Lymphatic malformation 6

Summary

Lymphatic malformation 6 (MONDO:0014797) is a disease caused by PIEZO1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIEZO1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 210

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphatic malformation 6
Mondo ID	MONDO:0014797
OMIM	616843
Orphanet	568062
UMLS	C4225184
MedGen	908120
GARD	0022301
Is cancer (heuristic)	no

Also known as: generalised lymphatic dysplasia of Fotiou · generalized lymphatic dysplasia of Fotiou · LMPH3 · lymphedema, hereditary, III · lymphedema, hereditary, type III · PIEZO1-related generalised lymphatic dysplasia with systemic involvement · PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis · PIEZO1-related generalized lymphatic dysplasia with systemic involvement · PIEZO1-related LRHF/GLD · PIEZO1-related lymphatic-related hydrops fetalis

Data availability: 210 ClinVar variants · 2 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 6

Related subtypes (27): microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, lymphatic malformation 1, 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 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

210 retrieved; paginated sample, class counts are floors:

73 uncertain significance, 42 conflicting classifications of pathogenicity, 33 benign, 22 likely pathogenic, 19 pathogenic, 17 benign/likely benign, 3 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1707478	NM_001142864.4(PIEZO1):c.1381C>T (p.Gln461Ter)	HSALR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223132	NM_001142864.4(PIEZO1):c.1669+1G>A	HSALR1	Pathogenic	no assertion criteria provided
2431217	NM_001142864.4(PIEZO1):c.612dup (p.Val205fs)	HSALR1	Pathogenic	criteria provided, single submitter
2431220	NM_001142864.4(PIEZO1):c.3025C>T (p.Gln1009Ter)	HSALR1	Pathogenic	criteria provided, single submitter
2441629	NM_001142864.4(PIEZO1):c.2838C>A (p.Tyr946Ter)	HSALR1	Pathogenic	criteria provided, single submitter
3376774	NM_001142864.4(PIEZO1):c.2248G>T (p.Glu750Ter)	HSALR1	Pathogenic	criteria provided, single submitter
1163992	NM_001142864.4(PIEZO1):c.5289C>G (p.Tyr1763Ter)	PIEZO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223127	NM_001142864.4(PIEZO1):c.2263G>T (p.Glu755Ter)	PIEZO1	Pathogenic	no assertion criteria provided
223128	NM_001142864.4(PIEZO1):c.4888G>T (p.Glu1630Ter)	PIEZO1	Pathogenic	no assertion criteria provided
223129	NM_001142864.4(PIEZO1):c.6682C>T (p.Gln2228Ter)	PIEZO1	Pathogenic	no assertion criteria provided
223130	NM_001142864.4(PIEZO1):c.3796+1G>A	PIEZO1	Pathogenic	criteria provided, single submitter
223133	NM_001142864.4(PIEZO1):c.7289C>T (p.Pro2430Leu)	PIEZO1	Pathogenic	no assertion criteria provided
2444346	NM_001142864.4(PIEZO1):c.4058+1G>C	PIEZO1	Pathogenic	criteria provided, single submitter
2506015	NM_001142864.4(PIEZO1):c.4914C>G (p.Tyr1638Ter)	PIEZO1	Pathogenic	criteria provided, single submitter
3581334	NM_001142864.4(PIEZO1):c.3367G>T (p.Glu1123Ter)	PIEZO1	Pathogenic	criteria provided, single submitter
3617924	NM_001142864.4(PIEZO1):c.3490C>T (p.Arg1164Ter)	PIEZO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418948	NM_001142864.4(PIEZO1):c.7477CTGGAG[3] (p.2493LE[3])	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
449461	NM_001142864.4(PIEZO1):c.1264C>T (p.Gln422Ter)	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
4795115	NM_001142864.4(PIEZO1):c.5242C>T (p.Gln1748Ter)	PIEZO1	Pathogenic	criteria provided, single submitter
55806	NM_001142864.4(PIEZO1):c.7367G>A (p.Arg2456His)	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
973951	NM_001142864.4(PIEZO1):c.6964G>T (p.Glu2322Ter)	PIEZO1	Pathogenic	no assertion criteria provided
985646	NM_001142864.4(PIEZO1):c.4275_4278del (p.Ser1425fs)	PIEZO1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698796	NM_001142864.4(PIEZO1):c.1297-1G>A	HSALR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3235942	NM_001142864.4(PIEZO1):c.3154C>T (p.Gln1052Ter)	HSALR1	Likely pathogenic	criteria provided, single submitter
3391363	NM_001142864.4(PIEZO1):c.813_823del (p.Gln272fs)	HSALR1	Likely pathogenic	criteria provided, single submitter
4056810	NM_001142864.4(PIEZO1):c.2330-2A>G	HSALR1	Likely pathogenic	criteria provided, single submitter
4849371	NM_001142864.4(PIEZO1):c.2180+1G>C	HSALR1	Likely pathogenic	criteria provided, single submitter
978720	NM_001142864.4(PIEZO1):c.3191G>T (p.Cys1064Phe)	HSALR1	Likely pathogenic	no assertion criteria provided
2431216	NM_001142864.4(PIEZO1):c.7488G>C (p.Glu2496Asp)	PIEZO1	Likely pathogenic	criteria provided, single submitter
2505200	NM_001142864.4(PIEZO1):c.4341del (p.Tyr1448fs)	PIEZO1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PIEZO1	Strong	Autosomal recessive	lymphatic malformation 6	7

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, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIEZO1	HGNC:28993	ENSG00000103335	Q92508	Piezo-type mechanosensitive ion channel component 1	gencc,clinvar
HSALR1	HGNC:56095	ENSG00000224888		HSP90AB1 associated lncRNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
PIEZO1	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
HSALR1	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
lower esophagus mucosa	1
muscle layer of sigmoid colon	1
upper lobe of left lung	1
bone marrow cell	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIEZO1	142	ubiquitous	marker	muscle layer of sigmoid colon, lower esophagus mucosa, upper lobe of left lung
HSALR1	126		yes	colonic epithelium, bone marrow cell, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIEZO1	2,266
HSALR1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIEZO1	Q92508	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.004	PIEZO1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.004	PIEZO1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.006	PIEZO1

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
positive regulation of cell-cell adhesion mediated by integrin	1	2106.5×	0.001	PIEZO1
positive regulation of integrin activation	1	1872.4×	0.001	PIEZO1
positive regulation of myotube differentiation	1	1532.0×	0.001	PIEZO1
detection of mechanical stimulus	1	1203.7×	0.001	PIEZO1
monoatomic cation transport	1	766.0×	0.002	PIEZO1
regulation of membrane potential	1	230.8×	0.005	PIEZO1
cellular response to mechanical stimulus	1	216.1×	0.005	PIEZO1

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
PIEZO1	0	0
HSALR1	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
PIEZO1	17	Binding:17

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PIEZO1, HSALR1

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)
PIEZO1	17	—
HSALR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.