Lymphedema

Summary

Lymphedema (MONDO:0019297) is a disease caused by HGF (GenCC Strong), with 15 cohort genes (6 GWAS associations across 2 studies) and 296 clinical trials. Top therapeutic interventions include doxycycline anhydrous, ketoprofen, and methylene blue cation.

At a glance

• Causal gene: HGF (GenCC Strong)
• Cohort genes: 15
• GWAS associations: 6
• ClinVar variants: 20
• Clinical trials: 296

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphedema
Mondo ID	MONDO:0019297
MeSH	D008209
Orphanet	79383
DOID	DOID:4977
NCIT	C3207
SNOMED CT	234097001
UMLS	C0024236
MedGen	6155
MedDRA	10025282
Is cancer (heuristic)	no

Also known as: lymphatic edema (morphologic abnormality) · lymphatic oedema · lymphatic oedema (morphologic abnormality)

Data availability: 20 ClinVar variants · 6 GWAS associations (2 studies) · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › lymphoid system disorder › lymphatic system disorder › lymphedema

Related subtypes (13): lymphatic system cancer, bubonic plague, splenic disorder, histiocytosis, lymphocele, lymph node disorder, lymphangitis, lymphogranuloma venereum, lymphangiectasis, hemophagocytic syndrome, plastic bronchitis, lymphatic vessel neoplasm, pseudolymphoma

Subtypes (2): elephantiasis, primary lymphedema

Genetics & variants

GWAS landscape

6 GWAS associations across 2 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs4959107	1e-08	HLA-DRB1 - HLA-DQA1	T	1.45
rs643644	4e-08	PAX7	?	1.4
rs11345494	6e-08	ATXN7L1	?	1.13
rs2735059	2e-07	HLA-F, HLA-F-AS1	A	1.39
rs76006134	2e-07	TAFA5	A	1.55
rs12933387	7e-07	ERN2 - CHP2	G	0.73

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90281190	Grover S	2023	1,166	1,492	First genome-wide association study for lymphatic filariasis in a West African population points to an HLA-mediated disease pathophysiology.
GCST90310286	Jandu HK	2023	0	0	Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
regulatory_region_variant	1
3_prime_UTR_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs4959107	6	32623913	C>T	0.286	regulatory_region_variant	HLA-DRB1 - HLA-DQA1	1e-08	Tier 3: regulatory
rs643644	1	18724402	A>C,G,T	0.05	intron_variant	PAX7	4e-08	Tier 4: intronic/intergenic
rs11345494	7	105842197	GTTTTT>G,GT,GTT,GTTT,GTTTT,GTTTTTT,GTTTTTTT,GTTTTTTTTT,GTTTTTTTTTTTTTTTTTT	0.05	intron_variant	ATXN7L1	6e-08	Tier 4: intronic/intergenic
rs2735059	6	29728077	G>A,C	0.313	3_prime_UTR_variant	HLA-F, HLA-F-AS1	2e-07	Tier 2: splice/UTR
rs76006134	22	48680428	G>A	0.143	intron_variant	TAFA5	2e-07	Tier 4: intronic/intergenic
rs12933387	16	23739895	A>G	0.324	intergenic_variant	ERN2 - CHP2	7e-07	Tier 4: intronic/intergenic

