brachydactyly type E1

Summary

brachydactyly type E1 (MONDO:0007223) 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: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly type E1
Mondo ID	MONDO:0007223
MeSH	C566194
OMIM	113300
DOID	DOID:0110972
UMLS	C1862102
MedGen	396291
GARD	0024533
Is cancer (heuristic)	no

Also known as: BDE1 · brachydactyly type E caused by mutation in HOXD13 · brachydactyly, type E1 · HOXD13 brachydactyly type E

Data availability: 15 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › brachydactyly › brachydactyly type E › brachydactyly type E1

Related subtypes (2): 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

15 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
242978	GRCh37/hg19 6p25.3-25.2(chr6:255350-3189972)x3	BPHL	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
689765	NM_000523.4(HOXD13):c.744_747del (p.Gln248fs)	HOXD13	Pathogenic	criteria provided, single submitter
3338640	NM_000316.3(PTH1R):c.1405G>A (p.Glu469Lys)	PTH1R	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
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
1395519	NM_000316.3(PTH1R):c.1393G>A (p.Glu465Lys)	PTH1R	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
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: 11 · 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
PTH1R	Orphanet:296	Ollier disease
PTH1R	Orphanet:33067	Metaphyseal chondrodysplasia, Jansen type
PTH1R	Orphanet:412206	Primary failure of tooth eruption
PTH1R	Orphanet:50945	Blomstrand lethal chondrodysplasia
PTH1R	Orphanet:79106	Eiken syndrome

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
BPHL	HGNC:1094	ENSG00000137274	Q86WA6	Serine hydrolase BPHL	clinvar
PTH1R	HGNC:9608	ENSG00000160801	Q03431	Parathyroid hormone/parathyroid hormone-related peptide receptor	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.
BPHL	Serine hydrolase BPHL	Specific alpha-amino acid ester serine hydrolase that prefers small, hydrophobic, and aromatic side chains and does not have a stringent requirement for the leaving group other than preferring a primary alcohol.
PTH1R	Parathyroid hormone/parathyroid hormone-related peptide receptor	G-protein-coupled receptor for parathyroid hormone (PTH) and for parathyroid hormone-related peptide (PTHLH).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · 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
GPCR	1	8.0×	0.360
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOXD13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
BPHL	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold
PTH1R	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_parathyroid_rcpt

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	2
muscle layer of sigmoid colon	1
urethra	1
vagina	1
liver	1
right lobe of liver	1
metanephros cortex	1
tibia	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
BPHL	253	ubiquitous	marker	right lobe of liver, adult mammalian kidney, liver
PTH1R	219	broad	marker	adult mammalian kidney, metanephros cortex, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTH1R	1,633
HOXD13	1,432
BPHL	1,390

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTH1R	Q03431	48
BPHL	Q86WA6	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXD13	P35453	57.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase I - Functionalization of compounds	1	109.8×	0.026	BPHL
Class B/2 (Secretin family receptors)	1	95.2×	0.026	PTH1R
Biological oxidations	1	64.9×	0.026	BPHL
G alpha (s) signalling events	1	36.6×	0.034	PTH1R
Metabolism	1	5.8×	0.165	BPHL

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
branch elongation of an epithelium	1	5617.3×	0.003	HOXD13
skeletal system development	2	83.8×	0.003	HOXD13, PTH1R
embryonic hindgut morphogenesis	1	1872.4×	0.006	HOXD13
morphogenesis of an epithelial fold	1	1404.3×	0.006	HOXD13
regulation of branching involved in prostate gland morphogenesis	1	1123.5×	0.006	HOXD13
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	802.5×	0.006	HOXD13
positive regulation of inositol phosphate biosynthetic process	1	802.5×	0.006	PTH1R
homocysteine metabolic process	1	624.1×	0.007	BPHL
osteoblast development	1	330.4×	0.012	PTH1R
male genitalia development	1	295.6×	0.012	HOXD13
amino acid metabolic process	1	267.5×	0.012	BPHL
bone resorption	1	193.7×	0.015	PTH1R
response to testosterone	1	156.0×	0.017	HOXD13
cell maturation	1	147.8×	0.017	PTH1R
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	112.3×	0.020	PTH1R
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1	104.0×	0.020	PTH1R
chondrocyte differentiation	1	100.3×	0.020	PTH1R
embryonic digit morphogenesis	1	100.3×	0.020	HOXD13
bone mineralization	1	90.6×	0.021	PTH1R
response to toxic substance	1	70.2×	0.026	BPHL
anterior/posterior pattern specification	1	60.4×	0.028	HOXD13
xenobiotic metabolic process	1	49.7×	0.032	BPHL
intracellular calcium ion homeostasis	1	48.4×	0.032	PTH1R
phospholipase C-activating G protein-coupled receptor signaling pathway	1	43.9×	0.034	PTH1R
regulation of cell population proliferation	1	38.5×	0.036	HOXD13
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	37.7×	0.036	PTH1R
cell population proliferation	1	34.2×	0.039	PTH1R
in utero embryonic development	1	24.0×	0.052	PTH1R
transcription by RNA polymerase II	1	23.5×	0.052	HOXD13
cell surface receptor signaling pathway	1	21.4×	0.055	PTH1R

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PTH1R	ABALOPARATIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTH1R	3	4
HOXD13	0	0
BPHL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABALOPARATIDE	4	PTH1R
TERIPARATIDE	4	PTH1R
PCO-371	1	PTH1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PTH1R	59	Functional:42, Binding:17
BPHL	4	Binding:4

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

3 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)
ABALOPARATIDE	4	PTH1R
TERIPARATIDE	4	PTH1R
PCO-371	1	PTH1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTH1R
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, BPHL

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	—
BPHL	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.