Lymphatic malformation 1

Summary

Lymphatic malformation 1 (MONDO:0007919) is a disease caused by FLT4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: FLT4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 69
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3	Israel	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001004	Lymphedema	Very frequent (80-99%)
HP:0000034	Hydrocele testis	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0001785	Ankle swelling	Frequent (30-79%)
HP:0002619	Varicose veins	Frequent (30-79%)
HP:0002624	Abnormal venous morphology	Frequent (30-79%)
HP:0003550	Predominantly lower limb lymphedema	Frequent (30-79%)
HP:0010741	Pedal edema	Frequent (30-79%)
HP:0100658	Cellulitis	Frequent (30-79%)
HP:0100797	Toenail dysplasia	Frequent (30-79%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0008069	Neoplasm of the skin	Occasional (5-29%)
HP:0100725	Lichenification	Occasional (5-29%)
HP:0200058	Angiosarcoma	Occasional (5-29%)
HP:0001055	Erysipelas	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphatic malformation 1
Mondo ID	MONDO:0007919
OMIM	153100
Orphanet	79452
DOID	DOID:0070210, DOID:0070212
SNOMED CT	399889006
UMLS	C1704423
MedGen	309963
GARD	0003328
Is cancer (heuristic)	no

Also known as: congenital hereditary lymphedema · early onset lymphedema · FLT4 hereditary lymphedema · hereditary lymphedema 1 · hereditary lymphedema caused by mutation in FLT4 · hereditary lymphedema type I · LMPH1A · lymphedema, early-onset · lymphedema, hereditary, 1A · lymphedema, hereditary, type 1A · Milroy disease · Nonne-Milroy disease · Nonne-Milroy lymphedema · Nonne-Milroy syndrome · Nonne’s syndrome · primary congenital lymphedema

Data availability: 69 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 › lymphatic malformation › lymphatic malformation 1

Related subtypes (27): microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, lymphatic malformation 5, yellow nail syndrome, lymphedema-distichiasis syndrome, campomelia, Cumming type, Dahlberg-Borer-Newcomer syndrome, Norman-Roberts syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, MPI-congenital disorder of glycosylation, hypotrichosis-lymphedema-telangiectasia syndrome, lymphatic malformation 2, lymphatic malformation 3, deafness-lymphedema-leukemia syndrome, lymphatic malformation 4, lymphatic malformation 6, lymphatic malformation 7, Hennekam syndrome, Noonan syndrome, hypotrichosis-lymphedema-telangiectasia-renal defect syndrome, lymphatic malformation 10, lymphatic malformation 9, lymphatic malformation 11, lymphatic malformation 12, lymphatic malformation 8, congenital primary lymphedema of Gordon, lymphatic malformation 13, lymphatic malformation 14

