Hennekam lymphangiectasia-lymphedema syndrome 3

Summary

Hennekam lymphangiectasia-lymphedema syndrome 3 (MONDO:0032564) is a disease caused by ADAMTS3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ADAMTS3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hennekam lymphangiectasia-lymphedema syndrome 3
Mondo ID	MONDO:0032564
OMIM	618154
UMLS	C4748408
MedGen	1648368
GARD	0016296
Is cancer (heuristic)	no

Also known as: HKLLS3

Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Hennekam syndrome › hennekam lymphangiectasia-lymphedema syndrome 3

Related subtypes (2): Hennekam lymphangiectasia-lymphedema syndrome 1, Hennekam lymphangiectasia-lymphedema syndrome 2

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

15 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 benign, 3 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
586987	NM_014243.3(ADAMTS3):c.503T>C (p.Leu168Pro)	ADAMTS3	Pathogenic	no assertion criteria provided
586988	NM_014243.3(ADAMTS3):c.872T>C (p.Ile291Thr)	ADAMTS3	Pathogenic	no assertion criteria provided
627548	NM_014243.3(ADAMTS3):c.280C>T (p.Arg94Ter)	ADAMTS3	Pathogenic	criteria provided, single submitter
3064779	NM_014243.3(ADAMTS3):c.3104G>A (p.Arg1035Gln)	ADAMTS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065425	NM_014243.3(ADAMTS3):c.2878C>T (p.Pro960Ser)	ADAMTS3	Uncertain significance	criteria provided, single submitter
3077262	NM_014243.3(ADAMTS3):c.3047A>G (p.Asn1016Ser)	ADAMTS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3590839	NM_014243.3(ADAMTS3):c.2296A>T (p.Asn766Tyr)	ADAMTS3	Uncertain significance	criteria provided, single submitter
3590840	NM_014243.3(ADAMTS3):c.1833C>A (p.Asp611Glu)	ADAMTS3	Uncertain significance	criteria provided, single submitter
4278245	NM_014243.3(ADAMTS3):c.2453C>G (p.Ser818Cys)	ADAMTS3	Uncertain significance	criteria provided, single submitter
4531943	NM_014243.3(ADAMTS3):c.2449C>G (p.Arg817Gly)	ADAMTS3	Uncertain significance	criteria provided, single submitter
4531944	NM_014243.3(ADAMTS3):c.505G>A (p.Ala169Thr)	ADAMTS3	Uncertain significance	criteria provided, single submitter
1188859	NM_014243.3(ADAMTS3):c.69+31del	ADAMTS3	Benign	criteria provided, single submitter
1189005	NM_014243.3(ADAMTS3):c.2179+21G>A	ADAMTS3	Benign	criteria provided, multiple submitters, no conflicts
1189006	NM_014243.3(ADAMTS3):c.413G>A (p.Arg138Lys)	ADAMTS3	Benign	criteria provided, multiple submitters, no conflicts
780467	NM_014243.3(ADAMTS3):c.661+7G>A	ADAMTS3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ADAMTS3	Strong	Autosomal recessive	hennekam lymphangiectasia-lymphedema syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS3	Orphanet:2136	Hennekam syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTS3	HGNC:219	ENSG00000156140	O15072	A disintegrin and metalloproteinase with thrombospondin motifs 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTS3	A disintegrin and metalloproteinase with thrombospondin motifs 3	Cleaves the propeptides of type II collagen prior to fibril assembly.

Protein-family classification

Druggable: 1 · 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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS3	Protease	yes	3.4.24.14	TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
endothelial cell	1
periodontal ligament	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTS3	189	broad	marker	endothelial cell, cartilage tissue, periodontal ligament

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAMTS3	1,242

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS3	O15072	71.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 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
Collagen formation	1	456.8×	0.013	ADAMTS3
Defective B3GALTL causes PpS	1	308.6×	0.013	ADAMTS3
O-glycosylation of TSR domain-containing proteins	1	300.5×	0.013	ADAMTS3
Diseases associated with O-glycosylation of proteins	1	215.5×	0.013	ADAMTS3
Collagen biosynthesis and modifying enzymes	1	170.4×	0.013	ADAMTS3
O-linked glycosylation	1	144.6×	0.013	ADAMTS3
Diseases of glycosylation	1	131.3×	0.013	ADAMTS3
Diseases of metabolism	1	80.4×	0.019	ADAMTS3
Extracellular matrix organization	1	63.1×	0.021	ADAMTS3
Post-translational protein modification	1	19.2×	0.063	ADAMTS3
Disease	1	13.1×	0.081	ADAMTS3
Metabolism of proteins	1	12.4×	0.081	ADAMTS3

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
vascular endothelial growth factor production	1	2407.4×	0.002	ADAMTS3
positive regulation of vascular endothelial growth factor signaling pathway	1	1123.5×	0.002	ADAMTS3
collagen biosynthetic process	1	1053.2×	0.002	ADAMTS3
supramolecular fiber organization	1	1053.2×	0.002	ADAMTS3
collagen catabolic process	1	391.9×	0.005	ADAMTS3
collagen fibril organization	1	224.7×	0.007	ADAMTS3
protein processing	1	170.2×	0.008	ADAMTS3
extracellular matrix organization	1	122.1×	0.010	ADAMTS3
in utero embryonic development	1	72.0×	0.015	ADAMTS3
proteolysis	1	34.2×	0.029	ADAMTS3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAMTS3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAMTS3	3.4.24.14	procollagen N-endopeptidase

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	1	ADAMTS3
E	Difficult family or no structure, no drug	0

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)
ADAMTS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.