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 conflicting classifications of pathogenicity, 4 benign/likely benign, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
374219	NM_004523.4(KIF11):c.862_871del (p.Ile288fs)	KIF11	Likely pathogenic	no assertion criteria provided
1100678	NM_182925.5(FLT4):c.521C>T (p.Ser174Leu)	FLT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134649	NM_000245.4(MET):c.71G>A (p.Gly24Glu)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
141747	NM_001042492.3(NF1):c.3604G>T (p.Ala1202Ser)	NF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207374	NM_001130438.3(SPTAN1):c.3779A>G (p.Asn1260Ser)	SPTAN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166577	NM_006005.3(WFS1):c.799G>A (p.Asp267Asn)	WFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4075235	NM_033641.4(COL4A6):c.610-8A>T	COL4A6	Uncertain significance	criteria provided, single submitter
1921519	NM_003737.4(DCHS1):c.5842A>G (p.Ile1948Val)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2230699	NM_003737.4(DCHS1):c.860A>G (p.Asn287Ser)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672203	NM_003737.4(DCHS1):c.767A>G (p.Asn256Ser)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672218	NM_003737.4(DCHS1):c.3017G>A (p.Arg1006His)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805042	NM_004444.5(EPHB4):c.853T>C (p.Cys285Arg)	EPHB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1753220	NM_000245.4(MET):c.638C>T (p.Ser213Leu)	MET	Uncertain significance	criteria provided, multiple submitters, no conflicts
841477	NM_000245.4(MET):c.1436T>C (p.Phe479Ser)	MET	Uncertain significance	criteria provided, multiple submitters, no conflicts
3188450	NM_005429.5(VEGFC):c.659A>G (p.Gln220Arg)	VEGFC	Uncertain significance	criteria provided, multiple submitters, no conflicts
502185	NM_033641.4(COL4A6):c.1379G>A (p.Arg460Gln)	COL4A6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
391893	NM_001291303.3(FAT4):c.524G>T (p.Arg175Leu)	FAT4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
4075074	NM_001291303.3(FAT4):c.11470G>A (p.Ala3824Thr)	FAT4	Benign	criteria provided, single submitter
96636	NM_001291867.2(NHS):c.2330T>C (p.Phe777Ser)	NHS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
207310	NM_001130438.3(SPTAN1):c.7319G>A (p.Arg2440Gln)	SPTAN1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 38 · 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
HGF	Strong	Autosomal dominant	lymphedema	6
IL6	Strong	Autosomal dominant	lymphedema	7
ARAP3	Moderate	Autosomal dominant	lymphedema

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HGF	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
IL6	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
VEGFC	Orphanet:569821	Congenital primary lymphedema of Gordon
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
DCHS1	Orphanet:314679	Cerebrofacioarticular syndrome
DCHS1	Orphanet:741	Familial mitral valve prolapse
COL4A6	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A6	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular syndrome
EPHB4	Orphanet:1053	Vein of Galen malformation
EPHB4	Orphanet:568065	EPHB4-related lymphatic-related hydrops fetalis
EPHB4	Orphanet:693912	EPHB4-related capillary malformation-arteriovenous malformation
EPHB4	Orphanet:90186	Meige disease
FLT4	Orphanet:3303	Tetralogy of Fallot
FLT4	Orphanet:79452	Milroy disease
KIF11	Orphanet:2526	Microcephaly-lymphedema-chorioretinopathy syndrome
MET	Orphanet:319298	Papillary renal cell carcinoma
MET	Orphanet:33402	Pediatric hepatocellular carcinoma
MET	Orphanet:47044	Hereditary papillary renal cell carcinoma
MET	Orphanet:488265	Osteofibrous dysplasia
MET	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
NHS	Orphanet:627	Nance-Horan syndrome
NHS	Orphanet:98991	Early-onset nuclear cataract
NHS	Orphanet:98994	Total early-onset cataract

