Dental enamel hypoplasia

Summary

Dental enamel hypoplasia (MONDO:0004038) is a disease with 1 cohort gene (15 GWAS associations across 2 studies) and 10 clinical trials.

At a glance

• Cohort genes: 1
• GWAS associations: 15
• ClinVar variants: 1
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dental enamel hypoplasia
Mondo ID	MONDO:0004038
EFO	EFO:1001304
MeSH	D003744
DOID	DOID:693
NCIT	C34529
SNOMED CT	26597004
UMLS	C0011351
MedGen	3730
Is cancer (heuristic)	no

Also known as: enamel hypoplasia

Data availability: 1 ClinVar variant · 15 GWAS associations (2 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › tooth disorder › tooth hard tissue disease › dental enamel hypoplasia

Related subtypes (6): tooth resorption, dentin sensitivity, dental caries, hypercementosis, tooth ankylosis, dentin dysplasia

Subtypes (1): amelogenesis imperfecta

Genetics & variants

GWAS landscape

15 GWAS associations across 2 studies. Top hits map to 12 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs79577009	3e-07	SMAD2	T
rs1359694	6e-07	PTPRD	A
rs12830414	6e-07	LINC02424 - SYT1	C
rs682846	6e-07	MYH14	C
rs11125855	9e-07	PAPOLG	G
rs56282801	1e-06	DHX37	A
rs4649222	2e-06	MAP3K21	A
rs2840075	2e-06	SLC4A4	C
rs62196465	3e-06	MACROD2	A
rs16968212	3e-06	SCAPER	C
rs6758898	3e-06	CHCHD5 - SLC20A1-DT	G
rs4868444	3e-06	MSX2 - MIR4634	T
rs5850440	3e-06	ROBO1	AT
rs7921002	4e-06	ZMIZ1	G
rs9846530	4e-06	SEMA5B	C

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90103973	Alotaibi RN	2022	0	0	Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.
GCST90204172	Alotaibi RN	2022	0	0	Multivariate GWAS of Structural Dental Anomalies and Dental Caries in a Multi-Ethnic Cohort.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	14

MAF distribution

Bucket	Variants
common (>=0.05)	15
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	14
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs79577009	18	47884850	C>T	0.05	intron_variant	SMAD2	3e-07	Tier 4: intronic/intergenic
rs1359694	9	9531084	C>A	0.05	intron_variant	PTPRD	6e-07	Tier 4: intronic/intergenic
rs12830414	12	78434042	T>A,C	0.05	intron_variant	LINC02424 - SYT1	6e-07	Tier 4: intronic/intergenic
rs682846	19	50192983	C>A,G	0.05	intron_variant	MYH14	6e-07	Tier 4: intronic/intergenic
rs11125855	2	60794214	A>G	0.05	intron_variant	PAPOLG	9e-07	Tier 4: intronic/intergenic
rs56282801	12	124974968	G>A,C	0.05	intron_variant	DHX37	1e-06	Tier 4: intronic/intergenic
rs4649222	1	233355691	G>A,T	0.05	intron_variant	MAP3K21	2e-06	Tier 4: intronic/intergenic
rs2840075	4	71126912	G>A,T	0.05	intron_variant	SLC4A4	2e-06	Tier 4: intronic/intergenic
rs62196465	20	15631311	G>A	0.05	intron_variant	MACROD2	3e-06	Tier 4: intronic/intergenic
rs16968212	15	76432541	T>C	0.05	intron_variant	SCAPER	3e-06	Tier 4: intronic/intergenic
rs6758898	2	112625107	G>A,C,T	0.05	intron_variant	CHCHD5 - SLC20A1-DT	3e-06	Tier 4: intronic/intergenic
rs4868444	5	174733110	T>A,C	0.05	regulatory_region_variant	MSX2 - MIR4634	3e-06	Tier 3: regulatory
rs5850440	3	79600650	ATT>A,AT,ATTT	0.05	intron_variant	ROBO1	3e-06	Tier 4: intronic/intergenic
rs7921002	10	79127964	T>G	0.05	intron_variant	ZMIZ1	4e-06	Tier 4: intronic/intergenic
rs9846530	3	122932696	G>A,C	0.05	intron_variant	SEMA5B	4e-06	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
684727	NM_000396.4(CTSK):c.905G>A (p.Trp302Ter)	CTSK	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTSK	Orphanet:763	Pycnodysostosis

