Gnathodiaphyseal dysplasia

Summary

Gnathodiaphyseal dysplasia (MONDO:0008151) is a disease caused by ANO5 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ANO5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,160
• Phenotypes (HPO): 7
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000935	Thickened cortex of long bones	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0012802	Broad jaw	Very frequent (80-99%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0007626	Mandibular osteomyelitis	Frequent (30-79%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002757	Recurrent fractures	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	gnathodiaphyseal dysplasia
Mondo ID	MONDO:0008151
MeSH	C536039
OMIM	166260
Orphanet	53697
DOID	DOID:0111533
ICD-11	1984860886
SNOMED CT	715568002
UMLS	C1833736
MedGen	331575
GARD	0008698
Is cancer (heuristic)	no

Also known as: GDD · gnathodiaphyseal dysplasia · Levin syndrome 2 · osteogenesis imperfecta Levin type

Data availability: 1,160 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 › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › gnathodiaphyseal dysplasia

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, geroderma osteodysplastica, osteogenesis imperfecta type 3, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, short stature-optic atrophy-Pelger-Huët anomaly syndrome, osteogenesis imperfecta type 14, osteogenesis imperfecta type 15, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18, osteogenesis imperfecta, type 19

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

600 retrieved; paginated sample, class counts are floors:

269 uncertain significance, 176 likely benign, 52 pathogenic, 48 conflicting classifications of pathogenicity, 20 likely pathogenic, 13 benign, 12 pathogenic/likely pathogenic, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1008638	NC_000011.9:g.(?22242633)(22242766_?)del	ANO5	Pathogenic	criteria provided, single submitter
1066105	NC_000011.9:g.(?22276907)(22301321_?)del	ANO5	Pathogenic	criteria provided, single submitter
1073054	NM_213599.3(ANO5):c.1690C>T (p.Gln564Ter)	ANO5	Pathogenic	criteria provided, single submitter
1075891	NM_213599.3(ANO5):c.1924C>T (p.Arg642Ter)	ANO5	Pathogenic	criteria provided, single submitter
1076523	NM_213599.3(ANO5):c.823C>T (p.Gln275Ter)	ANO5	Pathogenic	criteria provided, single submitter
1323166	NM_213599.3(ANO5):c.1716C>A (p.Cys572Ter)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
1323234	NM_213599.3(ANO5):c.1086T>A (p.Tyr362Ter)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
1326848	NM_213599.3(ANO5):c.294+5G>A	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350152	NC_000011.9:g.(?22242623)(22277088_?)del	ANO5	Pathogenic	criteria provided, single submitter
1358563	NM_213599.3(ANO5):c.1656T>G (p.Tyr552Ter)	ANO5	Pathogenic	criteria provided, single submitter
1374139	NM_213599.3(ANO5):c.773_774delinsAA (p.Trp258Ter)	ANO5	Pathogenic	criteria provided, single submitter
1380487	NM_213599.3(ANO5):c.766C>T (p.Gln256Ter)	ANO5	Pathogenic	criteria provided, single submitter
1382777	NM_213599.3(ANO5):c.1944_1945del (p.Lys650fs)	ANO5	Pathogenic	criteria provided, single submitter
1396797	NM_213599.3(ANO5):c.22G>T (p.Glu8Ter)	ANO5	Pathogenic	criteria provided, single submitter
140553	NM_213599.3(ANO5):c.1733T>C (p.Phe578Ser)	ANO5	Pathogenic	reviewed by expert panel
140555	NM_213599.3(ANO5):c.2018A>G (p.Tyr673Cys)	ANO5	Pathogenic	reviewed by expert panel
1406379	NM_213599.3(ANO5):c.1222del (p.Leu408fs)	ANO5	Pathogenic	criteria provided, single submitter
1432460	NC_000011.9:g.(?22225330)(22225416_?)del	ANO5	Pathogenic	criteria provided, single submitter
1440062	NM_213599.3(ANO5):c.2193_2197del (p.Gln731fs)	ANO5	Pathogenic	criteria provided, single submitter
1452790	NM_213599.3(ANO5):c.1531C>T (p.Gln511Ter)	ANO5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453293	NM_213599.3(ANO5):c.1045C>T (p.Gln349Ter)	ANO5	Pathogenic	criteria provided, single submitter
1454753	NC_000011.9:g.(?22261105)(22301321_?)del	ANO5	Pathogenic	criteria provided, single submitter
1455578	NM_213599.3(ANO5):c.989T>A (p.Leu330Ter)	ANO5	Pathogenic	criteria provided, single submitter
1457293	NC_000011.9:g.(?22281045)(22281307_?)del	ANO5	Pathogenic	criteria provided, single submitter
1457294	NC_000011.9:g.(?22215039)(22247618_?)del	ANO5	Pathogenic	criteria provided, single submitter
1457296	NC_000011.9:g.(?22242623)(22301311_?)del	ANO5	Pathogenic	criteria provided, single submitter
1457438	NM_213599.3(ANO5):c.258C>A (p.Tyr86Ter)	ANO5	Pathogenic	criteria provided, multiple submitters, no conflicts
1459484	NC_000011.9:g.(?22215039)(22225416_?)del	ANO5	Pathogenic	criteria provided, single submitter
1460312	NM_213599.3(ANO5):c.738C>G (p.Tyr246Ter)	ANO5	Pathogenic	criteria provided, single submitter
1906545	NM_213599.3(ANO5):c.1794_1798dup (p.Glu600fs)	ANO5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
ANO5	Definitive	Autosomal dominant	gnathodiaphyseal dysplasia	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANO5	Orphanet:206549	Anoctamin-5-related limb-girdle muscular dystrophy R12
ANO5	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
ANO5	Orphanet:399096	Distal anoctaminopathy
ANO5	Orphanet:53697	Gnathodiaphyseal dysplasia
ANO5	Orphanet:689021	Asymptomatic hyperCKemia-myalgia-rhabdomyolysis syndrome

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
ANO5	HGNC:27337	ENSG00000171714	Q75V66	Anoctamin-5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANO5	Anoctamin-5	Plays a role in plasma membrane repair in a process involving annexins.

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)
ANO5	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM

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
cardiac muscle of right atrium	1
left ventricle myocardium	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANO5	220	broad	marker	cardiac muscle of right atrium, left ventricle myocardium, vastus lateralis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANO5	790

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO5	Q75V66	82.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Induction of Cell-Cell Fusion	1	878.5×	0.013	ANO5
Late SARS-CoV-2 Infection Events	1	292.8×	0.016	ANO5
Regulation of clotting cascade	1	233.1×	0.016	ANO5
Stimuli-sensing channels	1	135.9×	0.020	ANO5
Ion channel transport	1	96.0×	0.023	ANO5
SARS-CoV-2 Infection	1	80.4×	0.023	ANO5
SARS-CoV Infections	1	55.4×	0.028	ANO5
Viral Infection Pathways	1	30.8×	0.044	ANO5
Transport of small molecules	1	25.1×	0.044	ANO5
Infectious disease	1	24.8×	0.044	ANO5
Disease	1	13.1×	0.076	ANO5

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
plasma membrane repair	1	581.1×	0.005	ANO5
chloride transmembrane transport	1	237.3×	0.005	ANO5
monoatomic ion transmembrane transport	1	208.1×	0.005	ANO5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANO5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANO5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANO5	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
NCT06155214	Not specified	UNKNOWN	Developmental Regression-related Disease Research and Achievement Transformation Innovation Team