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

69 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 10 pathogenic, 9 benign, 8 likely pathogenic, 5 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1700049	NM_004444.5(EPHB4):c.2011T>C (p.Phe671Leu)	EPHB4	Pathogenic	criteria provided, single submitter
994305	NM_004444.5(EPHB4):c.1423-6G>A	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16259	NM_182925.5(FLT4):c.2569G>A (p.Gly857Arg)	FLT4	Pathogenic	criteria provided, multiple submitters, no conflicts
16260	NM_182925.5(FLT4):c.3122G>C (p.Arg1041Pro)	FLT4	Pathogenic	criteria provided, single submitter
16261	NM_182925.5(FLT4):c.3131T>C (p.Leu1044Pro)	FLT4	Pathogenic	no assertion criteria provided
16263	NM_182925.5(FLT4):c.3104A>G (p.His1035Arg)	FLT4	Pathogenic	no assertion criteria provided
16265	NM_182925.5(FLT4):c.2632G>A (p.Val878Met)	FLT4	Pathogenic	no assertion criteria provided
16266	NM_182925.5(FLT4):c.3257T>C (p.Ile1086Thr)	FLT4	Pathogenic/Likely pathogenic	no assertion criteria provided
16267	NM_182925.5(FLT4):c.3316G>A (p.Glu1106Lys)	FLT4	Pathogenic	no assertion criteria provided
16268	NM_182925.5(FLT4):c.3320TCT[1] (p.Phe1108del)	FLT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1712154	NM_182925.5(FLT4):c.3122G>A (p.Arg1041Gln)	FLT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445224	NM_182925.5(FLT4):c.3332G>A (p.Gly1111Glu)	FLT4	Pathogenic	criteria provided, single submitter
2664278	NM_182925.5(FLT4):c.2771T>A (p.Met924Lys)	FLT4	Pathogenic	no assertion criteria provided
2664279	NM_182925.5(FLT4):c.3109G>A (p.Asp1037Asn)	FLT4	Pathogenic	no assertion criteria provided
692043	NM_182925.5(FLT4):c.3121C>T (p.Arg1041Trp)	FLT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030389	NM_182925.5(FLT4):c.3821A>T (p.Asp1274Val)	FLT4	Likely pathogenic	criteria provided, single submitter
16262	NM_182925.5(FLT4):c.3341C>T (p.Pro1114Leu)	FLT4	Likely pathogenic	criteria provided, single submitter
2635102	NM_182925.5(FLT4):c.3827G>A (p.Gly1276Glu)	FLT4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664275	NM_182925.5(FLT4):c.2717_2734dup (p.Asn911_Leu912insHisLeuAsnValValAsn)	FLT4	Likely pathogenic	no assertion criteria provided
3900720	NM_182925.5(FLT4):c.2741G>A (p.Gly914Glu)	FLT4	Likely pathogenic	criteria provided, single submitter
4532241	NM_182925.5(FLT4):c.3410C>G (p.Pro1137Arg)	FLT4	Likely pathogenic	criteria provided, single submitter
4818881	NM_182925.5(FLT4):c.3229C>T (p.Pro1077Ser)	FLT4	Likely pathogenic	criteria provided, single submitter
932061	NM_182925.5(FLT4):c.3410C>T (p.Pro1137Leu)	FLT4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1140580	NM_182925.5(FLT4):c.1472C>T (p.Ala491Val)	FLT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1297745	NM_182925.5(FLT4):c.3023C>T (p.Pro1008Leu)	FLT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3279264	NM_182925.5(FLT4):c.3955C>T (p.Arg1319Trp)	FLT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1331243	NM_182925.5(FLT4):c.3208C>T (p.Arg1070Cys)	FLT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
16269	NM_182925.5(FLT4):c.2563G>A (p.Ala855Thr)	FLT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1683756	NM_182925.5(FLT4):c.1093G>A (p.Glu365Lys)	FLT4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441699	NM_182925.5(FLT4):c.1104-2A>G	FLT4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
FLT4	Definitive	Autosomal dominant	lymphatic malformation 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLT4	Orphanet:3303	Tetralogy of Fallot
FLT4	Orphanet:79452	Milroy disease
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

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
FLT4	HGNC:3767	ENSG00000037280	P35916	Vascular endothelial growth factor receptor 3	gencc,clinvar
EPHB4	HGNC:3395	ENSG00000196411	P54760	Ephrin type-B receptor 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	2	27.7×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLT4	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
EPHB4	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
body of uterus	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLT4	172	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
EPHB4	282	ubiquitous	marker	olfactory bulb, type B pancreatic cell, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPHB4	2,547
FLT4	2,411

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPHB4	P54760	23
FLT4	P35916	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
VEGF binds to VEGFR leading to receptor dimerization	1	634.4×	0.008	FLT4
Ephrin signaling	1	285.5×	0.008	EPHB4
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.008	FLT4
EPHB-mediated forward signaling	1	132.8×	0.012	EPHB4
EPH-ephrin mediated repulsion of cells	1	109.8×	0.012	EPHB4
EPH-Ephrin signaling	1	82.8×	0.012	EPHB4
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.012	FLT4

