Hennekam lymphangiectasia-lymphedema syndrome 1

Summary

Hennekam lymphangiectasia-lymphedema syndrome 1 (MONDO:0009337) is a disease caused by CCBE1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CCBE1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 221

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hennekam lymphangiectasia-lymphedema syndrome 1
Mondo ID	MONDO:0009337
OMIM	235510
UMLS	C4012050
MedGen	860487
GARD	0015181
Is cancer (heuristic)	no

Also known as: CCBE1 Hennekam syndrome · Hennekam lymphangiectasia-lymphedema syndrome 1 · Hennekam lymphangiectasia-lymphedema syndrome type 1 · Hennekam syndrome caused by mutation in CCBE1 · HKLLS1 · lymphatic dysplasia, generalised

Data availability: 221 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 1

Related subtypes (2): Hennekam lymphangiectasia-lymphedema syndrome 2, hennekam lymphangiectasia-lymphedema syndrome 3

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

221 retrieved; paginated sample, class counts are floors:

128 uncertain significance, 47 benign, 22 conflicting classifications of pathogenicity, 14 likely benign, 6 pathogenic, 3 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2994186	NM_133459.4(CCBE1):c.322C>T (p.Arg108Ter)	CCBE1	Pathogenic	criteria provided, multiple submitters, no conflicts
445	NM_133459.4(CCBE1):c.223T>A (p.Cys75Ser)	CCBE1	Pathogenic	criteria provided, multiple submitters, no conflicts
446	NM_133459.4(CCBE1):c.305G>C (p.Cys102Ser)	CCBE1	Pathogenic	no assertion criteria provided
447	NM_133459.4(CCBE1):c.979G>C (p.Gly327Arg)	CCBE1	Pathogenic	no assertion criteria provided
448	NM_133459.4(CCBE1):c.683_684insT (p.Leu229fs)	CCBE1	Pathogenic	criteria provided, single submitter
450	NM_133459.4(CCBE1):c.520T>C (p.Cys174Arg)	CCBE1	Pathogenic	criteria provided, single submitter
3236090	NM_133459.4(CCBE1):c.293G>A (p.Cys98Tyr)	CCBE1	Likely pathogenic	criteria provided, single submitter
1344506	NM_133459.4(CCBE1):c.310G>A (p.Asp104Asn)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2078412	NM_133459.4(CCBE1):c.700A>G (p.Thr234Ala)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327705	NM_133459.4(CCBE1):c.654+10G>A	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327707	NM_133459.4(CCBE1):c.431C>T (p.Thr144Met)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327708	NM_133459.4(CCBE1):c.265+8A>C	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449	NM_133459.4(CCBE1):c.472C>T (p.Arg158Cys)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
515358	NM_133459.4(CCBE1):c.654+5G>A	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625905	NM_133459.4(CCBE1):c.260C>A (p.Pro87Gln)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
631807	NM_133459.4(CCBE1):c.916-2A>G	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
720411	NM_133459.4(CCBE1):c.1017A>G (p.Leu339=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
735571	NM_133459.4(CCBE1):c.843A>T (p.Pro281=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
758115	NM_133459.4(CCBE1):c.1163A>G (p.Asp388Gly)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
762247	NM_133459.4(CCBE1):c.519A>G (p.Thr173=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
811360	NM_133459.4(CCBE1):c.966G>A (p.Ala322=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888597	NM_133459.4(CCBE1):c.1064A>C (p.Lys355Thr)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888652	NM_133459.4(CCBE1):c.342T>C (p.Tyr114=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888655	NM_133459.4(CCBE1):c.171C>T (p.Tyr57=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
888656	NM_133459.4(CCBE1):c.131+10G>A	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890302	NM_133459.4(CCBE1):c.810C>T (p.Pro270=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890731	NM_133459.4(CCBE1):c.*2728A>G	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890866	NM_133459.4(CCBE1):c.552T>C (p.Thr184=)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892063	NM_133459.4(CCBE1):c.1079G>A (p.Arg360Gln)	CCBE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031116	NM_133459.4(CCBE1):c.274G>A (p.Val92Ile)	CCBE1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
CCBE1	Definitive	Autosomal recessive	Hennekam lymphangiectasia-lymphedema syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCBE1	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular syndrome

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
CCBE1	HGNC:29426	ENSG00000183287	Q6UXH8	Collagen and calcium-binding EGF domain-containing protein 1	gencc,clinvar
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCBE1	Collagen and calcium-binding EGF domain-containing protein 1	Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.

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)
CCBE1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

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
lower lobe of lung	1
oocyte	1
secondary oocyte	1
blood vessel layer	1
calcaneal tendon	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCBE1	172	ubiquitous	marker	secondary oocyte, lower lobe of lung, oocyte
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAT4	1,932
CCBE1	765

Intra-cohort edges

A	B	Sources
CCBE1	FAT4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAT4	Q6V0I7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CCBE1	Q6UXH8	65.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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 lymphangiogenesis	1	2808.7×	0.004	CCBE1
lymphatic endothelial cell migration	1	2808.7×	0.004	CCBE1
venous blood vessel morphogenesis	1	1203.7×	0.006	CCBE1
lymphangiogenesis	1	601.9×	0.006	CCBE1
positive regulation of protein processing	1	601.9×	0.006	CCBE1
positive regulation of vascular endothelial growth factor signaling pathway	1	561.7×	0.006	CCBE1
respiratory system process	1	468.1×	0.006	CCBE1
hippo signaling	1	366.4×	0.007	FAT4
positive regulation of vascular endothelial growth factor production	1	247.8×	0.008	CCBE1
sprouting angiogenesis	1	240.7×	0.008	CCBE1
cell-cell adhesion mediated by cadherin	1	205.5×	0.009	FAT4
heterophilic cell-cell adhesion	1	168.5×	0.010	FAT4
positive regulation of endothelial cell migration	1	125.8×	0.012	CCBE1
neurogenesis	1	104.0×	0.013	FAT4
cerebral cortex development	1	102.8×	0.013	FAT4
lung development	1	99.1×	0.013	CCBE1
epithelial cell differentiation	1	87.8×	0.013	FAT4
axonogenesis	1	80.2×	0.014	FAT4
homophilic cell-cell adhesion	1	70.2×	0.015	FAT4
positive regulation of angiogenesis	1	57.7×	0.017	CCBE1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
CCBE1	0	0
FAT4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	CCBE1, FAT4

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)
CCBE1	0	—
FAT4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.