brachydactyly type A1

Summary

brachydactyly type A1 (MONDO:0007215) is a disease caused by IHH (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: IHH (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 83
• Phenotypes (HPO): 12

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001773	Short foot	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005819	Short middle phalanx of finger	Very frequent (80-99%)
HP:0009778	Short thumb	Very frequent (80-99%)
HP:0010109	Short hallux	Very frequent (80-99%)
HP:0010579	Cone-shaped epiphysis	Frequent (30-79%)
HP:0001204	Distal symphalangism (hands)	Occasional (5-29%)
HP:0001230	Broad metacarpals	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003022	Hypoplasia of the ulna	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly type A1
Mondo ID	MONDO:0007215
MeSH	C537088
OMIM	112500
Orphanet	93388
DOID	DOID:0110964
ICD-11	568452529
SNOMED CT	715720006
UMLS	C1862151
MedGen	354673
GARD	0000978
Is cancer (heuristic)	no

Also known as: BDA1 · brachydactyly Farabee type · brachydactyly, Farabee type · brachydactyly, type A1

Data availability: 83 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › brachydactyly › brachydactyly type A1

Related subtypes (21): Cooks syndrome, brachydactyly-arterial hypertension syndrome, Ballard syndrome, 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 E, brachydactyly type A5, brachydactyly type A7, brachydactyly type A1A, Berk-Tabatznik syndrome, preaxial digit brachydactyly-webbed fingers