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ARAP3	HGNC:24097	ENSG00000120318	Q8WWN8	Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3	gencc
HGF	HGNC:4893	ENSG00000019991	P14210	Hepatocyte growth factor	gencc
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	gencc
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
VEGFC	HGNC:12682	ENSG00000150630	P49767	Vascular endothelial growth factor C	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
DCHS1	HGNC:13681	ENSG00000166341	Q96JQ0	Protocadherin-16	clinvar
COL4A6	HGNC:2208	ENSG00000197565	Q14031	Collagen alpha-6(IV) chain	clinvar
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	clinvar
EPHB4	HGNC:3395	ENSG00000196411	P54760	Ephrin type-B receptor 4	clinvar
FLT4	HGNC:3767	ENSG00000037280	P35916	Vascular endothelial growth factor receptor 3	clinvar
KIF11	HGNC:6388	ENSG00000138160	P52732	Kinesin-like protein KIF11	clinvar
MET	HGNC:7029	ENSG00000105976	P08581	Hepatocyte growth factor receptor	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
NHS	HGNC:7820	ENSG00000188158	Q6T4R5	Actin remodeling regulator NHS	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARAP3	Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3	Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members.
HGF	Hepatocyte growth factor	Potent mitogen for mature parenchymal hepatocyte cells, seems to be a hepatotrophic factor, and acts as a growth factor for a broad spectrum of tissues and cell types.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
VEGFC	Vascular endothelial growth factor C	Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
DCHS1	Protocadherin-16	Calcium-dependent cell-adhesion protein.
COL4A6	Collagen alpha-6(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.
EPHB4	Ephrin type-B receptor 4	Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
FLT4	Vascular endothelial growth factor receptor 3	Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic developm…
KIF11	Kinesin-like protein KIF11	Motor protein required for establishing a bipolar spindle and thus contributing to chromosome congression during mitosis.
MET	Hepatocyte growth factor receptor	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
NHS	Actin remodeling regulator NHS	May function in cell morphology by maintaining the integrity of the circumferential actin ring and controlling lamellipod formation.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 8 · Druggable fraction: 0.33

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
Kinase	3	5.5×	0.077
Scaffold/PPI	2	2.3×	0.535
Protease	1	2.4×	0.567
Other/Unknown	8	1.0×	0.729
Enzyme (other)	1	0.8×	0.729

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARAP3	Scaffold/PPI	no		RA_dom, RhoGAP_dom, ArfGAP_dom
HGF	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
VEGFC	Other/Unknown	no		PDGF/VEGF_dom, CXCXC_repeat, PD_growth_factor_CS
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
DCHS1	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
COL4A6	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
EPHB4	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom
FLT4	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
KIF11	Enzyme (other)	yes	5.6.1.3	Kinesin_motor_dom, Kinesin_motor_CS, Kinesin-assoc_MT-bd_dom
MET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Semap_dom
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
NHS	Other/Unknown	no		NHS-like

Expression context

Cohort genes with no expression data: 0.

15 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	2
cartilage tissue	2
right lobe of thyroid gland	2
thyroid gland	2
body of uterus	2
cortical plate	2
ganglionic eminence	2
calcaneal tendon	2
apex of heart	1
blood	1
right lung	1
placenta	1
visceral pleura	1
gall bladder	1
vena cava	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARAP3	228	ubiquitous	marker	apex of heart, right lung, blood
HGF	221	broad	marker	placenta, stromal cell of endometrium, visceral pleura
IL6	200	ubiquitous	marker	cartilage tissue, vena cava, gall bladder
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
VEGFC	224	ubiquitous	marker	stromal cell of endometrium, right lobe of thyroid gland, thyroid gland
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
DCHS1	259	broad	marker	tendon of biceps brachii, ganglionic eminence, cortical plate
COL4A6	197	broad	marker	mucosa of stomach, lower esophagus muscularis layer, lower esophagus
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer
EPHB4	282	ubiquitous	marker	olfactory bulb, type B pancreatic cell, body of uterus
FLT4	172	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
KIF11	205	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
MET	270	ubiquitous	marker	pigmented layer of retina, germinal epithelium of ovary, cartilage tissue
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
NHS	214	ubiquitous	marker	oviduct epithelium, buccal mucosa cell, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
MET	5,823
NF1	5,540
HGF	3,844
KIF11	3,788
WFS1	3,409
SPTAN1	3,083
VEGFC	2,803
EPHB4	2,547
FLT4	2,411

