amelogenesis imperfecta type 1H

Summary

amelogenesis imperfecta type 1H (MONDO:0014540) is a disease caused by ITGB6 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ITGB6 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amelogenesis imperfecta type 1H
Mondo ID	MONDO:0014540
OMIM	616221
DOID	DOID:0110064
UMLS	C4015557
MedGen	863994
GARD	0016071
Is cancer (heuristic)	no

Also known as: AI1H · amelogenesis imperfecta caused by mutation in ITGB6 · amelogenesis imperfecta, type IH · ITGB6 amelogenesis imperfecta

Data availability: 16 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › amelogenesis imperfecta › amelogenesis imperfecta type 1 › amelogenesis imperfecta type 1H

Related subtypes (5): amelogenesis imperfecta type 1B, amelogenesis imperfecta type 1A, amelogenesis imperfecta type 1C, amelogenesis imperfecta type 1F, amelogenesis imperfecta, type 1J

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

16 retrieved; paginated sample, class counts are floors:

5 pathogenic, 5 likely pathogenic, 3 uncertain significance, 2 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1333182	NM_000888.5(ITGB6):c.625G>T (p.Gly209Ter)	ITGB6	Pathogenic	criteria provided, single submitter
180683	NM_000888.5(ITGB6):c.427G>A (p.Ala143Thr)	ITGB6	Pathogenic	no assertion criteria provided
180684	NM_000888.5(ITGB6):c.825T>A (p.His275Gln)	ITGB6	Pathogenic	no assertion criteria provided
180685	NM_000888.5(ITGB6):c.1846C>T (p.Arg616Ter)	ITGB6	Pathogenic	no assertion criteria provided
4082036	NC_000016.10:g.78346685_78388773del	WWOX	Pathogenic	no assertion criteria provided
1333183	NM_000888.5(ITGB6):c.1661-3C>G	ITGB6	Likely pathogenic	criteria provided, single submitter
180686	NM_000888.5(ITGB6):c.586C>A (p.Pro196Thr)	ITGB6	Likely pathogenic	criteria provided, single submitter
2444003	NM_000888.5(ITGB6):c.718G>A (p.Glu240Lys)	ITGB6	Likely pathogenic	no assertion criteria provided
4849344	NM_000888.5(ITGB6):c.62-2A>G	ITGB6	Likely pathogenic	criteria provided, single submitter
4849433	NM_000888.5(ITGB6):c.594-1G>A	ITGB6	Likely pathogenic	criteria provided, single submitter
1309333	NM_000888.5(ITGB6):c.129G>A (p.Trp43Ter)	ITGB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3362752	NM_000888.5(ITGB6):c.871G>A (p.Gly291Arg)	ITGB6	Uncertain significance	criteria provided, single submitter
3584538	NM_000888.5(ITGB6):c.2020G>A (p.Gly674Arg)	ITGB6	Uncertain significance	criteria provided, single submitter
3891417	NM_000888.5(ITGB6):c.488T>C (p.Met163Thr)	ITGB6	Uncertain significance	criteria provided, single submitter
218475	NM_000888.5(ITGB6):c.2269-5del	ITGB6	Benign	criteria provided, multiple submitters, no conflicts
790339	NM_000888.5(ITGB6):c.1312G>A (p.Val438Met)	ITGB6	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 7 · 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
ITGB6	Strong	Autosomal recessive	amelogenesis imperfecta type 1H	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITGB6	Orphanet:100031	Hypoplastic amelogenesis imperfecta
ITGB6	Orphanet:100032	Hypocalcified amelogenesis imperfecta
ITGB6	Orphanet:2850	Alopecia-intellectual disability syndrome
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ITGB6	HGNC:6161	ENSG00000115221	P18564	Integrin beta-6	gencc,clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITGB6	Integrin beta-6	Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ITGB6	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, EGF_extracell
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
visceral pleura	1
cervix squamous epithelium	1
cranial nerve II	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITGB6	188	broad	marker	visceral pleura, biceps brachii, skeletal muscle tissue of rectus abdominis
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWOX	5,892
ITGB6	1,461

