acromesomelic dysplasia 2C, Hunter-Thompson type

Summary

acromesomelic dysplasia 2C, Hunter-Thompson type (MONDO:0008717) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 48
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0003028	Abnormality of the ankles	Very frequent (80-99%)
HP:0003042	Elbow dislocation	Very frequent (80-99%)
HP:0003086	Acromesomelia	Very frequent (80-99%)
HP:0007598	Bilateral single transverse palmar creases	Very frequent (80-99%)
HP:0008368	Tarsal synostosis	Very frequent (80-99%)
HP:0008890	Severe short-limb dwarfism	Very frequent (80-99%)
HP:0009778	Short thumb	Very frequent (80-99%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0002644	Abnormality of pelvic girdle bone morphology	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002827	Hip dislocation	Frequent (30-79%)
HP:0002999	Patellar dislocation	Frequent (30-79%)
HP:0006011	Cuboidal metacarpal	Frequent (30-79%)
HP:0006014	Abnormally shaped carpal bones	Frequent (30-79%)
HP:0010049	Short metacarpal	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acromesomelic dysplasia 2C, Hunter-Thompson type
Mondo ID	MONDO:0008717
OMIM	201250
Orphanet	968
DOID	DOID:0080051
UMLS	C2930970
MedGen	419681
GARD	0000506
Is cancer (heuristic)	no

Also known as: acromesomelic dwarfism · acromesomelic dysplasia 2C, Hunter-Thompson type · acromesomelic dysplasia Hunter Thompson type · acromesomelic dysplasia, Hunter-Thompson type · AMDH

Data availability: 48 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › acromesomelic dysplasia › acromesomelic dysplasia 2C, Hunter-Thompson type

Related subtypes (7): Osebold-Remondini syndrome, acromesomelic dysplasia 2A, acromesomelic dysplasia 2B, acromesomelic dysplasia 1, Maroteaux type, acromesomelic dysplasia 3, acromesomelic dysplasia, Campailla Martinelli type, acromesomelic dysplasia 4

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

48 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 11 benign/likely benign, 11 conflicting classifications of pathogenicity, 9 benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
817567	NM_000557.5(GDF5):c.788_810dup (p.Gly271Ter)	GDF5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8377	GDF5, 22-BP DUP	GDF5	Pathogenic	no assertion criteria provided
996696	NM_001203.3(BMPR1B):c.1190T>G (p.Met397Arg)	BMPR1B	Likely pathogenic	no assertion criteria provided
3764682	NM_000557.5(GDF5):c.784del (p.Gln262fs)	GDF5	Likely pathogenic	criteria provided, single submitter
338320	NM_000557.5(GDF5):c.855C>T (p.Gly285=)	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338323	NM_000557.5(GDF5):c.168C>A (p.Asn56Lys)	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895466	NM_000557.5(GDF5):c.*259G>C	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895609	NM_000557.5(GDF5):c.631+6G>A	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895673	NM_000557.5(GDF5):c.206C>G (p.Ala69Gly)	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896024	NM_000557.5(GDF5):c.-134C>G	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897014	NM_000557.5(GDF5):c.483G>A (p.Pro161=)	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897561	NM_000557.5(GDF5):c.57G>T (p.Leu19=)	GDF5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2631825	NM_000557.5(GDF5):c.1420A>T (p.Ile474Phe)	GDF5-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338317	NM_000557.5(GDF5):c.1104C>T (p.Thr368=)	GDF5-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896867	NM_000557.5(GDF5):c.1374C>G (p.Pro458=)	GDF5-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019956	NM_000557.5(GDF5):c.1198_1200dup (p.Cys400dup)	GDF5	Uncertain significance	criteria provided, multiple submitters, no conflicts
2143629	NM_000557.5(GDF5):c.519G>A (p.Met173Ile)	GDF5	Uncertain significance	criteria provided, multiple submitters, no conflicts
338327	NM_000557.5(GDF5):c.-220C>T	GDF5	Uncertain significance	criteria provided, single submitter
3893112	NM_000557.5(GDF5):c.71C>G (p.Thr24Ser)	GDF5	Uncertain significance	criteria provided, single submitter
595155	NM_000557.5(GDF5):c.25T>C (p.Phe9Leu)	GDF5	Uncertain significance	criteria provided, multiple submitters, no conflicts
816909	NM_000557.5(GDF5):c.1272C>G (p.Tyr424Ter)	GDF5	Uncertain significance	criteria provided, single submitter
895535	NM_000557.5(GDF5):c.1067A>G (p.Asn356Ser)	GDF5	Uncertain significance	criteria provided, multiple submitters, no conflicts
895610	NM_000557.5(GDF5):c.506C>A (p.Pro169His)	GDF5	Uncertain significance	criteria provided, single submitter
895672	NM_000557.5(GDF5):c.226G>T (p.Ala76Ser)	GDF5	Uncertain significance	criteria provided, single submitter
897084	NM_000557.5(GDF5):c.182G>A (p.Gly61Glu)	GDF5	Uncertain significance	criteria provided, single submitter
338315	NM_000557.5(GDF5):c.*166G>A	GDF5-AS1	Uncertain significance	criteria provided, single submitter
895743	NM_000557.5(GDF5):c.-97T>C	LOC109461476	Uncertain significance	criteria provided, single submitter
898778	NM_000557.5(GDF5):c.-236G>A	LOC109461476	Uncertain significance	criteria provided, single submitter
193119	NM_000557.5(GDF5):c.462C>A (p.Pro154=)	GDF5	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
256712	NM_000557.5(GDF5):c.-48=	GDF5	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 14 · 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
GDF5	Definitive	Autosomal recessive	acromesomelic dysplasia 2A	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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