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

83 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 14 benign, 13 pathogenic, 9 likely pathogenic, 8 benign/likely benign, 7 conflicting classifications of pathogenicity, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1217222	NM_002181.4(IHH):c.478C>T (p.Arg160Cys)	IHH	Pathogenic	criteria provided, single submitter
2151961	NM_002181.4(IHH):c.172G>A (p.Glu58Lys)	IHH	Pathogenic	criteria provided, single submitter
3341144	NM_002181.4(IHH):c.532G>C (p.Val178Leu)	IHH	Pathogenic	no assertion criteria provided
3341145	NM_002181.4(IHH):c.319del (p.Cys107fs)	IHH	Pathogenic	no assertion criteria provided
3341146	NM_002181.4(IHH):c.797dup (p.Arg267fs)	IHH	Pathogenic	criteria provided, single submitter
3341147	NM_002181.4(IHH):c.541del (p.Glu181fs)	IHH	Pathogenic	no assertion criteria provided
3341148	IHH, COMPLETE GENE DELETION	IHH	Pathogenic	no assertion criteria provided
834083	NM_002181.4(IHH):c.280GAG[1] (p.Glu95del)	IHH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8866	NM_002181.4(IHH):c.283G>A (p.Glu95Lys)	IHH	Pathogenic	criteria provided, single submitter
8868	NM_002181.4(IHH):c.300C>A (p.Asp100Glu)	IHH	Pathogenic	no assertion criteria provided
8869	NM_002181.4(IHH):c.298G>A (p.Asp100Asn)	IHH	Pathogenic	criteria provided, multiple submitters, no conflicts
8872	NM_002181.4(IHH):c.284A>G (p.Glu95Gly)	IHH	Pathogenic	no assertion criteria provided
8873	NM_002181.4(IHH):c.461C>T (p.Thr154Ile)	IHH	Pathogenic	no assertion criteria provided
8876	NM_002181.4(IHH):c.389C>A (p.Thr130Asn)	IHH	Pathogenic	no assertion criteria provided
273383	NM_002181.4(IHH):c.151C>A (p.Gln51Lys)	IHH	Likely pathogenic	criteria provided, single submitter
3376840	NM_002181.4(IHH):c.485A>C (p.Lys162Thr)	IHH	Likely pathogenic	criteria provided, single submitter
3775689	NM_002181.4(IHH):c.419C>G (p.Ser140Ter)	IHH	Likely pathogenic	criteria provided, single submitter
834082	NM_002181.4(IHH):c.484A>G (p.Lys162Glu)	IHH	Likely pathogenic	criteria provided, single submitter
834086	NM_002181.4(IHH):c.478C>A (p.Arg160Ser)	IHH	Likely pathogenic	criteria provided, single submitter
869103	NM_002181.4(IHH):c.448G>A (p.Ala150Thr)	IHH	Likely pathogenic	criteria provided, single submitter
8867	NM_002181.4(IHH):c.391G>A (p.Glu131Lys)	IHH	Likely pathogenic	criteria provided, single submitter
8875	NM_002181.4(IHH):c.383G>A (p.Arg128Gln)	IHH	Likely pathogenic	criteria provided, single submitter
929711	NM_002181.4(IHH):c.565_567dup (p.Ser189dup)	IHH	Likely pathogenic	criteria provided, single submitter
3340483	NM_002181.4(IHH):c.446G>A (p.Arg149His)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334436	NM_002181.4(IHH):c.857C>T (p.Pro286Leu)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
334446	NM_002181.4(IHH):c.227A>C (p.Glu76Ala)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896644	NM_002181.4(IHH):c.693C>G (p.Ala231=)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896649	NM_002181.4(IHH):c.540C>T (p.Tyr180=)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898206	NM_002181.4(IHH):c.1222G>A (p.Gly408Arg)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898207	NM_002181.4(IHH):c.1130C>T (p.Pro377Leu)	IHH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 47 · Orphanet: 16 · 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
BMPR1B	Definitive	Autosomal recessive	brachydactyly type A2	17
GDF5	Definitive	Semidominant	brachydactyly type C	20
IHH	Definitive	Autosomal dominant	brachydactyly type A1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IHH	Orphanet:63446	Acrocapitofemoral dysplasia
IHH	Orphanet:93388	Brachydactyly type A1
BMPR1B	Orphanet:2098	Acromesomelic dysplasia, Grebe type
BMPR1B	Orphanet:2639	Fibular aplasia-complex brachydactyly syndrome
BMPR1B	Orphanet:93384	Brachydactyly type C
BMPR1B	Orphanet:93388	Brachydactyly type A1
BMPR1B	Orphanet:93396	Brachydactyly type A2
GDF5	Orphanet:2098	Acromesomelic dysplasia, Grebe type
GDF5	Orphanet:2639	Fibular aplasia-complex brachydactyly syndrome
GDF5	Orphanet:3237	Multiple synostoses syndrome
GDF5	Orphanet:3250	Proximal symphalangism
GDF5	Orphanet:63442	Angel-shaped phalango-epiphyseal dysplasia
GDF5	Orphanet:93384	Brachydactyly type C
GDF5	Orphanet:93388	Brachydactyly type A1
GDF5	Orphanet:93396	Brachydactyly type A2
GDF5	Orphanet:968	Acromesomelic dysplasia, Hunter-Thompson 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
IHH	HGNC:5956	ENSG00000163501	Q14623	Indian hedgehog protein	gencc,clinvar
BMPR1B	HGNC:1077	ENSG00000138696	O00238	Bone morphogenetic protein receptor type-1B	gencc
GDF5	HGNC:4220	ENSG00000125965	P43026	Growth/differentiation factor 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IHH	Indian hedgehog protein	Plays a role in embryonic morphogenesis; it is involved in the regulation of endochondral skeleton formation, and the development of retinal pigment epithelium (RPE), photoreceptors and periocular tissues.
BMPR1B	Bone morphogenetic protein receptor type-1B	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
GDF5	Growth/differentiation factor 5	Growth factor involved in bone and cartilage formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
BMPR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
GDF5	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

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
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
bronchial epithelial cell	1
calcaneal tendon	1
cauda epididymis	1
cartilage tissue	1
parotid gland	1
pericardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IHH	94	broad	marker	mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BMPR1B	239	broad	marker	calcaneal tendon, bronchial epithelial cell, cauda epididymis
GDF5	116	broad	yes	parotid gland, pericardium, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IHH	2,370
GDF5	1,486
BMPR1B	116

Intra-cohort edges

A	B	Sources
BMPR1B	GDF5	biogrid_interaction, intact
GDF5	IHH	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF5	P43026	15
IHH	Q14623	8
BMPR1B	O00238	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HHAT G278V doesn’t palmitoylate Hh-Np	1	761.3×	0.005	IHH
RUNX2 regulates chondrocyte maturation	1	761.3×	0.005	IHH
Formation of lateral plate mesoderm	1	761.3×	0.005	IHH
Release of Hh-Np from the secreting cell	1	475.8×	0.005	IHH
Ligand-receptor interactions	1	475.8×	0.005	IHH
Activation of SMO	1	211.5×	0.010	IHH
Signaling by BMP	1	119.0×	0.016	BMPR1B
Molecules associated with elastic fibres	1	102.9×	0.016	GDF5
Hedgehog ligand biogenesis	1	70.5×	0.020	IHH
Class B/2 (Secretin family receptors)	1	63.4×	0.020	IHH
Hedgehog ‘on’ state	1	52.9×	0.022	IHH
Signaling by TGFB family members	1	38.5×	0.028	BMPR1B
Signal Transduction	1	3.4×	0.267	BMPR1B