Intra-cohort edges

A	B	Sources
DCHS1	FAT4	string_interaction
EPHB4	VEGFC	string_interaction
FLT4	VEGFC	biogrid_interaction, intact, string_interaction
HGF	MET	biogrid_interaction, intact, string_interaction
IL6	MET	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MET	P08581	130
KIF11	P52732	62
HGF	P14210	36
NF1	P21359	26
EPHB4	P54760	23
IL6	P05231	17
ARAP3	Q8WWN8	7
SPTAN1	Q13813	7
VEGFC	P49767	4
DCHS1	Q96JQ0	2
FAT4	Q6V0I7	2
FLT4	P35916	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WFS1	O76024	73.85
COL4A6	Q14031	48.27
NHS	Q6T4R5	43.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 129. Enrichment computed across 15 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Drug-mediated inhibition of MET activation	2	878.5×	2e-04	HGF, MET
MET activates STAT3	2	585.6×	2e-04	HGF, MET
MET activates PTPN11	2	351.4×	4e-04	HGF, MET
MET interacts with TNS proteins	2	351.4×	4e-04	HGF, MET
MET Receptor Activation	2	292.8×	4e-04	HGF, MET
MET activates PI3K/AKT signaling	2	292.8×	4e-04	HGF, MET
VEGF binds to VEGFR leading to receptor dimerization	2	195.2×	7e-04	VEGFC, FLT4
RAF/MAP kinase cascade	4	18.8×	7e-04	SPTAN1, HGF, MET, NF1
MET receptor recycling	2	175.7×	8e-04	HGF, MET
MET activates RAS signaling	2	159.7×	8e-04	HGF, MET
MET activates RAP1 and RAC1	2	159.7×	8e-04	HGF, MET
MAPK1/MAPK3 signaling	3	30.3×	0.001	SPTAN1, MET, NF1
MAPK family signaling cascades	3	23.7×	0.002	SPTAN1, MET, NF1
Negative regulation of MET activity	2	79.9×	0.003	HGF, MET
MET activates PTK2 signaling	2	58.6×	0.004	HGF, MET
Constitutive Signaling by Aberrant PI3K in Cancer	2	19.5×	0.037	HGF, MET
RAC3 GTPase cycle	2	18.3×	0.039	ARAP3, NHS
VEGF ligand-receptor interactions	1	146.4×	0.046	VEGFC
Interleukin-4 and Interleukin-13 signaling	2	15.8×	0.046	HGF, IL6
Post-translational protein phosphorylation	2	15.4×	0.046	WFS1, IL6
RAS signaling downstream of NF1 loss-of-function variants	1	125.5×	0.047	NF1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	14.9×	0.047	HGF, MET
Sema4D mediated inhibition of cell attachment and migration	1	109.8×	0.049	MET
Platelet degranulation	2	13.5×	0.049	VEGFC, HGF
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	13.3×	0.049	WFS1, IL6
MAPK1 (ERK2) activation	1	87.8×	0.054	IL6
CD163 mediating an anti-inflammatory response	1	87.8×	0.054	IL6
MAPK3 (ERK1) activation	1	79.9×	0.055	IL6
Listeria monocytogenes entry into host cells	1	79.9×	0.055	MET
Interleukin-6 signaling	1	73.2×	0.057	IL6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 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 hydrogen peroxide-mediated programmed cell death	2	561.7×	0.001	HGF, MET
hepatocyte growth factor receptor signaling pathway	2	280.9×	0.003	HGF, MET
liver development	3	44.4×	0.004	HGF, MET, NF1
vascular endothelial growth factor signaling pathway	2	140.4×	0.007	VEGFC, FLT4
hippo signaling	2	97.7×	0.010	DCHS1, FAT4
positive regulation of glial cell proliferation	2	93.6×	0.010	VEGFC, IL6
pancreas development	2	89.9×	0.010	WFS1, MET
neural tube development	2	70.2×	0.013	DCHS1, NF1
positive regulation of vascular endothelial growth factor production	2	66.1×	0.013	FLT4, IL6
sprouting angiogenesis	2	64.2×	0.013	VEGFC, FLT4
vascular endothelial growth factor receptor signaling pathway	2	64.2×	0.013	VEGFC, FLT4
positive regulation of mast cell apoptotic process	1	1123.5×	0.015	NF1
regulation of glial cell differentiation	1	1123.5×	0.015	NF1
observational learning	1	1123.5×	0.015	NF1
regulation of angiogenesis	2	56.2×	0.015	IL6, NF1
positive regulation of interleukin-10 production	2	53.5×	0.015	HGF, IL6
heterophilic cell-cell adhesion	2	44.9×	0.015	DCHS1, FAT4
positive regulation of MAPK cascade	3	16.1×	0.015	FLT4, HGF, IL6
negative regulation of apoptotic process	4	9.3×	0.015	WFS1, FLT4, HGF, IL6
gamma-aminobutyric acid secretion, neurotransmission	1	561.7×	0.019	NF1
regulation of astrocyte activation	1	561.7×	0.019	IL6
glucagon secretion	1	561.7×	0.019	IL6
negative regulation of ATF6-mediated unfolded protein response	1	561.7×	0.019	WFS1
neutrophil apoptotic process	1	374.5×	0.019	IL6
hepatic immune response	1	374.5×	0.019	IL6
mitral valve formation	1	374.5×	0.019	DCHS1
Schwann cell proliferation	1	374.5×	0.019	NF1
forebrain astrocyte development	1	374.5×	0.019	NF1
positive regulation of interleukin-21 production	1	374.5×	0.019	IL6
Schwann cell migration	1	374.5×	0.019	NF1