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
CTSK	HGNC:2536	ENSG00000143387	P43235	Cathepsin K	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTSK	Cathepsin K	Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTSK	Protease	yes	3.4.22.38	Pept_cys_AS, Peptidase_C1A_C, Peptidase_C1A

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
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTSK	254	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTSK	2,790

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTSK	P43235	70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
RUNX1 regulates transcription of genes involved in differentiation of keratinocytes	1	1142.0×	0.009	CTSK
Trafficking and processing of endosomal TLR	1	815.7×	0.009	CTSK
Activation of Matrix Metalloproteinases	1	308.6×	0.016	CTSK
Collagen degradation	1	175.7×	0.018	CTSK
Transcriptional regulation by RUNX1	1	146.4×	0.018	CTSK
Toll-like Receptor Cascades	1	124.1×	0.018	CTSK
Degradation of the extracellular matrix	1	117.7×	0.018	CTSK
MHC class II antigen presentation	1	89.2×	0.021	CTSK
Extracellular matrix organization	1	63.1×	0.026	CTSK
Adaptive Immune System	1	29.8×	0.050	CTSK
Innate Immune System	1	25.5×	0.053	CTSK
RNA Polymerase II Transcription	1	22.5×	0.055	CTSK
Gene expression (Transcription)	1	17.8×	0.065	CTSK
Generic Transcription Pathway	1	15.1×	0.071	CTSK
Immune System	1	13.0×	0.077	CTSK

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
negative regulation of cartilage development	1	2106.5×	0.004	CTSK
thyroid hormone generation	1	991.3×	0.004	CTSK
bone resorption	1	581.1×	0.004	CTSK
obsolete proteolysis involved in protein catabolic process	1	526.6×	0.004	CTSK
collagen catabolic process	1	391.9×	0.004	CTSK
extracellular matrix disassembly	1	366.4×	0.004	CTSK
mitophagy	1	318.0×	0.004	CTSK
proteolysis	1	34.2×	0.029	CTSK

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
CTSK	BOCEPREVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CTSK	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BOCEPREVIR	4	CTSK
TELAPREVIR	4	CTSK
NIRMATRELVIR	4	CTSK
ODANACATIB	3	CTSK
RELACATIB	2	CTSK
BALICATIB	2	CTSK
ATUZAGINSTAT	2	CTSK
IBUZATRELVIR	2	CTSK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CTSK	376	Binding:365, ADMET:5, Toxicity:5, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTSK	3.4.22.38	cathepsin K

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CTSK	376

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

8 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)
BOCEPREVIR	4	CTSK
TELAPREVIR	4	CTSK
NIRMATRELVIR	4	CTSK
ODANACATIB	3	CTSK
RELACATIB	2	CTSK
BALICATIB	2	CTSK
ATUZAGINSTAT	2	CTSK
IBUZATRELVIR	2	CTSK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CTSK
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: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06205420	PHASE4	COMPLETED	Injection Molding Technique: A Minimally Invasive Management for Enamel Hypoplasia Affecting Permanent Anterior Teeth in Children
NCT07330089	Not specified	RECRUITING	Retention of Pits and Fissure Sealants on Non Carious vs Initial Carious Enamel Lesions in Posterior Teeth
NCT03273725	Not specified	COMPLETED	Maternal Vitamin D Levels in Pregnancy and Dental Caries in Children
NCT03614819	Not specified	COMPLETED	Laser Used in the Treatment of Hypomineralized Occlusal Lesions in Teeth Enamel Affected by MIH
NCT04231019	Not specified	COMPLETED	Knowledge of Egyptian Dental Practitioners Regarding Molar-Incisor Hypomineralization
NCT04685889	Not specified	COMPLETED	Resin Infiltration Treatment for MIH
NCT05299489	Not specified	COMPLETED	Evaluation Direct and Indirect Composite Restoration in Hypomineralization Molars.
NCT06987448	Not specified	COMPLETED	Clinical Comparison of CAD/CAM Nanohybrid Composite and Hybrid Ceramic Overlays in Children With Molar-Incisor Hypomineralisation
NCT07118111	Not specified	COMPLETED	Effect of Resin Infiltration on Hypersensitivity and Satisfaction in Children With Enamel Defects
NCT07134348	Not specified	COMPLETED	Evaluation of Sequelae in Permanent Successors Following Traumatic Injuries to Primary Teeth