Ghosal hematodiaphyseal dysplasia

Summary

Ghosal hematodiaphyseal dysplasia (MONDO:0009274) is a disease caused by TBXAS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: TBXAS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002644	Abnormality of pelvic girdle bone morphology	Very frequent (80-99%)
HP:0002823	Abnormality of femur morphology	Very frequent (80-99%)
HP:0002992	Abnormality of tibia morphology	Very frequent (80-99%)
HP:0003103	Abnormal cortical bone morphology	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0004493	Craniofacial hyperostosis	Very frequent (80-99%)
HP:0005019	Diaphyseal thickening	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0010978	Abnormality of immune system physiology	Very frequent (80-99%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ghosal hematodiaphyseal dysplasia
Mondo ID	MONDO:0009274
MeSH	C565551
OMIM	231095
Orphanet	1802
DOID	DOID:0112251
SNOMED CT	389214003
UMLS	C1856465
MedGen	344739
GARD	0010297
Is cancer (heuristic)	no

Also known as: diaphyseal dysplasia-anemia syndrome · GHDD · ghosal hematodiaphyseal dysplasia · Ghosal hematodiaphyseal dysplasia syndrome · Ghosal syndrome

Data availability: 34 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › ghosal hematodiaphyseal dysplasia

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, 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, 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

34 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 8 conflicting classifications of pathogenicity, 5 likely pathogenic, 4 pathogenic, 2 benign/likely benign, 1 likely benign, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031016	NM_001061.7(TBXAS1):c.193G>T (p.Glu65Ter)	TBXAS1	Pathogenic	criteria provided, multiple submitters, no conflicts
11886	NM_001061.7(TBXAS1):c.1460T>C (p.Leu487Pro)	TBXAS1	Pathogenic	no assertion criteria provided
11888	NM_001061.7(TBXAS1):c.1441G>T (p.Gly481Trp)	TBXAS1	Pathogenic	no assertion criteria provided
194017	NM_001061.7(TBXAS1):c.1420del (p.Ala474fs)	TBXAS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992886	NM_001061.7(TBXAS1):c.122_135del (p.Lys41fs)	TBXAS1	Pathogenic	criteria provided, single submitter
1695387	NM_001061.7(TBXAS1):c.859C>T (p.His287Tyr)	TBXAS1	Likely pathogenic	no assertion criteria provided
3769419	NM_001061.7(TBXAS1):c.90-1G>A	TBXAS1	Likely pathogenic	criteria provided, single submitter
3897816	NM_001061.7(TBXAS1):c.451-2A>T	TBXAS1	Likely pathogenic	criteria provided, single submitter
4845772	NM_001061.7(TBXAS1):c.79del (p.Leu27fs)	TBXAS1	Likely pathogenic	criteria provided, single submitter
626225	NM_001061.7(TBXAS1):c.580_581del (p.Ala194fs)	TBXAS1	Likely pathogenic	criteria provided, single submitter
11887	NM_001061.7(TBXAS1):c.245T>C (p.Leu82Pro)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11889	NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394528	NM_001061.7(TBXAS1):c.1580A>G (p.Tyr527Cys)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1575649	NM_001061.7(TBXAS1):c.734A>G (p.Asn245Ser)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664045	NM_001061.7(TBXAS1):c.201A>C (p.Gln67His)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283839	NM_001061.7(TBXAS1):c.1520A>T (p.Glu507Val)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504161	NM_001061.7(TBXAS1):c.856C>T (p.Arg286Ter)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626181	NM_001061.7(TBXAS1):c.1417G>T (p.Gly473Trp)	TBXAS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1184409	NM_001061.7(TBXAS1):c.1420G>A (p.Ala474Thr)	TBXAS1	Uncertain significance	criteria provided, single submitter
1307069	NM_001061.7(TBXAS1):c.796C>T (p.Arg266Trp)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371893	NM_001061.7(TBXAS1):c.1279G>A (p.Ala427Thr)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2062884	NM_001061.7(TBXAS1):c.265G>A (p.Val89Ile)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2417307	NM_001061.7(TBXAS1):c.473C>A (p.Ala158Asp)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2436991	NM_001061.7(TBXAS1):c.824G>A (p.Arg275Gln)	TBXAS1	Uncertain significance	criteria provided, single submitter
3148960	NM_001061.7(TBXAS1):c.605G>A (p.Trp202Ter)	TBXAS1	Uncertain significance	criteria provided, single submitter
3377719	NM_001061.7(TBXAS1):c.1310C>T (p.Ala437Val)	TBXAS1	Uncertain significance	criteria provided, single submitter
3594392	NM_001061.7(TBXAS1):c.643C>T (p.Arg215Cys)	TBXAS1	Uncertain significance	criteria provided, single submitter
3769472	NM_001061.7(TBXAS1):c.652G>A (p.Glu218Lys)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4279664	NM_001061.7(TBXAS1):c.1420G>T (p.Ala474Ser)	TBXAS1	Uncertain significance	criteria provided, single submitter
432476	NM_001061.7(TBXAS1):c.790G>T (p.Ala264Ser)	TBXAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
TBXAS1	Definitive	Autosomal recessive	ghosal hematodiaphyseal dysplasia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBXAS1	Orphanet:1802	Ghosal hematodiaphyseal dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBXAS1	HGNC:11609	ENSG00000059377	P24557	Thromboxane-A synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBXAS1	Thromboxane-A synthase	Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBXAS1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBXAS1	180	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBXAS1	2,072

