Non-syndromic syndactyly

Summary

Non-syndromic syndactyly (MONDO:0019530) is a disease (an umbrella term covering 8 Mondo subtypes) with 4 cohort genes and 4 clinical trials. Top therapeutic interventions include sodium chloride.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 4
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	non-syndromic syndactyly
Mondo ID	MONDO:0019530
Orphanet	90025
ICD-11	1736296640
NCIT	C87125
UMLS	C5681365
MedGen	1842957
MedDRA	10042778
Is cancer (heuristic)	no

Also known as: chromosome 2q35 duplication syndrome · isolated syndactyly · nonsyndromic syndactyly · syndactyly

Data availability: 4 ClinVar variants.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › syndactyly › non-syndromic syndactyly

Related subtypes (1): polydactyly-syndactyly-triphalangism

Subtypes (8): non-syndromic synpolydactyly, syndactyly type 1, syndactyly type 3, syndactyly type 4, syndactyly type 5, syndactyly type 8, mesoaxial synostotic syndactyly with phalangeal reduction, syndactyly type 6

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

4 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1713128	NM_018046.5(AGGF1):c.112_132dup (p.Arg44_Glu45insSerCysLysArgGlnValArg)	AGGF1	Likely pathogenic	criteria provided, single submitter
1713129	NM_004525.3(LRP2):c.3889G>T (p.Gly1297Trp)	LRP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1713130	NM_031891.4(CDH20):c.2059C>T (p.Arg687Trp)	CDH20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1713131	NM_001008749.3(RAB19):c.331T>C (p.Trp111Arg)	RAB19	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGGF1	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
LRP2	Orphanet:2143	Donnai-Barrow syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDH20	HGNC:1760	ENSG00000101542	Q9HBT6	Cadherin-20	clinvar
RAB19	HGNC:19982	ENSG00000146955	A4D1S5	Ras-related protein Rab-19	clinvar
AGGF1	HGNC:24684	ENSG00000164252	Q8N302	Angiogenic factor with G patch and FHA domains 1	clinvar
LRP2	HGNC:6694	ENSG00000081479	P98164	Low-density lipoprotein receptor-related protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDH20	Cadherin-20	Cadherins are calcium-dependent cell adhesion proteins.
RAB19	Ras-related protein Rab-19	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
AGGF1	Angiogenic factor with G patch and FHA domains 1	Promotes angiogenesis and the proliferation of endothelial cells.
LRP2	Low-density lipoprotein receptor-related protein 2	Multiligand endocytic receptor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDH20	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
RAB19	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
AGGF1	Other/Unknown	no		FHA_dom, G_patch_dom, SMAD_FHA_dom_sf
LRP2	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
amygdala	1
ventricular zone	1
bone marrow	1
bone marrow cell	1
mucosa of transverse colon	1
choroid plexus epithelium	1
epithelium of nasopharynx	1
palpebral conjunctiva	1
adult mammalian kidney	1
adult organism	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDH20	148	broad	marker	ventricular zone, C1 segment of cervical spinal cord, amygdala
RAB19	73	broad	yes	mucosa of transverse colon, bone marrow cell, bone marrow
AGGF1	284	ubiquitous	marker	choroid plexus epithelium, epithelium of nasopharynx, palpebral conjunctiva
LRP2	169	broad	marker	adult organism, adult mammalian kidney, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP2	2,501
RAB19	1,309
AGGF1	1,205
CDH20	1,139

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRP2	P98164	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAB19	A4D1S5	83.68
CDH20	Q9HBT6	77.33
AGGF1	Q8N302	66.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transport of RCbl within the body	1	475.8×	0.033	LRP2
Vitamin D (calciferol) metabolism	1	292.8×	0.033	LRP2
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	211.5×	0.033	LRP2
Metabolism of fat-soluble vitamins	1	126.9×	0.036	LRP2
Visual phototransduction	1	86.5×	0.036	LRP2
Oncogenic MAPK signaling	1	82.8×	0.036	AGGF1
Retinoid metabolism and transport	1	82.8×	0.036	LRP2
Metabolism of water-soluble vitamins and cofactors	1	60.4×	0.037	LRP2
RAB geranylgeranylation	1	57.7×	0.037	RAB19
Signaling by BRAF and RAF1 fusions	1	56.8×	0.037	AGGF1
Metabolism of steroids	1	45.9×	0.041	LRP2
Metabolism of vitamins and cofactors	1	38.8×	0.045	LRP2
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.046	LRP2
Sensory Perception	1	31.7×	0.047	LRP2
Clathrin-mediated endocytosis	1	28.4×	0.049	LRP2
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.068	AGGF1
Membrane Trafficking	1	12.4×	0.097	LRP2
Vesicle-mediated transport	1	11.6×	0.098	LRP2
Metabolism of lipids	1	10.5×	0.102	LRP2
Disease	1	4.4×	0.223	AGGF1
Metabolism	1	3.9×	0.237	LRP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
diol metabolic process	1	4213.0×	0.009	LRP2
positive regulation of oligodendrocyte progenitor proliferation	1	2106.5×	0.009	LRP2
folate import across plasma membrane	1	1053.2×	0.009	LRP2
positive regulation of lysosomal protein catabolic process	1	842.6×	0.009	LRP2
pulmonary artery morphogenesis	1	702.2×	0.009	LRP2
ventricular compact myocardium morphogenesis	1	601.9×	0.009	LRP2
response to leptin	1	601.9×	0.009	LRP2
cobalamin transport	1	468.1×	0.009	LRP2
metal ion transport	1	468.1×	0.009	LRP2
coronary artery morphogenesis	1	468.1×	0.009	LRP2
neuron projection arborization	1	468.1×	0.009	LRP2
transcytosis	1	421.3×	0.009	LRP2
secondary heart field specification	1	383.0×	0.009	LRP2
vitamin D metabolic process	1	383.0×	0.009	LRP2
vagina development	1	383.0×	0.009	LRP2
amyloid-beta clearance	1	234.1×	0.013	LRP2
cranial skeletal system development	1	234.1×	0.013	LRP2
outflow tract septum morphogenesis	1	162.0×	0.018	LRP2
positive regulation of neurogenesis	1	145.3×	0.018	LRP2
aorta development	1	140.4×	0.018	LRP2
adherens junction organization	1	127.7×	0.018	CDH20
retinoid metabolic process	1	123.9×	0.018	LRP2
ventricular septum development	1	123.9×	0.018	LRP2
calcium-dependent cell-cell adhesion	1	120.4×	0.018	CDH20
cell-cell junction assembly	1	110.9×	0.019	CDH20
cell-cell adhesion mediated by cadherin	1	102.8×	0.019	CDH20
forebrain development	1	87.8×	0.022	LRP2
cellular response to growth factor stimulus	1	79.5×	0.023	LRP2
negative regulation of BMP signaling pathway	1	72.6×	0.025	LRP2
vasculogenesis	1	63.8×	0.027	AGGF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDH20	0	0
RAB19	0	0
AGGF1	0	0
LRP2	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
LRP2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	CDH20, RAB19, AGGF1, LRP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDH20	0	—
RAB19	0	—
AGGF1	0	—
LRP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT03107546	Not specified	COMPLETED	Comparison of Scar Formation in Syndactyly Release Surgery With Full Thickness Skin Graft Versus Skin Graft Substitute
NCT07596862	Not specified	COMPLETED	Remote Assesment of Functional Sequelae in Patients Operated for Congenital Syndactyly

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1