Therapeutics

Drugs indicated for this disease

1 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Zinc Oxide	Approved (phase 4)
Fibrin	Phase 3 (in late-stage trials)
Sirolimus	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alpelisib, Bleomycin, Maritime Pine, Oxygen, Pazopanib, Propranolol, Sodium Chloride, Tacrolimus Anhydrous.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 9

Druggability breadth: 11 of 15 evidence-associated genes (73%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
IL6	PREDNISOLONE
EPHB4	PONATINIB
FLT4	FEDRATINIB
MET	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MET	95	4
FLT4	72	4
EPHB4	46	4
KIF11	6	3
IL6	3	4
SPTAN1	1	2
ARAP3	0	0
HGF	0	0
VEGFC	0	0
WFS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	IL6
PONATINIB	4	EPHB4
FEDRATINIB	4	EPHB4, FLT4, MET
TIVOZANIB	4	EPHB4, FLT4, MET
SORAFENIB	4	EPHB4, FLT4, MET
DASATINIB ANHYDROUS	4	EPHB4
VANDETANIB	4	EPHB4, FLT4, MET
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4, MET
TOVORAFENIB	4	EPHB4
NINTEDANIB	4	EPHB4, FLT4, MET
SUNITINIB	4	EPHB4, FLT4, MET
DASATINIB	4	EPHB4
ERLOTINIB	4	EPHB4, FLT4, MET
CRIZOTINIB	4	EPHB4, MET
GEFITINIB	4	EPHB4, FLT4, MET
LENVATINIB	4	FLT4
AXITINIB	4	FLT4, MET
INFIGRATINIB PHOSPHATE	4	FLT4, MET
INFIGRATINIB	4	FLT4, MET
REGORAFENIB	4	FLT4
ENTRECTINIB	4	FLT4, MET
CABOZANTINIB	4	FLT4, MET
NINTEDANIB ESYLATE	4	FLT4
FILGOTINIB	4	FLT4
BRIGATINIB	4	FLT4, MET
FRUQUINTINIB	4	FLT4
PAZOPANIB	4	FLT4, MET
QUIZARTINIB	4	FLT4
MIDOSTAURIN	4	FLT4, MET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
MET	2,015	Binding:2005, Functional:6, ADMET:4
FLT4	717	Binding:683, Functional:32, ADMET:2
EPHB4	437	Binding:437
KIF11	193	Binding:185, Functional:8
IL6	16	Binding:16
SPTAN1	7	Binding:7
HGF	4	Binding:4
ARAP3	1	Binding:1
WFS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPHB4	2.7.10.1	receptor protein-tyrosine kinase
FLT4	2.7.10.1	receptor protein-tyrosine kinase
KIF11	5.6.1.3	plus-end-directed kinesin ATPase
MET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EPHB4	437
FLT4	717
KIF11	193
MET	2,015

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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.

