Hennekam lymphangiectasia-lymphedema syndrome 2

Summary

Hennekam lymphangiectasia-lymphedema syndrome 2 (MONDO:0014454) is a disease caused by FAT4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: FAT4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 616

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hennekam lymphangiectasia-lymphedema syndrome 2
Mondo ID	MONDO:0014454
OMIM	616006
UMLS	C4014939
MedGen	863376
GARD	0016047
Is cancer (heuristic)	no

Also known as: FAT4 Hennekam syndrome · Hennekam lymphangiectasia-lymphedema syndrome 2 · Hennekam lymphangiectasia-lymphedema syndrome type 2 · Hennekam syndrome caused by mutation in FAT4 · HKLLS2

Data availability: 616 ClinVar variants · 2 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 2

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

600 retrieved; paginated sample, class counts are floors:

496 uncertain significance, 66 conflicting classifications of pathogenicity, 15 benign, 7 likely pathogenic, 6 benign/likely benign, 5 likely benign, 3 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
156109	NM_001291303.3(FAT4):c.7035TGGAAC[3] (p.2346GT[3])	FAT4	Pathogenic	no assertion criteria provided
156110	NM_001291303.3(FAT4):c.1195del (p.Leu399fs)	FAT4	Pathogenic	no assertion criteria provided
156112	NM_001291303.3(FAT4):c.7204A>C (p.Arg2402=)	FAT4	Pathogenic	no assertion criteria provided
1703760	NM_001291303.3(FAT4):c.13588C>T (p.Gln4530Ter)	FAT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589971	NM_001291303.3(FAT4):c.5704C>T (p.Arg1902Ter)	FAT4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700623	NM_001291303.3(FAT4):c.12479+3A>G	FAT4	Likely pathogenic	no assertion criteria provided
3589912	NM_001291303.3(FAT4):c.2657del (p.Asp885_Leu886insTer)	FAT4	Likely pathogenic	criteria provided, single submitter
3589985	NM_001291303.3(FAT4):c.6457del (p.Ile2153fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590009	NM_001291303.3(FAT4):c.7312del (p.Val2438fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590090	NM_001291303.3(FAT4):c.11965del (p.Glu3989fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3590136	NM_001291303.3(FAT4):c.14610del (p.Lys4871fs)	FAT4	Likely pathogenic	criteria provided, single submitter
3891868	NM_001291303.3(FAT4):c.216C>G (p.Tyr72Ter)	FAT4	Likely pathogenic	criteria provided, single submitter
1012078	NM_001291303.3(FAT4):c.11260A>G (p.Ser3754Gly)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031381	NM_001291303.3(FAT4):c.12085G>A (p.Ala4029Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032176	NM_001291303.3(FAT4):c.8313T>C (p.Asn2771=)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1110181	NM_001291303.3(FAT4):c.12499G>A (p.Ala4167Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1112797	NM_001291303.3(FAT4):c.1244C>G (p.Pro415Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1125571	NM_001291303.3(FAT4):c.3067A>G (p.Lys1023Glu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1150708	NM_001291303.3(FAT4):c.7582G>A (p.Gly2528Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1165453	NM_001291303.3(FAT4):c.9451G>A (p.Ala3151Thr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1198532	NM_001291303.3(FAT4):c.6731C>T (p.Thr2244Met)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1214983	NM_001291303.3(FAT4):c.2273C>T (p.Ala758Val)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1254011	NM_001291303.3(FAT4):c.14362G>A (p.Gly4788Arg)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303353	NM_001291303.3(FAT4):c.4432A>C (p.Ile1478Leu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307026	NM_001291303.3(FAT4):c.4228G>A (p.Val1410Met)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314680	NM_001291303.3(FAT4):c.4199G>A (p.Arg1400His)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328875	NM_001291303.3(FAT4):c.12778G>A (p.Val4260Ile)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337703	NM_001291303.3(FAT4):c.9597T>A (p.Asp3199Glu)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357337	NM_001291303.3(FAT4):c.3637G>T (p.Asp1213Tyr)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365452	NM_001291303.3(FAT4):c.2824A>G (p.Ile942Val)	FAT4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
FAT4	Definitive	Autosomal recessive	Hennekam lymphangiectasia-lymphedema syndrome 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular 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
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

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
blood vessel layer	1
calcaneal tendon	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAT4	1,932

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAT4	Q6V0I7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hippo signaling	1	732.7×	0.007	FAT4
cell-cell adhesion mediated by cadherin	1	411.0×	0.007	FAT4
heterophilic cell-cell adhesion	1	337.0×	0.007	FAT4
neurogenesis	1	208.1×	0.007	FAT4
cerebral cortex development	1	205.5×	0.007	FAT4
epithelial cell differentiation	1	175.5×	0.007	FAT4
axonogenesis	1	160.5×	0.007	FAT4
homophilic cell-cell adhesion	1	140.4×	0.007	FAT4

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
FAT4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	FAT4

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)
FAT4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.