Diffuse lymphatic malformation

Summary

Diffuse lymphatic malformation (MONDO:0015408) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Cohort genes: 2
• ClinVar variants: 1
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diffuse lymphatic malformation
Mondo ID	MONDO:0015408
Orphanet	141209
DOID	DOID:0081031
ICD-11	913891613
SNOMED CT	703298001
UMLS	C3839921
MedGen	825766
GARD	0019961
Is cancer (heuristic)	no

Also known as: diffuse lymphangioma · diffuse lymphangiomatosis · disseminated lymphangioma · disseminated lymphangiomatosis · disseminated lymphatic malformation · generalised lymphatic anomaly · generalized lymphatic anomaly · GLA · Gla

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

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › benign neoplasm › cardiovascular organ benign neoplasm › lymphangioma › diffuse lymphatic malformation

Related subtypes (11): colonic lymphangioma, capillary lymphangioma, lymphangioendothelioma, Gorham-Stout disease, cystic hygroma, lymphedema-posterior choanal atresia syndrome, mixed cystic lymphatic malformation, multifocal lymphangioendotheliomatosis-thrombocytopenia syndrome, macrocystic lymphatic malformation, microcystic lymphatic malformation, skin lymphangioma

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

1 retrieved; paginated sample, class counts are floors:

1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3075989	NM_001142864.4(PIEZO1):c.5040C>A (p.Tyr1680Ter)	PIEZO1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · 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
ARAF	Limited	Autosomal dominant	diffuse lymphatic malformation

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIEZO1	Orphanet:3202	Dehydrated hereditary stomatocytosis
PIEZO1	Orphanet:568062	PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis

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
ARAF	HGNC:646	ENSG00000078061	P10398	Serine/threonine-protein kinase A-Raf	gencc
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARAF	Serine/threonine-protein kinase A-Raf	Involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
PIEZO1	Piezo-type mechanosensitive ion channel component 1	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28

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
gastrocnemius	1
granulocyte	1
hindlimb stylopod muscle	1
lower esophagus mucosa	1
muscle layer of sigmoid colon	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARAF	262	ubiquitous	marker	hindlimb stylopod muscle, granulocyte, gastrocnemius
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIEZO1	2,266
ARAF	759

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARAF	P10398	6
PIEZO1	Q92508	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
Signaling by MRAS-complex mutants	1	1427.5×	0.011	ARAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	713.8×	0.011	ARAF
Gain-of-function MRAS complexes activate RAF signaling	1	713.8×	0.011	ARAF
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	335.9×	0.012	PIEZO1
Signaling by RAS mutants	1	211.5×	0.012	ARAF
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.012	PIEZO1
RAF activation	1	167.9×	0.012	ARAF
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.012	ARAF
MAP2K and MAPK activation	1	142.8×	0.012	ARAF
Signaling by RAF1 mutants	1	139.3×	0.012	ARAF
Negative regulation of MAPK pathway	1	132.8×	0.012	ARAF
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.012	ARAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.012	ARAF
Signaling downstream of RAS mutants	1	126.9×	0.012	ARAF
Oncogenic MAPK signaling	1	124.1×	0.012	ARAF
Signaling by BRAF and RAF1 fusions	1	85.2×	0.017	ARAF
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.017	PIEZO1
MAPK1/MAPK3 signaling	1	65.6×	0.019	ARAF
MAPK family signaling cascades	1	51.4×	0.023	ARAF
RAF/MAP kinase cascade	1	30.5×	0.037	ARAF
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.038	ARAF
Disease	1	6.5×	0.154	ARAF
Signal Transduction	1	5.1×	0.187	ARAF

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
positive regulation of cell-cell adhesion mediated by integrin	1	1053.2×	0.004	PIEZO1
positive regulation of integrin activation	1	936.2×	0.004	PIEZO1
positive regulation of myotube differentiation	1	766.0×	0.004	PIEZO1
detection of mechanical stimulus	1	601.9×	0.004	PIEZO1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1	561.7×	0.004	ARAF
regulation of TOR signaling	1	468.1×	0.004	ARAF
monoatomic cation transport	1	383.0×	0.004	PIEZO1
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.004	ARAF
protein modification process	1	122.1×	0.011	ARAF
regulation of membrane potential	1	115.4×	0.011	PIEZO1
cellular response to mechanical stimulus	1	108.0×	0.011	PIEZO1
MAPK cascade	1	76.6×	0.014	ARAF
negative regulation of apoptotic process	1	17.4×	0.057	ARAF

Therapeutics

Drug target analysis

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

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
ARAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ARAF	9	4
PIEZO1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	ARAF
SORAFENIB	4	ARAF
DABRAFENIB	4	ARAF
NAPORAFENIB	3	ARAF
REBASTINIB	2	ARAF
BAFETINIB	2	ARAF
BELVARAFENIB	2	ARAF
EXARAFENIB	2	ARAF
LY-3009120	1	ARAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ARAF	92	Binding:92
PIEZO1	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ARAF	2.7.10.2	non-specific protein-tyrosine kinase

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

9 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)
VEMURAFENIB	4	ARAF
SORAFENIB	4	ARAF
DABRAFENIB	4	ARAF
NAPORAFENIB	3	ARAF
REBASTINIB	2	ARAF
BAFETINIB	2	ARAF
BELVARAFENIB	2	ARAF
EXARAFENIB	2	ARAF
LY-3009120	1	ARAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ARAF
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	1	PIEZO1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIEZO1	17	—

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
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT03001180	Not specified	RECRUITING	Identification of Biomarkers for Patients with Vascular Anomalies