Compound	Max phase	Cohort target (bioactivity)
PREDNISOLONE	4	IL6
PONATINIB	4	EPHB4
FEDRATINIB	4	EPHB4, FLT4, MET
TIVOZANIB	4	EPHB4, FLT4, MET
SORAFENIB	4	EPHB4, FLT4, MET
DASATINIB ANHYDROUS	4	EPHB4
VANDETANIB	4	EPHB4, FLT4, MET
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4, MET
TOVORAFENIB	4	EPHB4
NINTEDANIB	4	EPHB4, FLT4, MET
SUNITINIB	4	EPHB4, FLT4, MET
DASATINIB	4	EPHB4
ERLOTINIB	4	EPHB4, FLT4, MET
CRIZOTINIB	4	EPHB4, MET
GEFITINIB	4	EPHB4, FLT4, MET
LENVATINIB	4	FLT4
AXITINIB	4	FLT4, MET
INFIGRATINIB PHOSPHATE	4	FLT4, MET
INFIGRATINIB	4	FLT4, MET
REGORAFENIB	4	FLT4
ENTRECTINIB	4	FLT4, MET
CABOZANTINIB	4	FLT4, MET
NINTEDANIB ESYLATE	4	FLT4
FILGOTINIB	4	FLT4
BRIGATINIB	4	FLT4, MET
FRUQUINTINIB	4	FLT4
QUIZARTINIB	4	FLT4
MIDOSTAURIN	4	FLT4, MET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	IL6, EPHB4, FLT4, MET
B	Phased (≥1) drug, not yet approved	2	SPTAN1, KIF11
C	Druggable family + PDB, no drug	1	HGF
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	ARAP3, VEGFC, WFS1, DCHS1, COL4A6, FAT4, NF1, NHS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HGF	4	MET
VEGFC	0	FLT4
ARAP3	1	—
WFS1	1	—
DCHS1	0	—
COL4A6	0	—
FAT4	0	—
NF1	0	—
NHS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 296.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	246
PHASE2	20
PHASE3	8
PHASE1	7
PHASE4	5
PHASE1/PHASE2	5
EARLY_PHASE1	3
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00852930	PHASE4	COMPLETED	Low Level Laser Treatment and Breast Cancer Related Lymphedema
NCT01068431	PHASE4	COMPLETED	Short Term Effectiveness Study of Juxta-Fit Versus Trico Bandages in the Treatment of Leg Lymphedema
NCT02257970	PHASE4	COMPLETED	Lymphedema Study for Arm or Leg Lymphedema
NCT02375945	PHASE4	COMPLETED	Comparison Between a Non-elastic Falcro Device and Current Method After Total Knee Arthroplasty
NCT03584633	PHASE4	COMPLETED	Effect of Exercise on Indocyanine Green (ICG) Lymphography Imaging
NCT04228991	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated LocoRegional Radiotherapy in Breast Cancer
NCT06144164	PHASE3	RECRUITING	A Study of a Comprehensive Prevention Program to Reduce Lymphedema After Axillary Lymph Node Dissection in People With Breast Cancer
NCT06306274	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Topical Tacrolimus for Breast Cancer-related Lymphedema
NCT00028951	PHASE3	COMPLETED	Fibrin Sealant in Decreasing Lymphedema Following Surgery to Remove Lymph Nodes in Patients With Cancer of the Vulva
NCT00201890	PHASE3	COMPLETED	Trial of Decongestive Lymphatic Therapy for Lymphedema in Women With Breast Cancer DELTA STUDY
NCT00577317	PHASE3	TERMINATED	Flexitouch® Home Maintenance Therapy or Standard Home Maintenance Therapy in Treating Patients With Lower-Extremity Lymphedema Caused by Treatment for Cervical Cancer, Vulvar Cancer, or Endometrial Cancer
NCT02574780	PHASE2/PHASE3	COMPLETED	Lymphedema Upper Limb of Breast Cancer Through Muscle Strengthening Associated With Complex Physical Therapy
NCT02927496	PHASE3	COMPLETED	A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
NCT02929121	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in India
NCT02929134	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in Sri Lanka
