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Atlas / Disease / Isolated trigonocephaly

Isolated trigonocephaly

disease
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Also known as non-syndromic metopic craniosynostosisnonsyndromic trigonocephaly

Summary

Isolated trigonocephaly (MONDO:0018065) is a disease with 2 cohort genes.

At a glance

  • Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
  • Cohort genes: 2
  • Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Point prevalence1-5 / 10 00010.2979EuropeValidated
Prevalence at birth1-9 / 100 0006.7EuropeNot yet validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO IDTermFrequency
HP:0000243TrigonocephalyVery frequent (80-99%)
HP:0011330Metopic synostosisVery frequent (80-99%)
HP:0000336Prominent supraorbital ridgesFrequent (30-79%)
HP:0000341Narrow foreheadFrequent (30-79%)
HP:0000431Wide nasal bridgeFrequent (30-79%)
HP:0000601HypotelorismFrequent (30-79%)
HP:0000664SynophrysFrequent (30-79%)
HP:0002553Highly arched eyebrowFrequent (30-79%)
HP:0000750Delayed speech and language developmentOccasional (5-29%)
HP:0001539OmphaloceleOccasional (5-29%)
HP:0001085PapilledemaVery rare (<1-4%)
HP:0002516Increased intracranial pressureVery rare (<1-4%)

Identifiers

Disease identifiers

FieldValue
Canonical nameisolated trigonocephaly
Mondo IDMONDO:0018065
OMIM190440
Orphanet3366
UMLSC5575700
MedGen1812049
GARD0016626
Is cancer (heuristic)no

Also known as: non-syndromic metopic craniosynostosis · nonsyndromic trigonocephaly

Data availability: 2 GenCC gene-disease records.

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 › bone disorder › bone development disease › dysostosis › trigonocephaly › isolated trigonocephaly

Subtypes (2): trigonocephaly 1, trigonocephaly 2

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 51 · Orphanet: 21 · 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.

GeneClassificationInheritanceDiseaseRecords
FREM1StrongAutosomal dominanttrigonocephaly 215
FGFR1SupportiveAutosomal dominantisolated trigonocephaly36

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
FREM1Orphanet:217266BNAR syndrome
FREM1Orphanet:2717Oculotrichoanal syndrome
FREM1Orphanet:3366Non-syndromic metopic craniosynostosis
FREM1Orphanet:93100Renal agenesis, unilateral
FGFR1Orphanet:168953Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1Orphanet:2117Hartsfield syndrome
FGFR1Orphanet:220386Semilobar holoprosencephaly
FGFR1Orphanet:2396Encephalocraniocutaneous lipomatosis
FGFR1Orphanet:251576Gliosarcoma
FGFR1Orphanet:251579Giant cell glioblastoma
FGFR1Orphanet:251615Pilomyxoid astrocytoma
FGFR1Orphanet:2645Osteoglosphonic dysplasia
FGFR1Orphanet:280200Microform holoprosencephaly
FGFR1Orphanet:314950Primary hypereosinophilic syndrome
FGFR1Orphanet:3157Septo-optic dysplasia spectrum
FGFR1Orphanet:3366Non-syndromic metopic craniosynostosis
FGFR1Orphanet:432Normosmic congenital hypogonadotropic hypogonadism
FGFR1Orphanet:478Kallmann syndrome
FGFR1Orphanet:93258Pfeiffer syndrome type 1
FGFR1Orphanet:93924Lobar holoprosencephaly
FGFR1Orphanet:99798Oligodontia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence2

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
FREM1HGNC:23399ENSG00000164946Q5H8C1FRAS1-related extracellular matrix protein 1gencc
FGFR1HGNC:3688ENSG00000077782P11362Fibroblast growth factor receptor 1gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
FREM1FRAS1-related extracellular matrix protein 1Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
FGFR1Fibroblast growth factor receptor 1Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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.

FamilyGenesFoldFDR
Kinase113.9×0.142
Other/Unknown10.9×0.805

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
FREM1Other/UnknownnoC-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf
FGFR1Kinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2

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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)2
unknown0

Top tissues across cohort

TissueCohort genes
kidney epithelium1
metanephros1
smooth muscle tissue1
buccal mucosa cell1
calcaneal tendon1
stromal cell of endometrium1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
FREM1171broadmarkerkidney epithelium, smooth muscle tissue, metanephros
FGFR1292ubiquitousmarkerbuccal mucosa cell, stromal cell of endometrium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
FGFR15,693
FREM11,541

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
FGFR1P1136283

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
FREM1Q5H8C175.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 2 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.

PathwayCohort genesFoldFDRSample cohort genes
Signaling by FGFR1 amplification mutants15710.0×0.003FGFR1
FGFR1c and Klotho ligand binding and activation12855.0×0.003FGFR1
Signaling by plasma membrane FGFR1 fusions12855.0×0.003FGFR1
Epithelial-Mesenchymal Transition (EMT) during gastrulation11427.5×0.003FGFR1
FGFR1b ligand binding and activation11268.9×0.003FGFR1
Signaling by activated point mutants of FGFR11951.7×0.004FGFR1
FGFR1c ligand binding and activation1761.3×0.004FGFR1
Phospholipase C-mediated cascade: FGFR11671.8×0.004FGFR1
Downstream signaling of activated FGFR11543.8×0.004FGFR1
Signal transduction by L11519.1×0.004FGFR1
PI-3K cascade:FGFR11519.1×0.004FGFR1
SHC-mediated cascade:FGFR11496.5×0.004FGFR1
FRS-mediated FGFR1 signaling1456.8×0.004FGFR1
Formation of paraxial mesoderm1407.9×0.004FGFR1
Negative regulation of FGFR1 signaling1368.4×0.004FGFR1
Signaling by FGFR1 in disease1292.8×0.004FGFR1
PI3K Cascade1271.9×0.004FGFR1
NCAM signaling for neurite out-growth1271.9×0.004FGFR1
Constitutive Signaling by Aberrant PI3K in Cancer1126.9×0.009FGFR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling196.8×0.011FGFR1
PIP3 activates AKT signaling166.8×0.016FGFR1
RAF/MAP kinase cascade161.1×0.016FGFR1

