0.019	CYLD

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
negative regulation of interleukin-18-mediated signaling pathway	1	16852.0×	0.001	CYLD
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.001	CYLD
ripoptosome assembly involved in necroptotic process	1	5617.3×	0.001	CYLD
protein linear deubiquitination	1	5617.3×	0.001	CYLD
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	2808.7×	0.002	CYLD
regulation of intrinsic apoptotic signaling pathway	1	2407.4×	0.002	CYLD
negative regulation of p38MAPK cascade	1	2106.5×	0.002	CYLD
regulation of necroptotic process	1	1872.4×	0.002	CYLD
positive regulation of protein localization	1	1404.3×	0.002	CYLD
regulation of B cell differentiation	1	1296.3×	0.002	CYLD
necroptotic process	1	1053.2×	0.003	CYLD
positive regulation of T cell receptor signaling pathway	1	766.0×	0.003	CYLD
regulation of tumor necrosis factor-mediated signaling pathway	1	702.2×	0.003	CYLD
homeostasis of number of cells	1	674.1×	0.003	CYLD
protein K63-linked deubiquitination	1	624.1×	0.003	CYLD
regulation of cilium assembly	1	601.9×	0.003	CYLD
negative regulation of JNK cascade	1	561.7×	0.003	CYLD
regulation of microtubule cytoskeleton organization	1	543.6×	0.003	CYLD
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.003	CYLD
negative regulation of type I interferon production	1	495.6×	0.003	CYLD
positive regulation of T cell differentiation	1	455.5×	0.003	CYLD
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.003	CYLD
obsolete negative regulation of NF-kappaB transcription factor activity	1	358.6×	0.004	CYLD
regulation of mitotic cell cycle	1	240.7×	0.006	CYLD
protein deubiquitination	1	177.4×	0.007	CYLD
negative regulation of canonical NF-kappaB signal transduction	1	172.0×	0.007	CYLD
regulation of inflammatory response	1	168.5×	0.007	CYLD
negative regulation of inflammatory response	1	137.0×	0.008	CYLD
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.009	CYLD
Wnt signaling pathway	1	99.7×	0.011	CYLD

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYLD	0	0
CYLD-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CYLD	3	Binding:3

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	1	CYLD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CYLD-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYLD	3	—
CYLD-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.