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
GDF5	HGNC:4220	ENSG00000125965	P43026	Growth/differentiation factor 5	gencc,clinvar
BMPR1B	HGNC:1077	ENSG00000138696	O00238	Bone morphogenetic protein receptor type-1B	clinvar
GDF5-AS1	HGNC:33435	ENSG00000204183	Q5U4N7	Protein GDF5-AS1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDF5	Growth/differentiation factor 5	Growth factor involved in bone and cartilage formation.
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.

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)
GDF5	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
BMPR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
GDF5-AS1	Other/Unknown	no		GDF5OS

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
parotid gland	1
pericardium	1
bronchial epithelial cell	1
calcaneal tendon	1
cauda epididymis	1
colonic epithelium	1
cortical plate	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDF5	116	broad	yes	parotid gland, pericardium, cartilage tissue
BMPR1B	239	broad	marker	calcaneal tendon, bronchial epithelial cell, cauda epididymis
GDF5-AS1	68		yes	colonic epithelium, cortical plate, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDF5	1,486
BMPR1B	116
GDF5-AS1	15

Intra-cohort edges

A	B	Sources
BMPR1B	GDF5	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF5	P43026	15
BMPR1B	O00238	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDF5-AS1	Q5U4N7	58.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Signaling by BMP	1	178.4×	0.013	BMPR1B
Molecules associated with elastic fibres	1	154.3×	0.013	GDF5
Signaling by TGFB family members	1	57.7×	0.023	BMPR1B
Signal Transduction	1	5.1×	0.187	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 2 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	802.5×	7e-05	GDF5, BMPR1B
BMP signaling pathway	2	200.6×	5e-04	GDF5, BMPR1B
ossification involved in bone remodeling	1	2808.7×	0.003	GDF5
ovarian cumulus expansion	1	2106.5×	0.003	BMPR1B
endochondral bone morphogenesis	1	2106.5×	0.003	BMPR1B
negative regulation of chondrocyte proliferation	1	2106.5×	0.003	BMPR1B
chondroblast differentiation	1	1685.2×	0.004	GDF5
hindlimb morphogenesis	1	1404.3×	0.004	GDF5
ovulation cycle	1	1203.7×	0.004	BMPR1B
negative regulation of mesenchymal cell apoptotic process	1	1203.7×	0.004	GDF5
forelimb morphogenesis	1	1053.2×	0.004	GDF5
mesenchymal cell apoptotic process	1	766.0×	0.005	GDF5
positive regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	702.2×	0.005	BMPR1B
chondrocyte development	1	468.1×	0.006	BMPR1B
positive regulation of cartilage development	1	468.1×	0.006	BMPR1B
proteoglycan biosynthetic process	1	421.3×	0.006	BMPR1B
cartilage condensation	1	383.0×	0.006	BMPR1B
retinal ganglion cell axon guidance	1	383.0×	0.006	BMPR1B
negative regulation of chondrocyte differentiation	1	337.0×	0.007	GDF5
regulation of multicellular organism growth	1	324.1×	0.007	GDF5
central nervous system neuron differentiation	1	300.9×	0.007	BMPR1B
cellular response to BMP stimulus	1	280.9×	0.007	BMPR1B
positive regulation of BMP signaling pathway	1	227.7×	0.008	GDF5
dorsal/ventral pattern formation	1	210.7×	0.008	BMPR1B
embryonic limb morphogenesis	1	200.6×	0.008	GDF5
positive regulation of bone mineralization	1	195.9×	0.008	BMPR1B
positive regulation of SMAD protein signal transduction	1	191.5×	0.008	GDF5
eye development	1	175.5×	0.009	BMPR1B
cellular response to growth factor stimulus	1	159.0×	0.009	BMPR1B
chondrocyte differentiation	1	150.5×	0.009	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
GDF5	0	0
GDF5-AS1	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: 2; 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	GDF5, GDF5-AS1

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)
GDF5	0	—
GDF5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.