Syndactyly type 5

Summary

Syndactyly type 5 (MONDO:0008516) is a disease caused by HOXD13 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HOXD13 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 15
• Phenotypes (HPO): 8

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

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0001440	Metatarsal synostosis	Very frequent (80-99%)
HP:0009465	Ulnar deviation of finger	Very frequent (80-99%)
HP:0009701	Metacarpal synostosis	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0004691	2-3 toe syndactyly	Frequent (30-79%)
HP:0006097	3-4 finger syndactyly	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndactyly type 5
Mondo ID	MONDO:0008516
MeSH	C538155
OMIM	186300
Orphanet	93406
DOID	DOID:0111819
ICD-11	283224140
SNOMED CT	719159004
UMLS	C1861348
MedGen	350010
GARD	0005089
Is cancer (heuristic)	no

Also known as: postaxial syndactyly with metacarpal synostosis · SD5 · SDTY5 · syndactyly with associated metacarpal and metatarsal fusion

Data availability: 15 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 › syndactyly › non-syndromic syndactyly › syndactyly type 5

Related subtypes (7): non-syndromic synpolydactyly, syndactyly type 1, syndactyly type 3, syndactyly type 4, 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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1451293	NM_000523.4(HOXD13):c.186_212dup (p.Ala63_Ala71dup)	HOXD13	Pathogenic	criteria provided, multiple submitters, no conflicts
14873	NM_000523.4(HOXD13):c.209_210insGGCTGCGGCGGCGGCAGCGGC (p.Ala65_Ala71dup)	HOXD13	Pathogenic	criteria provided, multiple submitters, no conflicts
14874	NM_000523.4(HOXD13):c.974A>G (p.Gln325Arg)	HOXD13	Pathogenic	no assertion criteria provided
1919465	NM_000523.4(HOXD13):c.183_203dup (p.Ala71_Ser72insAlaAlaAlaAlaAlaAlaAla)	HOXD13	Pathogenic	criteria provided, multiple submitters, no conflicts
689765	NM_000523.4(HOXD13):c.744_747del (p.Gln248fs)	HOXD13	Pathogenic	criteria provided, single submitter
1323061	NM_000523.4(HOXD13):c.183_206dup (p.Ala64_Ala71dup)	HOXD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374019	NM_000523.4(HOXD13):c.820C>T (p.Arg274Ter)	HOXD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
829870	NM_000165.5(GJA1):c.917G>A (p.Ser306Asn)	GJA1	Uncertain significance	criteria provided, single submitter
1350734	NM_000523.4(HOXD13):c.202G>C (p.Ala68Pro)	HOXD13	Uncertain significance	criteria provided, multiple submitters, no conflicts
1392506	NM_000523.4(HOXD13):c.170C>T (p.Ala57Val)	HOXD13	Uncertain significance	criteria provided, multiple submitters, no conflicts
3585054	NM_000523.4(HOXD13):c.1007C>G (p.Ser336Cys)	HOXD13	Uncertain significance	criteria provided, single submitter
3891344	NM_000523.4(HOXD13):c.469G>A (p.Ala157Thr)	HOXD13	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891345	NM_000523.4(HOXD13):c.955C>A (p.Gln319Lys)	HOXD13	Uncertain significance	criteria provided, single submitter
493303	NM_000523.4(HOXD13):c.296C>G (p.Pro99Arg)	HOXD13	Uncertain significance	criteria provided, multiple submitters, no conflicts
193107	NM_000523.4(HOXD13):c.204G>A (p.Ala68=)	HOXD13	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 13 · 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
HOXD13	Definitive	Autosomal dominant	brachydactyly-syndactyly syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HOXD13	Orphanet:295191	Zygodactyly type 3
HOXD13	Orphanet:295195	Synpolydactyly type 1
HOXD13	Orphanet:887	VACTERL/VATER association
HOXD13	Orphanet:93387	Brachydactyly type E
HOXD13	Orphanet:93406	Syndactyly type 5
HOXD13	Orphanet:93409	Brachydactyly-syndactyly, Zhao type
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3

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
HOXD13	HGNC:5136	ENSG00000128714	P35453	Homeobox protein Hox-D13	gencc,clinvar
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HOXD13	Homeobox protein Hox-D13	Sequence-specific transcription factor that binds gene promoters and activates their transcription.
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOXD13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

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
muscle layer of sigmoid colon	1
urethra	1
vagina	1
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HOXD13	47	tissue_specific	marker	urethra, vagina, muscle layer of sigmoid colon
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942
HOXD13	1,432

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXD13	P35453	57.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Oligomerization of connexins into connexons	1	3806.7×	1e-03	GJA1
Transport of connexins along the secretory pathway	1	3806.7×	1e-03	GJA1
Regulation of gap junction activity	1	3806.7×	1e-03	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	2284.0×	0.001	GJA1
Formation of annular gap junctions	1	1038.2×	0.002	GJA1
Gap junction degradation	1	951.7×	0.002	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.002	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.003	GJA1
Gap junction assembly	1	292.8×	0.004	GJA1
RHOJ GTPase cycle	1	200.3×	0.005	GJA1
RHOQ GTPase cycle	1	181.3×	0.006	GJA1

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
branch elongation of an epithelium	1	8426.0×	0.002	HOXD13
microtubule-based transport	1	8426.0×	0.002	GJA1
positive regulation of mesodermal cell differentiation	1	8426.0×	0.002	GJA1
negative regulation of gonadotropin secretion	1	4213.0×	0.003	GJA1
embryonic hindgut morphogenesis	1	2808.7×	0.003	HOXD13
positive regulation of morphogenesis of an epithelium	1	2808.7×	0.003	GJA1
cell communication by electrical coupling	1	2106.5×	0.003	GJA1
morphogenesis of an epithelial fold	1	2106.5×	0.003	HOXD13
regulation of branching involved in prostate gland morphogenesis	1	1685.2×	0.003	HOXD13
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	1203.7×	0.003	HOXD13
negative regulation of trophoblast cell migration	1	1203.7×	0.003	GJA1
gap junction assembly	1	1053.2×	0.004	GJA1
glutamate secretion	1	842.6×	0.004	GJA1
atrial cardiac muscle cell action potential	1	842.6×	0.004	GJA1
export across plasma membrane	1	842.6×	0.004	GJA1
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.004	GJA1
cardiac conduction system development	1	526.6×	0.005	GJA1
bone remodeling	1	468.1×	0.005	GJA1
male genitalia development	1	443.5×	0.005	HOXD13
xenobiotic transport	1	421.3×	0.005	GJA1
positive regulation of stem cell proliferation	1	263.3×	0.008	GJA1
establishment of mitotic spindle orientation	1	240.7×	0.008	GJA1
maintenance of blood-brain barrier	1	240.7×	0.008	GJA1
response to testosterone	1	234.1×	0.008	HOXD13
positive regulation of vascular associated smooth muscle cell proliferation	1	216.1×	0.008	GJA1
cellular response to amyloid-beta	1	195.9×	0.009	GJA1
embryonic digit morphogenesis	1	150.5×	0.011	HOXD13
bone development	1	138.1×	0.012	GJA1
monoatomic ion transmembrane transport	1	104.0×	0.015	GJA1
anterior/posterior pattern specification	1	90.6×	0.017	HOXD13

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4
HOXD13	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GJA1	4	Binding:4

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
KANAMYCIN	4	GJA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
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	HOXD13

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)
HOXD13	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.