Brachydactyly-syndactyly syndrome

Summary

Brachydactyly-syndactyly syndrome (MONDO:0012544) is a disease caused by HOXD13 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HOXD13 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 12
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0004220	Short middle phalanx of the 5th finger	Very frequent (80-99%)
HP:0004704	Short fifth metatarsal	Very frequent (80-99%)
HP:0009577	Short middle phalanx of the 2nd finger	Very frequent (80-99%)
HP:0010047	Short 5th metacarpal	Very frequent (80-99%)
HP:0001822	Hallux valgus	Frequent (30-79%)
HP:0009773	Symphalangism affecting the phalanges of the hand	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly-syndactyly syndrome
Mondo ID	MONDO:0012544
MeSH	C565193
OMIM	610713
Orphanet	93409
DOID	DOID:0050689
UMLS	C1853137
MedGen	377836
GARD	0016821
Is cancer (heuristic)	no

Also known as: BDSD · brachydactyly-syndactyly syndrome

Data availability: 12 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 › autosomal genetic disease › brachydactyly-syndactyly syndrome

Related subtypes (7): autosomal dominant disease, autosomal recessive disease, septooptic dysplasia, congenital factor XII deficiency, camptodactyly-tall stature-scoliosis-hearing loss syndrome, congenital factor XI deficiency, Weill-Marchesani syndrome

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

12 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 3 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14875	NM_000523.4(HOXD13):c.183_203del (p.Ala65_Ala71del)	HOXD13	Pathogenic	no assertion criteria provided
1324539	NM_000523.4(HOXD13):c.203_204insA (p.Ala69fs)	HOXD13	Likely 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
1338819	NM_000523.4(HOXD13):c.168GGC[6] (p.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
1034246	NM_000523.4(HOXD13):c.217G>A (p.Gly73Ser)	HOXD13	Uncertain significance	criteria provided, multiple submitters, no conflicts
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

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	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

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
HOXD13	HGNC:5136	ENSG00000128714	P35453	Homeobox protein Hox-D13	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOXD13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
muscle layer of sigmoid colon	1
urethra	1
vagina	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HOXD13	1,432

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXD13	P35453	57.18

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
branch elongation of an epithelium	1	16852.0×	9e-04	HOXD13
embryonic hindgut morphogenesis	1	5617.3×	0.001	HOXD13
morphogenesis of an epithelial fold	1	4213.0×	0.001	HOXD13
regulation of branching involved in prostate gland morphogenesis	1	3370.4×	0.001	HOXD13
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	2407.4×	0.001	HOXD13
male genitalia development	1	887.0×	0.003	HOXD13
response to testosterone	1	468.1×	0.005	HOXD13
embryonic digit morphogenesis	1	300.9×	0.006	HOXD13
anterior/posterior pattern specification	1	181.2×	0.009	HOXD13
skeletal system development	1	125.8×	0.012	HOXD13
regulation of cell population proliferation	1	115.4×	0.012	HOXD13
transcription by RNA polymerase II	1	70.5×	0.018	HOXD13
regulation of DNA-templated transcription	1	31.6×	0.037	HOXD13
positive regulation of transcription by RNA polymerase II	1	14.9×	0.072	HOXD13
regulation of transcription by RNA polymerase II	1	11.7×	0.086	HOXD13

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
HOXD13	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	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.