Dentinogenesis imperfecta

Summary

Dentinogenesis imperfecta (MONDO:0018849) is a disease caused by DSPP (GenCC Definitive), with 3 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: DSPP (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 9
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	14.5	Europe	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0006350	Obliteration of the pulp chamber	Very frequent (80-99%)
HP:0006486	Abnormality of the dental root	Very frequent (80-99%)
HP:0000683	Grayish enamel	Frequent (30-79%)
HP:0000694	Odontodysplasia	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0006282	Generalized hypoplasia of dental enamel	Frequent (30-79%)
HP:0006286	Yellow-brown discoloration of the teeth	Frequent (30-79%)
HP:0006479	Abnormality of the dental pulp	Frequent (30-79%)
HP:0010299	Abnormality of dentin	Frequent (30-79%)
HP:0011084	Hypocalcification of dental enamel	Frequent (30-79%)
HP:0025124	Fragile teeth	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001592	Selective tooth agenesis	Occasional (5-29%)
HP:0006094	Finger joint hypermobility	Occasional (5-29%)
HP:0006335	Persistence of primary teeth	Occasional (5-29%)
HP:0006336	Short dental roots	Occasional (5-29%)
HP:0010485	Hyperextensibility at elbow	Occasional (5-29%)
HP:0045086	Knee joint hypermobility	Occasional (5-29%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000592	Blue sclerae	Very rare (<1-4%)
HP:0003010	Prolonged bleeding time	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dentinogenesis imperfecta
Mondo ID	MONDO:0018849
MeSH	D003811
Orphanet	49042
DOID	DOID:4154
ICD-11	2090257992
NCIT	C84667
SNOMED CT	196286005
UMLS	C0011436
MedGen	8313
GARD	0006258
MedDRA	10054013
Is cancer (heuristic)	no

Also known as: dentinogenesis imperfecta · dentinogenesis imperfecta (disease) · dentinogenesis imperfecta without osteogenesis imperfecta · DGI · DGI without OI · DI · non-syndromic dentinogenesis imperfecta · non-syndromic DGI · opalescent teeth without OI · opalescent teeth without osteogenesis imperfecta

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › tooth disorder › dentinogenesis imperfecta

Related subtypes (10): dental abscess, tooth hard tissue disease, tooth erosion, non-bacterial, dental pulp disorder, tooth agenesis, dental fluorosis, anodontia, taurodontism, odontogenic neoplasm, dental radicular dysplasia

Subtypes (2): dentinogenesis imperfecta type 2, dentinogenesis imperfecta type 3

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

9 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098566	NM_000089.4(COL1A2):c.3233G>A (p.Gly1078Asp)	COL1A2	Pathogenic	criteria provided, single submitter
425645	NM_000089.4(COL1A2):c.1171G>A (p.Gly391Ser)	COL1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548666	NM_000089.4(COL1A2):c.2027G>A (p.Gly676Asp)	COL1A2	Pathogenic	criteria provided, single submitter
1343806	NM_014208.3(DSPP):c.52-2del	DMP1-AS1	Pathogenic	no assertion criteria provided
1343807	NM_014208.3(DSPP):c.135+1G>C	DMP1-AS1	Pathogenic	no assertion criteria provided
1343808	NM_014208.3(DSPP):c.135G>A (p.Gln45=)	DMP1-AS1	Pathogenic	no assertion criteria provided
760963	NM_014208.3(DSPP):c.412G>A (p.Gly138Arg)	DMP1-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3376839	NM_014208.3(DSPP):c.1847G>T (p.Ser616Ile)	DMP1-AS1	Uncertain significance	criteria provided, single submitter
16858	NM_014208.3(DSPP):c.202A>T (p.Arg68Trp)	DMP1-AS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 12 · 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
DSPP	Definitive	Autosomal dominant	dentinogenesis imperfecta	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSPP	Orphanet:166260	Dentinogenesis imperfecta type 2
DSPP	Orphanet:166265	Dentinogenesis imperfecta type 3
DSPP	Orphanet:99789	Dentin dysplasia type I
DSPP	Orphanet:99791	Dentin dysplasia type II
COL1A2	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A2	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A2	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A2	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A2	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A2	Orphanet:230851	Cardiac-valvular Ehlers-Danlos syndrome
COL1A2	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A2	Orphanet:314029	High bone mass osteogenesis imperfecta

