Synpolydactyly type 1

Summary

Synpolydactyly type 1 (MONDO:0008513) is a disease caused by HOXD13 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: HOXD13 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	synpolydactyly type 1
Mondo ID	MONDO:0008513
OMIM	186000
Orphanet	295195
ICD-11	1701170393
UMLS	C5574994
MedGen	1809573
GARD	0017358
Is cancer (heuristic)	no

Also known as: HOXD13 non-syndromic synpolydactyly · non-syndromic synpolydactyly caused by mutation in HOXD13 · SD2, Vordingborg type · SD2a · SPD, Vordingborg type · SPD1 · synpolydactyly 1 · synpolydactyly type 1 · synpolydactyly, Vordingborg type

Data availability: 29 ClinVar variants · 3 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 › non-syndromic synpolydactyly › synpolydactyly type 1

Related subtypes (3): polysyndactyly 4, synpolydactyly type 2, synpolydactyly type 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

29 retrieved; paginated sample, class counts are floors:

14 pathogenic, 8 uncertain significance, 4 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332838	NM_000523.4(HOXD13):c.708del (p.Asn236fs)	HOXD13	Pathogenic	criteria provided, single submitter
14867	NM_000523.4(HOXD13):c.323_336del (p.Pro108fs)	HOXD13	Pathogenic	no assertion criteria provided
14868	NM_000523.4(HOXD13):c.834del (p.Lys279fs)	HOXD13	Pathogenic	no assertion criteria provided
14871	NM_000523.4(HOXD13):c.782-2del	HOXD13	Pathogenic	no assertion criteria provided
14872	NM_000523.4(HOXD13):c.916C>T (p.Arg306Trp)	HOXD13	Pathogenic/Likely 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
14876	NM_000523.4(HOXD13):c.683G>T (p.Gly228Val)	HOXD13	Pathogenic	no assertion criteria provided
225650	NM_000523.4(HOXD13):c.742C>T (p.Gln248Ter)	HOXD13	Pathogenic	no assertion criteria provided
225652	NM_000523.4(HOXD13):c.917G>A (p.Arg306Gln)	HOXD13	Pathogenic	no assertion criteria provided
225653	NM_000523.4(HOXD13):c.781+1G>A	HOXD13	Pathogenic	no assertion criteria provided
225654	NM_000523.4(HOXD13):c.683G>C (p.Gly228Ala)	HOXD13	Pathogenic	no assertion criteria provided
225656	NM_000523.4(HOXD13):c.916C>G (p.Arg306Gly)	HOXD13	Pathogenic	no assertion criteria provided
3382450	NM_000523.4(HOXD13):c.673del (p.Ser225fs)	HOXD13	Pathogenic	criteria provided, single submitter
689765	NM_000523.4(HOXD13):c.744_747del (p.Gln248fs)	HOXD13	Pathogenic	criteria provided, single submitter
916250	NM_000523.4(HOXD13):c.212_213insGGCGGCTGCGGCGGCGGCAGCGGCAGC (p.Ala63_Ala71dup)	HOXD13	Pathogenic	criteria provided, multiple submitters, no conflicts
3239637	NC_000002.12:g.176073523_176079120del	EVX2	Likely pathogenic	criteria provided, single submitter
559505	NM_018413.6(CHST11):c.482_496del (p.Leu161_Asn165del)	CHST11	Conflicting classifications of pathogenicity	no assertion criteria provided
1323061	NM_000523.4(HOXD13):c.183_206dup (p.Ala64_Ala71dup)	HOXD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225651	NM_000523.4(HOXD13):c.32G>C (p.Gly11Ala)	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
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
1695392	NM_000523.4(HOXD13):c.623A>T (p.Asp208Val)	HOXD13	Uncertain significance	criteria provided, single submitter
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
930707	NM_000523.4(HOXD13):c.709G>C (p.Gly237Arg)	HOXD13	Uncertain significance	criteria provided, single submitter
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: 6 · 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	Strong	Autosomal dominant	synpolydactyly type 1	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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HOXD13	HGNC:5136	ENSG00000128714	P35453	Homeobox protein Hox-D13	gencc,clinvar
CHST11	HGNC:17422	ENSG00000171310	Q9NPF2	Carbohydrate sulfotransferase 11	clinvar
EVX2	HGNC:3507	ENSG00000174279	Q03828	Homeobox even-skipped homolog protein 2	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.
CHST11	Carbohydrate sulfotransferase 11	Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	2	5.5×	0.081
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOXD13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
CHST11	Enzyme (other)	yes	2.8.2.5	Sulfotransferase, Carb_sulfotrans_8-10
EVX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
muscle layer of sigmoid colon	1
urethra	1
vagina	1
blood	1
cartilage tissue	1
tibia	1
calcaneal tendon	1
ectocervix	1
male germ line stem cell (sensu Vertebrata) in testis	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
CHST11	243	ubiquitous	marker	tibia, blood, cartilage tissue
EVX2	25		yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, ectocervix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HOXD13	1,432
CHST11	932
EVX2	623