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITGB6	P18564	14
WWOX	Q9NZC7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	571.0×	0.013	WWOX
Activation of the TFAP2 (AP-2) family of transcription factors	1	475.8×	0.013	WWOX
Nuclear signaling by ERBB4	1	173.0×	0.013	WWOX
Elastic fibre formation	1	167.9×	0.013	ITGB6
TGF-beta receptor signaling activates SMADs	1	163.1×	0.013	ITGB6
Molecules associated with elastic fibres	1	154.3×	0.013	ITGB6
Signaling by TGF-beta Receptor Complex	1	100.2×	0.017	ITGB6
ECM proteoglycans	1	75.1×	0.020	ITGB6
Integrin cell surface interactions	1	67.2×	0.020	ITGB6
Signaling by TGFB family members	1	57.7×	0.021	ITGB6
Extracellular matrix organization	1	31.6×	0.034	ITGB6
Signal Transduction	1	5.1×	0.187	ITGB6

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
transforming growth factor beta production	1	4213.0×	0.005	ITGB6
memory T cell differentiation	1	2808.7×	0.005	ITGB6
Langerhans cell differentiation	1	2106.5×	0.005	ITGB6
bronchiole development	1	1685.2×	0.005	ITGB6
hard palate development	1	842.6×	0.007	ITGB6
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	766.0×	0.007	WWOX
amelogenesis	1	702.2×	0.007	ITGB6
enamel mineralization	1	601.9×	0.007	ITGB6
phospholipid homeostasis	1	495.6×	0.008	ITGB6
surfactant homeostasis	1	401.2×	0.008	ITGB6
cell adhesion mediated by integrin	1	337.0×	0.009	ITGB6
intrinsic apoptotic signaling pathway by p53 class mediator	1	290.6×	0.010	WWOX
skeletal system morphogenesis	1	247.8×	0.010	WWOX
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.010	WWOX
skin development	1	221.7×	0.010	ITGB6
cellular response to ionizing radiation	1	205.5×	0.010	ITGB6
lung alveolus development	1	175.5×	0.011	ITGB6
negative regulation of Wnt signaling pathway	1	172.0×	0.011	WWOX
extrinsic apoptotic signaling pathway	1	153.2×	0.012	WWOX
bone development	1	138.1×	0.012	ITGB6
cellular response to transforming growth factor beta stimulus	1	138.1×	0.012	WWOX
wound healing	1	113.9×	0.014	ITGB6
cell-matrix adhesion	1	81.8×	0.017	ITGB6
integrin-mediated signaling pathway	1	80.2×	0.017	ITGB6
transforming growth factor beta receptor signaling pathway	1	79.5×	0.017	ITGB6
cell morphogenesis	1	78.8×	0.017	ITGB6
response to virus	1	72.0×	0.017	ITGB6
osteoblast differentiation	1	60.6×	0.020	WWOX
cell-cell adhesion	1	50.8×	0.023	ITGB6
Wnt signaling pathway	1	49.9×	0.023	WWOX

Therapeutics

Drug target analysis

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

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
ITGB6	5	3
WWOX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CILENGITIDE	3	ITGB6
NESVATEGRAST	2	ITGB6
GLPG-0187	1	ITGB6
GSK-3008348 FREE BASE	1	ITGB6
GSK-3008348	1	ITGB6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ITGB6	79	Binding:75, ADMET:2, Functional:2

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

5 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)
CILENGITIDE	3	ITGB6
NESVATEGRAST	2	ITGB6
GLPG-0187	1	ITGB6
GSK-3008348 FREE BASE	1	ITGB6
GSK-3008348	1	ITGB6

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	1	ITGB6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	WWOX

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)
WWOX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.