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSPP	HGNC:3054	ENSG00000152591	Q9NZW4	Dentin sialophosphoprotein	gencc
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	clinvar
DMP1-AS1	HGNC:58144	ENSG00000249001		DMP1 and DSPP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSPP	Dentin sialophosphoprotein	DSP may be an important factor in dentinogenesis.
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSPP	Other/Unknown	no
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily
DMP1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
myocardium	1
tendon of biceps brachii	1
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSPP	76		marker	buccal mucosa cell, tendon of biceps brachii, myocardium
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip
DMP1-AS1	108		yes	male germ line stem cell (sensu Vertebrata) in testis, sperm, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSPP	1,199
COL1A2	179
DMP1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A2	P08123	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSPP	Q9NZW4	39.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. 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
ECM proteoglycans	2	150.3×	0.001	COL1A2, DSPP
Defective VWF binding to collagen type I	1	1903.3×	0.005	COL1A2
Enhanced cleavage of VWF variant by ADAMTS13	1	1427.5×	0.005	COL1A2
Defective VWF cleavage by ADAMTS13 variant	1	1427.5×	0.005	COL1A2
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	815.7×	0.006	COL1A2
Defective binding of VWF variant to GPIb:IX:V	1	815.7×	0.006	COL1A2
GP1b-IX-V activation signalling	1	475.8×	0.008	COL1A2
Anchoring fibril formation	1	380.7×	0.008	COL1A2
Platelet Adhesion to exposed collagen	1	335.9×	0.008	COL1A2
Scavenging by Class A Receptors	1	300.5×	0.008	COL1A2
Fibronectin matrix formation	1	285.5×	0.008	COL1A2
Crosslinking of collagen fibrils	1	285.5×	0.008	COL1A2
Platelet Aggregation (Plug Formation)	1	219.6×	0.009	COL1A2
Syndecan interactions	1	211.5×	0.009	COL1A2
MET activates PTK2 signaling	1	190.3×	0.009	COL1A2
GPVI-mediated activation cascade	1	154.3×	0.010	COL1A2
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	154.3×	0.010	COL1A2
Collagen chain trimerization	1	129.8×	0.012	COL1A2
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.012	COL1A2
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.013	COL1A2
Collagen degradation	1	87.8×	0.014	COL1A2
Collagen biosynthesis and modifying enzymes	1	85.2×	0.014	COL1A2
Non-integrin membrane-ECM interactions	1	77.2×	0.015	COL1A2
Integrin cell surface interactions	1	67.2×	0.017	COL1A2
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.021	COL1A2
Cell surface interactions at the vascular wall	1	47.6×	0.022	COL1A2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL1A2

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
protein heterotrimerization	1	8426.0×	0.002	COL1A2
regulation of odontoblast differentiation	1	4213.0×	0.002	DSPP
odontoblast differentiation	1	1053.2×	0.004	DSPP
dentinogenesis	1	1053.2×	0.004	DSPP
skin morphogenesis	1	702.2×	0.005	COL1A2
collagen metabolic process	1	526.6×	0.005	COL1A2
extracellular matrix assembly	1	468.1×	0.005	COL1A2
biomineral tissue development	1	324.1×	0.007	DSPP
odontogenesis	1	263.3×	0.007	COL1A2
blood vessel development	1	187.2×	0.009	COL1A2
cellular response to amino acid stimulus	1	153.2×	0.010	COL1A2
bone mineralization	1	135.9×	0.010	COL1A2
Rho protein signal transduction	1	123.9×	0.010	COL1A2
collagen fibril organization	1	112.3×	0.010	COL1A2
regulation of blood pressure	1	110.9×	0.010	COL1A2
transforming growth factor beta receptor signaling pathway	1	79.5×	0.013	COL1A2
skeletal system development	1	62.9×	0.016	COL1A2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSPP	0	0
COL1A2	0	0
DMP1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
COL1A2	4	Functional:4

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

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	3	DSPP, COL1A2, DMP1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DSPP	0	—
COL1A2	4	—
DMP1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta