acromesomelic dysplasia 1, Maroteaux type

Summary

acromesomelic dysplasia 1, Maroteaux type (MONDO:0011275) is a disease caused by NPR2 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NPR2 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 578
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	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:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000912	Sprengel anomaly	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0003086	Acromesomelia	Frequent (30-79%)
HP:0003300	Ovoid vertebral bodies	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0003312	Abnormal form of the vertebral bodies	Frequent (30-79%)
HP:0003498	Disproportionate short stature	Frequent (30-79%)
HP:0004568	Beaking of vertebral bodies	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0006487	Bowing of the long bones	Frequent (30-79%)
HP:0008422	Vertebral wedging	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acromesomelic dysplasia 1, Maroteaux type
Mondo ID	MONDO:0011275
MeSH	C535661
OMIM	602875
Orphanet	40
DOID	DOID:0080050
SNOMED CT	718559000
UMLS	C1864356
MedGen	355199
GARD	0000507
Is cancer (heuristic)	no

Also known as: acromesomelic dwarfism Maroteux type · acromesomelic dysplasia 1, Maroteaux type · acromesomelic dysplasia Maroteaux type · acromesomelic dysplasia, Maroteaux type · AMDM

Data availability: 578 ClinVar variants · 5 GenCC gene-disease records.

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 1, Maroteaux type

Related subtypes (7): Osebold-Remondini syndrome, acromesomelic dysplasia 2A, acromesomelic dysplasia 2C, Hunter-Thompson type, acromesomelic dysplasia 2B, 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

578 retrieved; paginated sample, class counts are floors:

298 uncertain significance, 160 likely benign, 46 pathogenic, 33 conflicting classifications of pathogenicity, 19 likely pathogenic, 8 pathogenic/likely pathogenic, 7 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1224426	NM_003995.4(NPR2):c.895C>T (p.Arg299Ter)	NPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333327	NM_003995.4(NPR2):c.2245C>T (p.Arg749Trp)	NPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333664	NM_003995.4(NPR2):c.1111C>T (p.Arg371Ter)	NPR2	Pathogenic	criteria provided, single submitter
1395420	NM_003995.4(NPR2):c.507del (p.Tyr170fs)	NPR2	Pathogenic	criteria provided, single submitter
1433253	NM_003995.4(NPR2):c.2845C>T (p.Arg949Ter)	NPR2	Pathogenic	criteria provided, single submitter
1452537	NM_003995.4(NPR2):c.60del (p.Ala22fs)	NPR2	Pathogenic	criteria provided, single submitter
1453237	NM_003995.4(NPR2):c.1699G>T (p.Glu567Ter)	NPR2	Pathogenic	criteria provided, single submitter
1454887	NM_003995.4(NPR2):c.613C>T (p.Arg205Ter)	NPR2	Pathogenic	criteria provided, single submitter
1459715	NM_003995.4(NPR2):c.2221C>T (p.Arg741Ter)	NPR2	Pathogenic	criteria provided, single submitter
1459896	NM_003995.4(NPR2):c.2341C>T (p.Gln781Ter)	NPR2	Pathogenic	criteria provided, single submitter
1683471	NM_003995.4(NPR2):c.125_126insTGGCG (p.Trp42fs)	NPR2	Pathogenic	criteria provided, single submitter
1695394	NM_003995.4(NPR2):c.1087C>T (p.Arg363Ter)	NPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
17785	NM_003995.4(NPR2):c.343T>G (p.Trp115Gly)	NPR2	Pathogenic	no assertion criteria provided
17786	NM_003995.4(NPR2):c.528T>A (p.Asp176Glu)	NPR2	Pathogenic	no assertion criteria provided
17787	NM_003995.4(NPR2):c.1162C>T (p.Arg388Ter)	NPR2	Pathogenic	criteria provided, single submitter
2025379	NM_003995.4(NPR2):c.721C>T (p.Gln241Ter)	NPR2	Pathogenic	criteria provided, single submitter
2032731	NM_003995.4(NPR2):c.1511C>G (p.Ser504Ter)	NPR2	Pathogenic	criteria provided, single submitter
208355	NM_003995.4(NPR2):c.1092del (p.Ile364fs)	NPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2096788	NM_003995.4(NPR2):c.2424T>G (p.Tyr808Ter)	NPR2	Pathogenic	criteria provided, single submitter
2183283	NM_003995.4(NPR2):c.2965C>T (p.Arg989Ter)	NPR2	Pathogenic	criteria provided, single submitter
2194018	NM_003995.4(NPR2):c.1257G>A (p.Trp419Ter)	NPR2	Pathogenic	criteria provided, single submitter
2925446	NM_003995.4(NPR2):c.844C>T (p.Gln282Ter)	NPR2	Pathogenic	criteria provided, single submitter
2925448	NM_003995.4(NPR2):c.1801C>A (p.Arg601Ser)	NPR2	Pathogenic	criteria provided, single submitter
2944318	NM_003995.4(NPR2):c.2738dup (p.Met913fs)	NPR2	Pathogenic	criteria provided, single submitter
3602727	NM_003995.4(NPR2):c.674A>G (p.Tyr225Cys)	NPR2	Pathogenic	criteria provided, single submitter
375290	NM_003995.4(NPR2):c.1435C>T (p.Arg479Ter)	NPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375291	NM_003995.4(NPR2):c.2302T>C (p.Cys768Arg)	NPR2	Pathogenic	criteria provided, single submitter
375292	NM_003995.4(NPR2):c.1758del (p.Ala585_Cys586insTer)	NPR2	Pathogenic	criteria provided, single submitter
375293	NM_003995.4(NPR2):c.560T>A (p.Val187Asp)	NPR2	Pathogenic	criteria provided, single submitter
375294	NM_003995.4(NPR2):c.2944G>A (p.Asp982Asn)	NPR2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 5 · 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
NPR2	Definitive	Autosomal recessive	acromesomelic dysplasia 1, Maroteaux type	12
NPRL2	Definitive	Autosomal recessive	acromesomelic dysplasia 1, Maroteaux type	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
NPR2	Orphanet:329191	Tall stature-long halluces-multiple extra-epiphyses syndrome
NPR2	Orphanet:40	Acromesomelic dysplasia, Maroteaux type
IHH	Orphanet:63446	Acrocapitofemoral dysplasia
IHH	Orphanet:93388	Brachydactyly type A1