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 blood vessel remodeling	1	2808.7×	0.010	FLT4
lymph vessel development	1	936.2×	0.010	FLT4
lymphangiogenesis	1	601.9×	0.010	FLT4
vasculature development	1	561.7×	0.010	FLT4
vascular endothelial growth factor signaling pathway	1	526.6×	0.010	FLT4
respiratory system process	1	468.1×	0.010	FLT4
blood vessel morphogenesis	1	401.2×	0.010	FLT4
cell migration involved in sprouting angiogenesis	1	324.1×	0.010	EPHB4
cellular response to vascular endothelial growth factor stimulus	1	280.9×	0.010	FLT4
positive regulation of vascular endothelial growth factor production	1	247.8×	0.010	FLT4
sprouting angiogenesis	1	240.7×	0.010	FLT4
vascular endothelial growth factor receptor signaling pathway	1	240.7×	0.010	FLT4
peptidyl-tyrosine phosphorylation	1	210.7×	0.011	FLT4
heart morphogenesis	1	187.2×	0.011	EPHB4
lung alveolus development	1	175.5×	0.011	FLT4
ephrin receptor signaling pathway	1	172.0×	0.011	EPHB4
positive regulation of protein phosphorylation	1	138.1×	0.013	FLT4
positive regulation of endothelial cell migration	1	125.8×	0.013	FLT4
positive regulation of endothelial cell proliferation	1	115.4×	0.014	FLT4
cell surface receptor protein tyrosine kinase signaling pathway	1	86.9×	0.017	FLT4
positive regulation of JNK cascade	1	81.8×	0.017	FLT4
protein autophosphorylation	1	72.6×	0.019	FLT4
positive regulation of ERK1 and ERK2 cascade	1	42.6×	0.030	FLT4
positive regulation of MAPK cascade	1	40.3×	0.031	FLT4
angiogenesis	1	31.2×	0.036	EPHB4
positive regulation of cell migration	1	30.9×	0.036	FLT4
cell migration	1	30.8×	0.036	FLT4
cell adhesion	1	18.7×	0.056	EPHB4
negative regulation of apoptotic process	1	17.4×	0.059	FLT4
positive regulation of cell population proliferation	1	16.8×	0.059	FLT4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
FLT4	FEDRATINIB
EPHB4	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLT4	72	4
EPHB4	46	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	EPHB4, FLT4
TIVOZANIB	4	EPHB4, FLT4
LENVATINIB	4	FLT4
AXITINIB	4	FLT4
SORAFENIB	4	EPHB4, FLT4
INFIGRATINIB PHOSPHATE	4	FLT4
INFIGRATINIB	4	FLT4
REGORAFENIB	4	FLT4
ENTRECTINIB	4	FLT4
CABOZANTINIB	4	FLT4
VANDETANIB	4	EPHB4, FLT4
NINTEDANIB ESYLATE	4	FLT4
FILGOTINIB	4	FLT4
BRIGATINIB	4	FLT4
FRUQUINTINIB	4	FLT4
PAZOPANIB	4	FLT4
NINTEDANIB	4	EPHB4, FLT4
SUNITINIB	4	EPHB4, FLT4
ERLOTINIB	4	EPHB4, FLT4
QUIZARTINIB	4	FLT4
MIDOSTAURIN	4	FLT4
GEFITINIB	4	EPHB4, FLT4
PONATINIB	4	EPHB4
DASATINIB ANHYDROUS	4	EPHB4
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4
TOVORAFENIB	4	EPHB4
DASATINIB	4	EPHB4
CRIZOTINIB	4	EPHB4
VATALANIB	3	FLT4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FLT4	717	Binding:683, Functional:32, ADMET:2
EPHB4	437	Binding:437

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FLT4	2.7.10.1	receptor protein-tyrosine kinase
EPHB4	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
FLT4	717
EPHB4	437

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

30 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)
FEDRATINIB	4	EPHB4, FLT4
TIVOZANIB	4	EPHB4, FLT4
LENVATINIB	4	FLT4
AXITINIB	4	FLT4
SORAFENIB	4	EPHB4, FLT4
INFIGRATINIB PHOSPHATE	4	FLT4
INFIGRATINIB	4	FLT4
REGORAFENIB	4	FLT4
ENTRECTINIB	4	FLT4
CABOZANTINIB	4	FLT4
VANDETANIB	4	EPHB4, FLT4
NINTEDANIB ESYLATE	4	FLT4
FILGOTINIB	4	FLT4
BRIGATINIB	4	FLT4
FRUQUINTINIB	4	FLT4
PAZOPANIB	4	FLT4
NINTEDANIB	4	EPHB4, FLT4
SUNITINIB	4	EPHB4, FLT4
ERLOTINIB	4	EPHB4, FLT4
QUIZARTINIB	4	FLT4
MIDOSTAURIN	4	FLT4
GEFITINIB	4	EPHB4, FLT4
PONATINIB	4	EPHB4
DASATINIB ANHYDROUS	4	EPHB4
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4
TOVORAFENIB	4	EPHB4
DASATINIB	4	EPHB4
CRIZOTINIB	4	EPHB4
VATALANIB	3	FLT4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	FLT4, EPHB4
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.