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBXAS1	P24557	91.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 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
Defective TBXAS1 causes GHDD	1	11420.0×	0.001	TBXAS1
Eicosanoids	1	951.7×	0.004	TBXAS1
Metabolic disorders of biological oxidation enzymes	1	878.5×	0.004	TBXAS1
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)	1	761.3×	0.004	TBXAS1
Cytochrome P450 - arranged by substrate type	1	713.8×	0.004	TBXAS1
Arachidonate metabolism	1	571.0×	0.004	TBXAS1
Phase I - Functionalization of compounds	1	219.6×	0.008	TBXAS1
Fatty acid metabolism	1	131.3×	0.011	TBXAS1
Biological oxidations	1	129.8×	0.011	TBXAS1
Diseases of metabolism	1	80.4×	0.016	TBXAS1
Metabolism of lipids	1	31.6×	0.037	TBXAS1
Disease	1	13.1×	0.083	TBXAS1
Metabolism	1	11.6×	0.086	TBXAS1

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
prostanoid biosynthetic process	1	2407.4×	0.002	TBXAS1
icosanoid metabolic process	1	1872.4×	0.002	TBXAS1
intracellular chloride ion homeostasis	1	1685.2×	0.002	TBXAS1
prostaglandin biosynthetic process	1	1123.5×	0.002	TBXAS1
response to fatty acid	1	1053.2×	0.002	TBXAS1
positive regulation of vasoconstriction	1	601.9×	0.002	TBXAS1
long-chain fatty acid biosynthetic process	1	443.5×	0.003	TBXAS1
response to ethanol	1	146.5×	0.007	TBXAS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
TBXAS1	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBXAS1	46	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	TBXAS1
CISPLATIN	4	TBXAS1
SAQUINAVIR	4	TBXAS1
AMPRENAVIR	4	TBXAS1
OZAGREL	4	TBXAS1
GRAMICIDIN	4	TBXAS1
ROSIGLITAZONE	4	TBXAS1
SULCONAZOLE	4	TBXAS1
OXICONAZOLE	4	TBXAS1
KETOCONAZOLE	4	TBXAS1
VINBLASTINE	4	TBXAS1
RITONAVIR	4	TBXAS1
NIFEDIPINE	4	TBXAS1
BITHIONOL	4	TBXAS1
3,3’,4’,5-TETRACHLOROSALICYLANILIDE	4	TBXAS1
TROGLITAZONE	4	TBXAS1
DIETHYLSTILBESTROL	4	TBXAS1
SULFASALAZINE	4	TBXAS1
TROVAFLOXACIN	4	TBXAS1
ERGOTAMINE	4	TBXAS1
AMINOGLUTETHIMIDE	4	TBXAS1
HEXACHLOROPHENE	4	TBXAS1
TANNIC ACID	4	TBXAS1
NELFINAVIR	4	TBXAS1
INDOMETHACIN	4	TBXAS1
ZAFIRLUKAST	4	TBXAS1
MONTELUKAST	4	TBXAS1
ECONAZOLE	4	TBXAS1
TAMOXIFEN	4	TBXAS1
MICONAZOLE	4	TBXAS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TBXAS1	210	Binding:138, Functional:72

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TBXAS1	210

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

30 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)
CLOTRIMAZOLE	4	TBXAS1
CISPLATIN	4	TBXAS1
SAQUINAVIR	4	TBXAS1
AMPRENAVIR	4	TBXAS1
OZAGREL	4	TBXAS1
GRAMICIDIN	4	TBXAS1
ROSIGLITAZONE	4	TBXAS1
SULCONAZOLE	4	TBXAS1
OXICONAZOLE	4	TBXAS1
KETOCONAZOLE	4	TBXAS1
VINBLASTINE	4	TBXAS1
RITONAVIR	4	TBXAS1
NIFEDIPINE	4	TBXAS1
BITHIONOL	4	TBXAS1
3,3’,4’,5-TETRACHLOROSALICYLANILIDE	4	TBXAS1
TROGLITAZONE	4	TBXAS1
DIETHYLSTILBESTROL	4	TBXAS1
SULFASALAZINE	4	TBXAS1
TROVAFLOXACIN	4	TBXAS1
ERGOTAMINE	4	TBXAS1
AMINOGLUTETHIMIDE	4	TBXAS1
HEXACHLOROPHENE	4	TBXAS1
TANNIC ACID	4	TBXAS1
NELFINAVIR	4	TBXAS1
INDOMETHACIN	4	TBXAS1
ZAFIRLUKAST	4	TBXAS1
MONTELUKAST	4	TBXAS1
ECONAZOLE	4	TBXAS1
TAMOXIFEN	4	TBXAS1
MICONAZOLE	4	TBXAS1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TBXAS1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.