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	gencc,clinvar
NPR2	HGNC:7944	ENSG00000159899	P20594	Atrial natriuretic peptide receptor 2	gencc,clinvar
SPAG8	HGNC:14105	ENSG00000137098	Q99932	Sperm-associated antigen 8	clinvar
FAM219A	HGNC:19920	ENSG00000164970	Q8IW50	Protein FAM219A	clinvar
IHH	HGNC:5956	ENSG00000163501	Q14623	Indian hedgehog protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
NPR2	Atrial natriuretic peptide receptor 2	Receptor for the C-type natriuretic peptide NPPC/CNP hormone.
SPAG8	Sperm-associated antigen 8	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	5.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPRL2	Other/Unknown	no		NPR2-like
NPR2	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, ANPR/GUC
SPAG8	Other/Unknown	no		Sperm-assoc_Ag8
FAM219A	Other/Unknown	no		FAM219
IHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
right uterine tube	2
granulocyte	1
olfactory segment of nasal mucosa	1
tendon of biceps brachii	1
medulla oblongata	1
superior vestibular nucleus	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPRL2	285	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
NPR2	267	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
SPAG8	246	broad	marker	right uterine tube, tendon of biceps brachii, olfactory segment of nasal mucosa
FAM219A	245	ubiquitous	yes	ventricular zone, superior vestibular nucleus, medulla oblongata
IHH	94	broad	marker	mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IHH	2,370
NPRL2	1,222
SPAG8	1,151
NPR2	885
FAM219A	411

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPRL2	Q8WTW4	10
IHH	Q14623	8
SPAG8	Q99932	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPR2	P20594	84.00
FAM219A	Q8IW50	63.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 5 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
Physiological factors	1	223.9×	0.009	NPR2
Activation of SMO	1	211.5×	0.009	IHH
Hedgehog ligand biogenesis	1	70.5×	0.020	IHH
Amino acids regulate mTORC1	1	66.8×	0.020	NPRL2
Class B/2 (Secretin family receptors)	1	63.4×	0.020	IHH
Hedgehog ‘on’ state	1	52.9×	0.022	IHH
Cardiac conduction	1	36.2×	0.030	NPR2
Muscle contraction	1	25.7×	0.038	NPR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chondrocyte proliferation	2	526.6×	3e-04	NPR2, IHH
smooth muscle tissue development	2	526.6×	3e-04	NPR2, IHH
vestibulocochlear nerve maturation	1	4213.0×	0.004	NPR2
vitelline membrane formation	1	4213.0×	0.004	IHH
negative regulation of eye pigmentation	1	4213.0×	0.004	IHH
camera-type eye photoreceptor cell fate commitment	1	4213.0×	0.004	IHH
multicellular organism growth	2	68.5×	0.005	NPR2, IHH
intein-mediated protein splicing	1	2106.5×	0.005	IHH
response to luteinizing hormone	1	2106.5×	0.005	NPR2
activation of meiosis involved in egg activation	1	2106.5×	0.005	NPR2
cumulus cell differentiation	1	1404.3×	0.005	NPR2
gastric emptying	1	1404.3×	0.005	NPR2
negative regulation of alpha-beta T cell differentiation	1	1404.3×	0.005	IHH
c-di-GMP signaling	1	1404.3×	0.005	NPR2
negative regulation of kinase activity	1	1053.2×	0.006	NPRL2
negative regulation of meiotic cell cycle	1	1053.2×	0.006	NPR2
genitalia morphogenesis	1	842.6×	0.006	NPR2
embryonic skeletal joint development	1	842.6×	0.006	IHH
negative regulation of oocyte maturation	1	842.6×	0.006	NPR2
chondrocyte differentiation involved in endochondral bone morphogenesis	1	702.2×	0.006	IHH
negative regulation of T cell differentiation in thymus	1	702.2×	0.006	IHH
negative regulation of immature T cell proliferation in thymus	1	702.2×	0.006	IHH
meiotic cell cycle process involved in oocyte maturation	1	702.2×	0.006	NPR2
female genitalia development	1	601.9×	0.006	NPR2
bone growth	1	601.9×	0.006	NPR2
growth plate cartilage development	1	526.6×	0.006	NPR2
head morphogenesis	1	526.6×	0.006	IHH
cellular response to cGMP	1	526.6×	0.006	NPR2
response to fibroblast growth factor	1	526.6×	0.006	NPR2
response to salt	1	526.6×	0.006	NPR2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPRL2	0	0
NPR2	0	0
SPAG8	0	0
FAM219A	0	0
IHH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NPR2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NPR2	4.6.1.2	guanylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	NPR2
E	Difficult family or no structure, no drug	4	NPRL2, SPAG8, FAM219A, IHH

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NPRL2	0	—
NPR2	11	—
SPAG8	0	—
FAM219A	0	—
IHH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.