Intra-cohort edges

A	B	Sources
EVX2	HOXD13	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST11	Q9NPF2	89.39
HOXD13	P35453	57.18
EVX2	Q03828	56.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
CS-GAG biosynthesis	1	543.8×	0.002	CHST11

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic digit morphogenesis	2	200.6×	0.001	HOXD13, CHST11
polysaccharide localization	1	5617.3×	0.002	CHST11
branch elongation of an epithelium	1	5617.3×	0.002	HOXD13
regulation of cell population proliferation	2	77.0×	0.002	HOXD13, CHST11
embryonic hindgut morphogenesis	1	1872.4×	0.003	HOXD13
morphogenesis of an epithelial fold	1	1404.3×	0.004	HOXD13
regulation of branching involved in prostate gland morphogenesis	1	1123.5×	0.004	HOXD13
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	802.5×	0.005	HOXD13
embryonic viscerocranium morphogenesis	1	561.7×	0.006	CHST11
carbohydrate biosynthetic process	1	510.7×	0.006	CHST11
limb morphogenesis	1	351.1×	0.008	EVX2
chondrocyte development	1	312.1×	0.008	CHST11
male genitalia development	1	295.6×	0.008	HOXD13
proteoglycan biosynthetic process	1	280.9×	0.008	CHST11
post-anal tail morphogenesis	1	244.2×	0.008	CHST11
developmental growth	1	244.2×	0.008	CHST11
respiratory gaseous exchange by respiratory system	1	208.1×	0.008	CHST11
chondroitin sulfate proteoglycan biosynthetic process	1	208.1×	0.008	CHST11
response to testosterone	1	156.0×	0.010	HOXD13
post-embryonic development	1	68.5×	0.023	CHST11
anterior/posterior pattern specification	1	60.4×	0.024	HOXD13
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.024	CHST11
transforming growth factor beta receptor signaling pathway	1	53.0×	0.025	CHST11
regulation of transcription by RNA polymerase II	2	7.8×	0.027	HOXD13, EVX2
skeletal system development	1	41.9×	0.029	HOXD13
in utero embryonic development	1	24.0×	0.048	CHST11
transcription by RNA polymerase II	1	23.5×	0.048	HOXD13
negative regulation of apoptotic process	1	11.6×	0.093	CHST11
regulation of DNA-templated transcription	1	10.5×	0.098	HOXD13
apoptotic process	1	9.6×	0.104	CHST11

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
HOXD13	0	0
CHST11	0	0
EVX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHST11	2.8.2.5	chondroitin 4-sulfotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	CHST11
E	Difficult family or no structure, no drug	2	HOXD13, EVX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HOXD13	0	—
CHST11	0	—
EVX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.