Multiple endocrine neoplasia type 4

Summary

Multiple endocrine neoplasia type 4 (MONDO:0012552) is a disease caused by CDKN1B (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: CDKN1B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 863
• Phenotypes (HPO): 39
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000818	Abnormality of the endocrine system	Very frequent (80-99%)
HP:0000843	Hyperparathyroidism	Very frequent (80-99%)
HP:0002897	Parathyroid adenoma	Very frequent (80-99%)
HP:0003072	Hypercalcemia	Very frequent (80-99%)
HP:0003165	Elevated circulating parathyroid hormone level	Very frequent (80-99%)
HP:0008208	Parathyroid hyperplasia	Very frequent (80-99%)
HP:0000825	Hyperinsulinemic hypoglycemia	Frequent (30-79%)
HP:0000845	Elevated circulating growth hormone concentration	Frequent (30-79%)
HP:0000854	Thyroid adenoma	Frequent (30-79%)
HP:0001031	Subcutaneous lipoma	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002044	Zollinger-Ellison syndrome	Frequent (30-79%)
HP:0002574	Episodic abdominal pain	Frequent (30-79%)
HP:0002893	Pituitary adenoma	Frequent (30-79%)
HP:0004398	Peptic ulcer	Frequent (30-79%)
HP:0006767	Pituitary prolactin cell adenoma	Frequent (30-79%)
HP:0006772	Renal angiomyolipoma	Frequent (30-79%)
HP:0008256	Adrenocortical adenoma	Frequent (30-79%)
HP:0008283	Fasting hyperinsulinemia	Frequent (30-79%)
HP:0010615	Angiofibromas	Frequent (30-79%)
HP:0011760	Pituitary growth hormone cell adenoma	Frequent (30-79%)
HP:0011761	Pituitary null cell adenoma	Frequent (30-79%)
HP:0012091	Abnormality of pancreas physiology	Frequent (30-79%)
HP:0012197	Insulinoma	Frequent (30-79%)
HP:0030445	Pulmonary carcinoid tumor	Frequent (30-79%)
HP:0100633	Esophagitis	Frequent (30-79%)
HP:0100634	Neuroendocrine neoplasm	Frequent (30-79%)
HP:0003118	Increased circulating cortisol level	Occasional (5-29%)
HP:0006780	Parathyroid carcinoma	Occasional (5-29%)
HP:0007449	Confetti-like hypopigmented macules	Occasional (5-29%)
HP:0008291	Pituitary corticotropic cell adenoma	Occasional (5-29%)
HP:0010783	Erythema	Occasional (5-29%)
HP:0010788	Testicular neoplasm	Occasional (5-29%)
HP:0012030	Increased urinary cortisol level	Occasional (5-29%)
HP:0012334	Extrahepatic cholestasis	Occasional (5-29%)
HP:0030079	Cervix cancer	Occasional (5-29%)
HP:0030688	Increased glucagon level	Occasional (5-29%)
HP:0100570	Carcinoid tumor	Occasional (5-29%)
HP:0100522	Thymoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple endocrine neoplasia type 4
Mondo ID	MONDO:0012552
MeSH	C567059
OMIM	610755
Orphanet	276152
DOID	DOID:0080137
ICD-11	157945677
NCIT	C157449
SNOMED CT	715907003
UMLS	C1970712
MedGen	373469
GARD	0017275
Is cancer (heuristic)	no

Also known as: CDKN1B multiple endocrine neoplasia · MEN4 · multiple endocrine neoplasia caused by mutation in CDKN1B · multiple endocrine neoplasia type 4 · multiple endocrine neoplasia, type IV

Data availability: 863 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › multiple endocrine neoplasia type 4

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, Brooke-Spiegler syndrome, 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, 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

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:

