Brooke-Spiegler syndrome

Summary

Brooke-Spiegler syndrome (MONDO:0011512) is a disease caused by CYLD (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CYLD (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 132
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0031024	Cylindroma	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Frequent (30-79%)
HP:0000464	Abnormality of the neck	Frequent (30-79%)
HP:0001965	Abnormality of the scalp	Frequent (30-79%)
HP:0012842	Skin appendage neoplasm	Frequent (30-79%)
HP:0025367	Trichoepithelioma	Frequent (30-79%)
HP:0200036	Skin nodule	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002671	Basal cell carcinoma	Occasional (5-29%)
HP:0007606	Multiple cutaneous malignancies	Occasional (5-29%)
HP:0010732	Nodular changes affecting the eyelids	Occasional (5-29%)
HP:0025512	Skin-colored papule	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000372	Abnormality of the auditory canal	Very rare (<1-4%)
HP:0000505	Visual impairment	Very rare (<1-4%)
HP:0010287	Abnormality of the submandibular glands	Very rare (<1-4%)
HP:0010288	Abnormality of the sublingual glands	Very rare (<1-4%)
HP:0010628	Facial palsy	Very rare (<1-4%)
HP:0100684	Salivary gland neoplasm	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Brooke-Spiegler syndrome
Mondo ID	MONDO:0011512
OMIM	605041
Orphanet	79493
DOID	DOID:0050693
NCIT	C205541
SNOMED CT	703531009
UMLS	C1857941
MedGen	346703
GARD	0010179
Is cancer (heuristic)	no

Also known as: Brooke-Spiegler syndrome · BRSS · CYLD cutaneous syndrome

Data availability: 132 ClinVar variants · 3 GenCC gene-disease records.

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

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (2): familial cylindromatosis, familial multiple trichoepithelioma

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

132 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 31 benign, 13 pathogenic, 7 benign/likely benign, 5 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267230	NM_001378743.1(CYLD):c.968_977del (p.Ser323fs)	CYLD	Pathogenic	criteria provided, single submitter
267232	NM_001378743.1(CYLD):c.1112C>A (p.Ser371Ter)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
267235	NM_001378743.1(CYLD):c.1537dup (p.Cys513fs)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
267236	NM_001378743.1(CYLD):c.1599dup (p.Val534fs)	CYLD	Pathogenic	criteria provided, single submitter
267245	NM_001378743.1(CYLD):c.2108G>A (p.Arg703Lys)	CYLD	Pathogenic	criteria provided, single submitter
267246	NM_001378743.1(CYLD):c.2138_2139dup (p.Phe714fs)	CYLD	Pathogenic	criteria provided, single submitter
267249	NM_001378743.1(CYLD):c.2299A>T (p.Lys767Ter)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
5253	NM_001378743.1(CYLD):c.2272C>T (p.Arg758Ter)	CYLD	Pathogenic	criteria provided, multiple submitters, no conflicts
5254	NM_001378743.1(CYLD):c.2252del (p.Cys751fs)	CYLD	Pathogenic	no assertion criteria provided
5255	NM_001378743.1(CYLD):c.2172del (p.Val725fs)	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
5261	NM_001378743.1(CYLD):c.1392dup (p.Gly465fs)	CYLD	Pathogenic	no assertion criteria provided
267248	NM_001378743.1(CYLD):c.2291_2295del (p.Lys764fs)	CYLD-AS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1801315	NM_001378743.1(CYLD):c.2616del (p.His871_Tyr872insTer)	CYLD	Likely pathogenic	criteria provided, single submitter
1803149	NM_001378743.1(CYLD):c.2723dup (p.Cys909fs)	CYLD	Likely pathogenic	criteria provided, single submitter
4820185	NM_001378743.1(CYLD):c.2455_2464del (p.Thr819fs)	CYLD-AS2	Likely pathogenic	criteria provided, single submitter
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
1327096	NM_001378743.1(CYLD):c.170A>G (p.His57Arg)	CYLD	Uncertain significance	criteria provided, single submitter
133957	NM_001378743.1(CYLD):c.665C>A (p.Thr222Lys)	CYLD	Uncertain significance	criteria provided, single submitter
267250	NM_001378743.1(CYLD):c.2342T>C (p.Leu781Pro)	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

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	Definitive	Autosomal dominant	Brooke-Spiegler syndrome	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.