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 termCohort genesFoldFDRSample cohort genes
vitamin D3 metabolic process14213.0×0.004FGFR1
positive regulation of mitotic cell cycle DNA replication14213.0×0.004FGFR1
positive regulation of parathyroid hormone secretion14213.0×0.004FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand14213.0×0.004FGFR1
regulation of phosphate transport12808.7×0.004FGFR1
fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development12808.7×0.004FGFR1
regulation of lateral mesodermal cell fate specification12808.7×0.004FGFR1
ventricular zone neuroblast division12106.5×0.004FGFR1
negative regulation of fibroblast growth factor production12106.5×0.004FGFR1
positive regulation of phospholipase activity11685.2×0.004FGFR1
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling11685.2×0.004FGFR1
diphosphate metabolic process11685.2×0.004FGFR1
chordate embryonic development11404.3×0.004FGFR1
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway11404.3×0.004FGFR1
cementum mineralization11203.7×0.004FGFR1
auditory receptor cell development1936.2×0.004FGFR1
paraxial mesoderm development1842.6×0.004FGFR1
lung-associated mesenchyme development1842.6×0.004FGFR1
craniofacial suture morphogenesis1842.6×0.004FREM1
response to sodium phosphate1842.6×0.004FGFR1
outer ear morphogenesis1766.0×0.004FGFR1
branching involved in salivary gland morphogenesis1702.2×0.005FGFR1
organ induction1601.9×0.005FGFR1
mesenchymal cell proliferation1561.7×0.005FGFR1
positive regulation of endothelial cell chemotaxis1495.6×0.006FGFR1
cell projection assembly1468.1×0.006FGFR1
regulation of postsynaptic density assembly1443.5×0.006FGFR1
cell communication1421.3×0.006FREM1
positive regulation of vascular endothelial cell proliferation1421.3×0.006FGFR1
middle ear morphogenesis1351.1×0.007FGFR1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

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.

SymbolExample approved molecule
FGFR1PONATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
FGFR1934
FREM100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PONATINIB4FGFR1
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1
FEDRATINIB4FGFR1
TIVOZANIB4FGFR1
LENVATINIB4FGFR1
AXITINIB4FGFR1
SORAFENIB4FGFR1
NICLOSAMIDE4FGFR1
INFIGRATINIB PHOSPHATE4FGFR1
INFIGRATINIB4FGFR1
REGORAFENIB4FGFR1
ENTRECTINIB4FGFR1
CABOZANTINIB4FGFR1
CAPIVASERTIB4FGFR1
VANDETANIB4FGFR1
NINTEDANIB ESYLATE4FGFR1
BRIGATINIB4FGFR1
ERDAFITINIB4FGFR1
UPADACITINIB4FGFR1
FUTIBATINIB4FGFR1
PAZOPANIB4FGFR1
SUNITINIB4FGFR1
DASATINIB4FGFR1
MIDOSTAURIN4FGFR1
LINIFANIB3FGFR1
SEMAXANIB3FGFR1
OLVEREMBATINIB3FGFR1
BRIVANIB ALANINATE3FGFR1
ORANTINIB3FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

SymbolAssaysType breakdown
FGFR11,465Binding:1428, Functional:24, ADMET:13

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
FGFR12.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

SymbolChEMBL assays
FGFR11,465

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

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.

CompoundMax phaseCohort target (bioactivity)
PONATINIB4FGFR1
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1
FEDRATINIB4FGFR1
TIVOZANIB4FGFR1
LENVATINIB4FGFR1
AXITINIB4FGFR1
SORAFENIB4FGFR1
NICLOSAMIDE4FGFR1
INFIGRATINIB PHOSPHATE4FGFR1
INFIGRATINIB4FGFR1
REGORAFENIB4FGFR1
ENTRECTINIB4FGFR1
CABOZANTINIB4FGFR1
CAPIVASERTIB4FGFR1
VANDETANIB4FGFR1
NINTEDANIB ESYLATE4FGFR1
BRIGATINIB4FGFR1
ERDAFITINIB4FGFR1
UPADACITINIB4FGFR1
FUTIBATINIB4FGFR1
PAZOPANIB4FGFR1
SUNITINIB4FGFR1
DASATINIB4FGFR1
MIDOSTAURIN4FGFR1
LINIFANIB3FGFR1
SEMAXANIB3FGFR1
OLVEREMBATINIB3FGFR1
BRIVANIB ALANINATE3FGFR1
ORANTINIB3FGFR1

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1FGFR1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug1FREM1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
FREM10—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
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Sources 68

This page pulls from 68 datasets indexed by BioBTree:

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