NCT06494111	PHASE2	RECRUITING	Systemic Therapy of Open-label Prophylactic Pravastatin or Pentoxifylline/Tocopherol Prevention of Lymphedema Advancing to Eventual Fibrosis: an Interventional Registry-embedded Bayesian Randomized Trial for Radiation Sequelae (STOP4-LATE-FIBROSE)
NCT06912763	PHASE2	RECRUITING	Reversing External-beam Radiotherapy-associated Fibrosis Syndrome: an Interventional Bayesian Adaptive Randomized-controlled Orphan Drug Platform Trial for Orodental Sequelae (Reverse-fibrose)
NCT06989099	PHASE2	RECRUITING	Lymphedema Prevention Through Immediate Lymphatic Reconstruction (LILY) Trial.
NCT00022204	PHASE2	COMPLETED	Vitamin E and Pentoxifylline in Treating Women With Lymphedema After Radiation Therapy for Breast Cancer
NCT00058851	PHASE2	COMPLETED	Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms
NCT00064857	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors
NCT00077090	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy Compared With Standard Therapy in Treating Chronic Arm Lymphedema in Patients Who Have Undergone Radiation Therapy for Cancer
NCT00155220	PHASE2	UNKNOWN	Treatment of Lymphedema: Application of the Kinesio Taping
NCT00188604	PHASE2	COMPLETED	The Use of Selenium to Treat Secondary Lymphedema - Breast Cancer
NCT00214032	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema
NCT00589121	PHASE2	COMPLETED	Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
NCT00827372	PHASE2	COMPLETED	A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer
NCT01003951	PHASE2	COMPLETED	Acupuncture for the Treatment of Chronic Lymphedema
NCT01112189	PHASE1/PHASE2	COMPLETED	Use of Stem Cells in Lymphedema Post Mastectomy
NCT01276054	PHASE2	TERMINATED	Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity of Arm Lymphedema in Stage 0-2 Patients.
NCT01318785	PHASE2	UNKNOWN	Therapeutical Assessment of Compression Armsleeves for Lymphatic Indications
NCT01406769	PHASE2	COMPLETED	Bioimpedance Spectroscopy in Detecting Lower-Extremity Lymphedema in Patients With Stage I, Stage II, Stage III, or Stage IV Vulvar Cancer Undergoing Surgery and Lymphadenectomy
NCT01928030	PHASE1/PHASE2	TERMINATED	Recombinant Human Hyaluronidase in Treating Lymphedema in Patients With Cancer
NCT02592213	PHASE1/PHASE2	UNKNOWN	Treatment of Breast Cancer Related Lymphedema With Cell-assisted Lipotransfer
NCT02650297	PHASE1/PHASE2	COMPLETED	The Effect of Combined Decongestive Therapy and Pneumatic Compression Pump on Body Image in Patients With Lymphedema
NCT02700529	PHASE2	COMPLETED	Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)
NCT02895724	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy to Reduce Lymphedema After Breast Cancer -an Explorative Clinical Trial
NCT03658967	PHASE2	COMPLETED	Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)
NCT03776721	PHASE2	COMPLETED	Treatment of Breast Cancer-related Lymphedema With Stem Cells and Fat Grafting
NCT04390685	PHASE1/PHASE2	UNKNOWN	Prevention of Breast Cancer-related Lymphedma With Tacrolimus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXYCYCLINE ANHYDROUS	4	8
KETOPROFEN	4	3
METHYLENE BLUE CATION	4	3
PENTOXIFYLLINE	4	3
INDOCYANINE GREEN ACID FORM	4	2
PRAVASTATIN	4	2
TECHNETIUM TC 99M SULFUR COLLOID	4	2
PAZOPANIB	4	1
VITAMIN E	4	1
MARITIME PINE	3	2
FIBRIN	3	1
SODIUM SELENATE	3	1
SODIUM SELENITE	3	1
UBENIMEX	2	1
CHEMBL4068768	0	1
CHEMBL4171277	0	1
ALPHA-TOCOPHEROL	0	1