Diaphyseal medullary stenosis-bone malignancy syndrome

Summary

Diaphyseal medullary stenosis-bone malignancy syndrome (MONDO:0007205) is a disease caused by MTAP (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: MTAP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 119
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diaphyseal medullary stenosis-bone malignancy syndrome
Mondo ID	MONDO:0007205
OMIM	112250
Orphanet	85182
DOID	DOID:0080664
NCIT	C122660
UMLS	C1862177
MedGen	350613
GARD	0010072
Is cancer (heuristic)	no

Also known as: BDMF · bone dysplasia-medullary fibrosarcoma syndrome · diaphyseal medullary stenosis with malignant fibrous histiocytoma · diaphyseal medullary stenosis-bone malignancy syndrome · diaphyseal medullary stenosis-malignant fibrous histiocytoma syndrome · DMS-MFH · DMSMFH · Hardcastle syndrome · Hardcastle’s syndrome

Data availability: 119 ClinVar variants · 7 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › diaphyseal medullary stenosis-bone malignancy syndrome

Related subtypes (118): osteochondrodysplasia, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

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

119 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 48 benign, 5 benign/likely benign, 2 pathogenic, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
29790	NC_000009.12:g.21931079A>G	ERVFRD-3	Pathogenic	no assertion criteria provided
29791	NC_000009.12:g.21931006A>G	ERVFRD-3	Pathogenic	no assertion criteria provided
914527	NM_002451.4(MTAP):c.788G>T (p.Trp263Leu)	MTAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319954	NM_002451.4(MTAP):c.278C>T (p.Thr93Ile)	MTAP	Uncertain significance	criteria provided, single submitter
366240	NM_002451.4(MTAP):c.187A>G (p.Arg63Gly)	MTAP	Uncertain significance	criteria provided, single submitter
366241	NM_002451.4(MTAP):c.300G>A (p.Glu100=)	MTAP	Uncertain significance	criteria provided, single submitter
366253	NM_002451.4(MTAP):c.*102A>G	MTAP	Uncertain significance	criteria provided, single submitter
366259	NM_002451.4(MTAP):c.*378T>C	MTAP	Uncertain significance	criteria provided, single submitter
366273	NM_002451.4(MTAP):c.*1140A>G	MTAP	Uncertain significance	criteria provided, single submitter
366275	NM_002451.4(MTAP):c.*1197C>G	MTAP	Uncertain significance	criteria provided, single submitter
366278	NM_002451.4(MTAP):c.*1384G>C	MTAP	Uncertain significance	criteria provided, single submitter
366279	NM_002451.4(MTAP):c.*1482A>G	MTAP	Uncertain significance	criteria provided, single submitter
366285	NM_002451.4(MTAP):c.*1760A>G	MTAP	Uncertain significance	criteria provided, single submitter
366286	NM_002451.4(MTAP):c.*1831T>A	MTAP	Uncertain significance	criteria provided, single submitter
366289	NM_002451.4(MTAP):c.*2171G>A	MTAP	Uncertain significance	criteria provided, single submitter
366295	NM_002451.4(MTAP):c.*2383C>T	MTAP	Uncertain significance	criteria provided, single submitter
366298	NM_002451.4(MTAP):c.*2606G>C	MTAP	Uncertain significance	criteria provided, single submitter
366299	NM_002451.4(MTAP):c.*2638G>A	MTAP	Uncertain significance	criteria provided, single submitter
366300	NM_002451.4(MTAP):c.*2651G>A	MTAP	Uncertain significance	criteria provided, single submitter
366301	NM_002451.4(MTAP):c.*2837T>A	MTAP	Uncertain significance	criteria provided, single submitter
366303	NM_002451.4(MTAP):c.*2912G>C	MTAP	Uncertain significance	criteria provided, single submitter
366304	NM_002451.4(MTAP):c.*2968T>C	MTAP	Uncertain significance	criteria provided, single submitter
366305	NM_002451.4(MTAP):c.*3052C>T	MTAP	Uncertain significance	criteria provided, single submitter
366306	NM_002451.4(MTAP):c.*3072G>A	MTAP	Uncertain significance	criteria provided, single submitter
366309	NM_002451.4(MTAP):c.*3206C>T	MTAP	Uncertain significance	criteria provided, single submitter
366311	NM_002451.4(MTAP):c.*3361C>T	MTAP	Uncertain significance	criteria provided, single submitter
366312	NM_002451.4(MTAP):c.*3389T>C	MTAP	Uncertain significance	criteria provided, single submitter
366313	NM_002451.4(MTAP):c.*3766C>T	MTAP	Uncertain significance	criteria provided, single submitter
366318	NM_002451.4(MTAP):c.*3943G>A	MTAP	Uncertain significance	criteria provided, single submitter
3779967	NM_002451.4(MTAP):c.347+3A>C	MTAP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
MTAP	Strong	Autosomal dominant	diaphyseal medullary stenosis-bone malignancy syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTAP	Orphanet:85182	Diaphyseal medullary stenosis-bone malignancy syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTAP	HGNC:7413	ENSG00000099810	Q13126	S-methyl-5’-thioadenosine phosphorylase	gencc,clinvar
ERVFRD-3	HGNC:49792	ENSG00000264801		endogenous retrovirus group FRD member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTAP	S-methyl-5’-thioadenosine phosphorylase	Catalyzes the reversible phosphorylation of S-methyl-5’-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTAP	Enzyme (other)	yes	2.4.2.28	Nucleoside_phosphorylase_d, MTAP, Purine_phosphorylase-2_CS
ERVFRD-3	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1
bone marrow cell	1
endometrium	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTAP	239	ubiquitous	marker	adrenal tissue, calcaneal tendon, colonic epithelium
ERVFRD-3	61		yes	endometrium, bone marrow cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTAP	2,086
ERVFRD-3	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTAP	Q13126	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Methionine salvage pathway	1	1903.3×	0.005	MTAP
Sulfur amino acid metabolism	1	571.0×	0.006	MTAP
Interleukin-12 family signaling	1	475.8×	0.006	MTAP
Interleukin-12 signaling	1	407.9×	0.006	MTAP
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	300.5×	0.007	MTAP
Metabolism of amino acids and derivatives	1	67.6×	0.022	MTAP
Signaling by Interleukins	1	64.2×	0.022	MTAP
Cytokine Signaling in Immune system	1	40.8×	0.031	MTAP
Immune System	1	13.0×	0.086	MTAP
Metabolism	1	11.6×	0.086	MTAP

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete L-methionine salvage from methylthioadenosine	1	3370.4×	0.001	MTAP
purine ribonucleoside salvage	1	2407.4×	0.001	MTAP
nucleobase-containing compound metabolic process	1	526.6×	0.003	MTAP
response to testosterone	1	468.1×	0.003	MTAP
methylation	1	170.2×	0.006	MTAP

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
MTAP	0	0
ERVFRD-3	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
MTAP	24	Binding:23, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTAP	2.4.2.28	S-methyl-5’-thioadenosine phosphorylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	MTAP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ERVFRD-3

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)
MTAP	24	—
ERVFRD-3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05523076	Not specified	COMPLETED	Transdiagnostic Markers of Cognitive Symptoms in Disorders Affective.