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
positive regulation of chondrocyte differentiation	2	535.0×	3e-04	BMPR1B, GDF5
negative regulation of chondrocyte differentiation	2	449.4×	3e-04	IHH, GDF5
response to mechanical stimulus	2	200.6×	1e-03	IHH, GDF5
BMP signaling pathway	2	133.8×	0.002	BMPR1B, GDF5
vitelline membrane formation	1	5617.3×	0.002	IHH
negative regulation of eye pigmentation	1	5617.3×	0.002	IHH
camera-type eye photoreceptor cell fate commitment	1	5617.3×	0.002	IHH
osteoblast differentiation	2	80.8×	0.002	IHH, BMPR1B
intein-mediated protein splicing	1	2808.7×	0.004	IHH
ossification involved in bone remodeling	1	1872.4×	0.004	GDF5
negative regulation of alpha-beta T cell differentiation	1	1872.4×	0.004	IHH
ovarian cumulus expansion	1	1404.3×	0.004	BMPR1B
endochondral bone morphogenesis	1	1404.3×	0.004	BMPR1B
negative regulation of chondrocyte proliferation	1	1404.3×	0.004	BMPR1B
cell-cell signaling	2	46.4×	0.004	IHH, GDF5
chondroblast differentiation	1	1123.5×	0.005	GDF5
embryonic skeletal joint development	1	1123.5×	0.005	IHH
chondrocyte differentiation involved in endochondral bone morphogenesis	1	936.2×	0.005	IHH
negative regulation of T cell differentiation in thymus	1	936.2×	0.005	IHH
negative regulation of immature T cell proliferation in thymus	1	936.2×	0.005	IHH
hindlimb morphogenesis	1	936.2×	0.005	GDF5
ovulation cycle	1	802.5×	0.005	BMPR1B
negative regulation of mesenchymal cell apoptotic process	1	802.5×	0.005	GDF5
forelimb morphogenesis	1	702.2×	0.005	GDF5
head morphogenesis	1	702.2×	0.005	IHH
proteoglycan metabolic process	1	624.1×	0.006	IHH
retinal pigment epithelium development	1	561.7×	0.006	IHH
positive regulation of alpha-beta T cell differentiation	1	561.7×	0.006	IHH
positive regulation of T cell differentiation in thymus	1	510.7×	0.006	IHH
mesenchymal cell apoptotic process	1	510.7×	0.006	GDF5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
BMPR1B	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMPR1B	28	4
IHH	0	0
GDF5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1B
FEDRATINIB	4	BMPR1B
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B
CRIZOTINIB	4	BMPR1B
SARACATINIB	3	BMPR1B
LINIFANIB	3	BMPR1B
CANERTINIB	3	BMPR1B
ALVOCIDIB	3	BMPR1B
LESTAURTINIB	3	BMPR1B
SU-014813	2	BMPR1B
R-406	2	BMPR1B
AT-9283	2	BMPR1B
ZILURGISERTIB	2	BMPR1B
TOZASERTIB	2	BMPR1B
KER-047	2	BMPR1B
TAK-285	1	BMPR1B
KW-2449	1	BMPR1B
MLN-8054	1	BMPR1B
XL-228	1	BMPR1B
ASP-3026	1	BMPR1B
AEW-541	1	BMPR1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BMPR1B	166	Binding:164, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1B	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
BMPR1B	166

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

28 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)
MOMELOTINIB	4	BMPR1B
FEDRATINIB	4	BMPR1B
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B
CRIZOTINIB	4	BMPR1B
SARACATINIB	3	BMPR1B
LINIFANIB	3	BMPR1B
CANERTINIB	3	BMPR1B
ALVOCIDIB	3	BMPR1B
LESTAURTINIB	3	BMPR1B
SU-014813	2	BMPR1B
R-406	2	BMPR1B
AT-9283	2	BMPR1B
ZILURGISERTIB	2	BMPR1B
TOZASERTIB	2	BMPR1B
KER-047	2	BMPR1B
TAK-285	1	BMPR1B
KW-2449	1	BMPR1B
MLN-8054	1	BMPR1B
XL-228	1	BMPR1B
ASP-3026	1	BMPR1B
AEW-541	1	BMPR1B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BMPR1B
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	IHH, GDF5

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)
IHH	0	—
GDF5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.