303 uncertain significance, 142 likely benign, 65 conflicting classifications of pathogenicity, 50 pathogenic, 15 benign, 14 benign/likely benign, 6 likely pathogenic, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068845	NM_004064.5(CDKN1B):c.186del (p.Phe62fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1069229	NM_004064.5(CDKN1B):c.276del (p.Arg93fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1069331	NM_004064.5(CDKN1B):c.80_81del (p.Ser27fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1070862	NC_000012.11:g.(?12870768)(12871886_?)del	CDKN1B	Pathogenic	criteria provided, single submitter
1072624	NM_004064.5(CDKN1B):c.385dup (p.His129fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1072930	NM_004064.5(CDKN1B):c.15_16dup (p.Val6fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1075662	NM_004064.5(CDKN1B):c.174del (p.Lys59fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1386042	NM_004064.5(CDKN1B):c.267_268del (p.Tyr89_Arg90delinsTer)	CDKN1B	Pathogenic	criteria provided, single submitter
1398606	NM_004064.5(CDKN1B):c.460C>T (p.Arg154Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1405782	NM_004064.5(CDKN1B):c.226_227insA (p.Trp76Ter)	CDKN1B	Pathogenic	criteria provided, single submitter
1410246	NM_004064.5(CDKN1B):c.86dup (p.Cys29fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1413501	NM_004064.5(CDKN1B):c.388_392del (p.Leu130fs)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1421490	NM_004064.5(CDKN1B):c.21dup (p.Asn8Ter)	CDKN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1439402	NM_004064.5(CDKN1B):c.421C>T (p.Gln141Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1452550	NM_004064.5(CDKN1B):c.487C>T (p.Gln163Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1453444	NM_004064.5(CDKN1B):c.185dup (p.Asp63fs)	CDKN1B	Pathogenic	criteria provided, single submitter
1455877	NM_004064.5(CDKN1B):c.410del (p.Pro137fs)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1728762	NM_004064.5(CDKN1B):c.319C>T (p.Gln107Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1729610	NM_004064.5(CDKN1B):c.326del (p.Val109fs)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1780338	NM_004064.5(CDKN1B):c.179G>A (p.Trp60Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1780560	NM_004064.5(CDKN1B):c.180G>A (p.Trp60Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
183391	NM_004064.5(CDKN1B):c.59_77dup (p.Ser27fs)	CDKN1B	Pathogenic	no assertion criteria provided
183395	NM_004064.5(CDKN1B):c.374_375del (p.Asn124_Ser125insTer)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
2018951	NM_004064.5(CDKN1B):c.413_414dup (p.Asp139fs)	CDKN1B	Pathogenic	criteria provided, single submitter
2092093	NM_004064.5(CDKN1B):c.396_397insTT (p.Pro133fs)	CDKN1B	Pathogenic	criteria provided, single submitter
2419784	NM_004064.5(CDKN1B):c.375dup (p.Glu126Ter)	CDKN1B	Pathogenic	criteria provided, single submitter
2579973	NM_004064.5(CDKN1B):c.229C>T (p.Gln77Ter)	CDKN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585892	NM_004064.5(CDKN1B):c.169C>T (p.Gln57Ter)	CDKN1B	Pathogenic	criteria provided, multiple submitters, no conflicts
2695719	NM_004064.5(CDKN1B):c.379dup (p.Asp127fs)	CDKN1B	Pathogenic	criteria provided, single submitter
2700986	NM_004064.5(CDKN1B):c.43_44insCCTAGCCTGCAGC (p.Arg15delinsProTer)	CDKN1B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
CDKN1B	Definitive	Autosomal dominant	multiple endocrine neoplasia type 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDKN1B	Orphanet:276152	Multiple endocrine neoplasia type 4
CDKN1B	Orphanet:652	Multiple endocrine neoplasia type 1
LRP6	Orphanet:1810	Autosomal dominant hypohidrotic ectodermal dysplasia
LRP6	Orphanet:99798	Oligodontia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDKN1B	HGNC:1785	ENSG00000111276	P46527	Cyclin-dependent kinase inhibitor 1B	gencc,clinvar
LRP6	HGNC:6698	ENSG00000070018	O75581	Low-density lipoprotein receptor-related protein 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDKN1B	Cyclin-dependent kinase inhibitor 1B	Important regulator of cell cycle progression.
LRP6	Low-density lipoprotein receptor-related protein 6	Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDKN1B	Other/Unknown	no		CDI_dom, CDI_dom_sf
LRP6	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
pigmented layer of retina	1
retina	1
calcaneal tendon	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDKN1B	301	ubiquitous	marker	pigmented layer of retina, retina, ventricular zone
LRP6	139	ubiquitous	marker	calcaneal tendon, corpus callosum, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDKN1B	4,635
LRP6	2,525

