brachydactyly type E

Summary

brachydactyly type E (MONDO:0019677) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 10

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0005863	Type E brachydactyly	Very frequent (80-99%)
HP:0010049	Short metacarpal	Very frequent (80-99%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0009882	Short distal phalanx of finger	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0010076	Aplasia/Hypoplasia of the distal phalanx of the hallux	Occasional (5-29%)
HP:0010743	Short metatarsal	Occasional (5-29%)
HP:0100560	Upper limb asymmetry	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly type E
Mondo ID	MONDO:0019677
Orphanet	93387
ICD-11	712007423
UMLS	C4315392
MedGen	939359
GARD	0000987
Is cancer (heuristic)	no

Also known as: type E brachydactyly

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › brachydactyly › brachydactyly type E

Related subtypes (21): Cooks syndrome, brachydactyly-arterial hypertension syndrome, Ballard syndrome, brachydactyly type A1, brachydactyly type A2, brachydactyly type A3, brachydactyly type A4, Osebold-Remondini syndrome, brachydactyly type C, brachydactyly type D, camptobrachydactyly, brachydactyly type A1B, brachydactyly type A1C, brachydactyly type A1D, non-syndromic brachydactyly, brachydactyly type B, brachydactyly type A5, brachydactyly type A7, brachydactyly type A1A, Berk-Tabatznik syndrome, preaxial digit brachydactyly-webbed fingers

Subtypes (3): brachydactyly type E1, brachydactyly, type E, with atrial septal defect, type 2, brachydactyly type E2

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14869	NM_000523.4(HOXD13):c.964A>C (p.Ile322Leu)	HOXD13	Pathogenic	no assertion criteria provided
14870	NM_000523.4(HOXD13):c.947C>G (p.Ser316Cys)	HOXD13	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 7 · 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
PTHLH	Definitive	Autosomal dominant	brachydactyly type E2	4

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
PTHLH	Orphanet:93387	Brachydactyly type E

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
PTHLH	HGNC:9607	ENSG00000087494	P12272	Parathyroid hormone-related protein	gencc

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.
PTHLH	Parathyroid hormone-related protein	Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport.

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
PTHLH	Other/Unknown	no		PTH/PTH-rel, PTH-rel

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
periodontal ligament	1
primordial germ cell in gonad	1
stromal cell of endometrium	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
PTHLH	202	broad	marker	periodontal ligament, primordial germ cell in gonad, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTHLH	1,599
HOXD13	1,432

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTHLH	P12272	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXD13	P35453	57.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Class B/2 (Secretin family receptors)	1	190.3×	0.011	PTHLH
G alpha (s) signalling events	1	73.2×	0.014	PTHLH

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
skeletal system development	2	125.8×	0.002	HOXD13, PTHLH
adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway	1	4213.0×	0.002	PTHLH
embryonic hindgut morphogenesis	1	2808.7×	0.002	HOXD13
negative regulation of chondrocyte development	1	2808.7×	0.002	PTHLH
cAMP metabolic process	1	2106.5×	0.002	PTHLH
morphogenesis of an epithelial fold	1	2106.5×	0.002	HOXD13
regulation of branching involved in prostate gland morphogenesis	1	1685.2×	0.002	HOXD13
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	1203.7×	0.003	HOXD13
regulation of chondrocyte differentiation	1	702.2×	0.004	PTHLH
osteoblast development	1	495.6×	0.005	PTHLH
male genitalia development	1	443.5×	0.005	HOXD13
negative regulation of chondrocyte differentiation	1	337.0×	0.007	PTHLH
response to testosterone	1	234.1×	0.009	HOXD13
embryonic digit morphogenesis	1	150.5×	0.013	HOXD13
bone mineralization	1	135.9×	0.013	PTHLH
female pregnancy	1	105.3×	0.015	PTHLH
epidermis development	1	105.3×	0.015	PTHLH
anterior/posterior pattern specification	1	90.6×	0.017	HOXD13
regulation of cell population proliferation	1	57.7×	0.024	HOXD13
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.024	PTHLH
regulation of gene expression	1	41.7×	0.031	PTHLH
transcription by RNA polymerase II	1	35.3×	0.034	HOXD13
cell-cell signaling	1	34.8×	0.034	PTHLH
negative regulation of cell population proliferation	1	21.1×	0.054	PTHLH
positive regulation of cell population proliferation	1	16.8×	0.065	PTHLH
regulation of DNA-templated transcription	1	15.8×	0.067	HOXD13
positive regulation of transcription by RNA polymerase II	1	7.4×	0.135	HOXD13
regulation of transcription by RNA polymerase II	1	5.8×	0.164	HOXD13

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PTHLH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	HOXD13, PTHLH

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.