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRP6	O75581	30
CDKN1B	P46527	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PTK6 Regulates Cell Cycle	1	951.7×	0.013	CDKN1B
Signaling by RNF43 mutants	1	634.4×	0.013	LRP6
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	439.2×	0.013	CDKN1B
AKT phosphorylates targets in the cytosol	1	407.9×	0.013	CDKN1B
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	356.9×	0.013	LRP6
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	1	356.9×	0.013	CDKN1B
p53-Dependent G1 DNA Damage Response	1	356.9×	0.013	CDKN1B
p53-Dependent G1/S DNA damage checkpoint	1	356.9×	0.013	CDKN1B
G1/S DNA Damage Checkpoints	1	335.9×	0.013	CDKN1B
FOXO-mediated transcription of cell cycle genes	1	335.9×	0.013	CDKN1B
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	317.2×	0.013	CDKN1B
Signaling by WNT in cancer	1	300.5×	0.013	LRP6
RHO GTPases activate CIT	1	300.5×	0.013	CDKN1B
TP53 Regulates Transcription of Cell Cycle Genes	1	271.9×	0.013	CDKN1B
Signaling by PTK6	1	271.9×	0.013	CDKN1B
Signaling by Non-Receptor Tyrosine Kinases	1	271.9×	0.013	CDKN1B
Regulation of FZD by ubiquitination	1	259.6×	0.013	LRP6
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	219.6×	0.013	CDKN1B
Constitutive Signaling by AKT1 E17K in Cancer	1	211.5×	0.013	CDKN1B
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	203.9×	0.013	CDKN1B
G1 Phase	1	196.9×	0.013	CDKN1B
Diseases of mitotic cell cycle	1	196.9×	0.013	CDKN1B
PI3K/AKT Signaling in Cancer	1	184.2×	0.013	CDKN1B
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.013	LRP6
FLT3 Signaling	1	173.0×	0.013	CDKN1B
FOXO-mediated transcription	1	167.9×	0.013	CDKN1B
Diseases of signal transduction by growth factor receptors and second messengers	2	56.8×	0.013	CDKN1B, LRP6
Disease	2	13.1×	0.013	CDKN1B, LRP6
Cyclin E associated events during G1/S transition	1	142.8×	0.014	CDKN1B
Cyclin A:Cdk2-associated events at S phase entry	1	132.8×	0.015	CDKN1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of lens fiber cell differentiation	1	4213.0×	0.006	CDKN1B
negative regulation of cardiac muscle tissue regeneration	1	4213.0×	0.006	CDKN1B
autophagic cell death	1	1685.2×	0.006	CDKN1B
negative regulation of epithelial cell proliferation involved in prostate gland development	1	1404.3×	0.006	CDKN1B
cellular response to antibiotic	1	1203.7×	0.006	CDKN1B
epithelial cell proliferation involved in prostate gland development	1	1053.2×	0.006	CDKN1B
neural crest formation	1	936.2×	0.006	LRP6
neural crest cell differentiation	1	766.0×	0.006	LRP6
nuclear export	1	766.0×	0.006	CDKN1B
regulation of cell cycle G1/S phase transition	1	766.0×	0.006	CDKN1B
negative regulation of smooth muscle cell apoptotic process	1	702.2×	0.006	LRP6
regulation of exit from mitosis	1	601.9×	0.006	CDKN1B
negative regulation of epithelial cell apoptotic process	1	601.9×	0.006	CDKN1B
midbrain dopaminergic neuron differentiation	1	601.9×	0.006	LRP6
cellular response to lithium ion	1	561.7×	0.006	CDKN1B
cellular response to cholesterol	1	421.3×	0.007	LRP6
epithelial cell apoptotic process	1	421.3×	0.007	CDKN1B
negative regulation of mitotic cell cycle	1	401.2×	0.007	CDKN1B
regulation of cyclin-dependent protein serine/threonine kinase activity	1	366.4×	0.007	CDKN1B
positive regulation of microtubule polymerization	1	337.0×	0.007	CDKN1B
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.007	CDKN1B
dopaminergic neuron differentiation	1	312.1×	0.008	LRP6
positive regulation of DNA replication	1	290.6×	0.008	CDKN1B
placenta development	1	221.7×	0.009	CDKN1B
positive regulation of cell cycle	1	221.7×	0.009	LRP6
response to peptide hormone	1	195.9×	0.010	LRP6
inner ear development	1	187.2×	0.010	CDKN1B
DNA damage response, signal transduction by p53 class mediator	1	179.3×	0.010	CDKN1B
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.012	CDKN1B
cellular senescence	1	147.8×	0.012	CDKN1B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKN1B	0	0
LRP6	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
LRP6	9	Binding:9
CDKN1B	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
E	Difficult family or no structure, no drug	2	CDKN1B, LRP6

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)
CDKN1B	5	—
LRP6	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients