Craniosynostosis 4

Summary

Craniosynostosis 4 (MONDO:0010929) is a disease caused by ERF (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ERF (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	craniosynostosis 4
Mondo ID	MONDO:0010929
OMIM	600775
DOID	DOID:0061012
UMLS	C3806917
MedGen	813247
GARD	0024762
Is cancer (heuristic)	no

Also known as: craniosynostosis 4 · craniosynostosis caused by mutation in ERF · craniosynostosis type 4 · CRS4 · ERF craniosynostosis · ERF-related craniosynostosis

Data availability: 3 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › craniosynostosis 4

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, Baller-Gerold syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, lethal occipital encephalocele-skeletal dysplasia syndrome, TCF12-related craniosynostosis, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka syndrome

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
420168	NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849235	NM_006494.4(ERF):c.258-2A>G	ERF	Likely pathogenic	criteria provided, single submitter
4755416	NM_006494.4(ERF):c.347A>G (p.Tyr116Cys)	ERF	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 2 · 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
ERF	Definitive	Autosomal dominant	craniosynostosis 4	10
ETF1	Definitive	Autosomal dominant	craniosynostosis 4	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERF	Orphanet:207	Crouzon syndrome
ERF	Orphanet:647681	Craniosynostosis-facial dysmorphism-Chiari-1 malformation-developmental and language delay syndrome

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
ERF	HGNC:3444	ENSG00000105722	P50548	ETS domain-containing transcription factor ERF	gencc,clinvar
ETF1	HGNC:3477	ENSG00000120705	P62495	Eukaryotic peptide chain release factor subunit 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERF	ETS domain-containing transcription factor ERF	Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter.
ETF1	Eukaryotic peptide chain release factor subunit 1	Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERF	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
ETF1	Other/Unknown	no		Peptide_chain-rel_eRF1/aRF1, eRF1_Pelota-like_N, eRF1_2

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
gall bladder	1
mucosa of stomach	1
right uterine tube	1
islet of Langerhans	1
mucosa of sigmoid colon	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERF	242	ubiquitous	marker	right uterine tube, mucosa of stomach, gall bladder
ETF1	293	ubiquitous	marker	islet of Langerhans, upper leg skin, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERF	1,115
ETF1	313

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETF1	P62495	33
ERF	P50548	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Protein hydroxylation	1	271.9×	0.018	ETF1
Oncogene Induced Senescence	1	167.9×	0.018	ERF
Eukaryotic Translation Termination	1	60.1×	0.024	ETF1
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	58.9×	0.024	ETF1
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	48.8×	0.024	ETF1
Regulation of expression of SLITs and ROBOs	1	34.6×	0.029	ETF1

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
cytoplasmic translational termination	1	4213.0×	0.002	ETF1
regulation of translational termination	1	1404.3×	0.002	ETF1
translational termination	1	1203.7×	0.002	ETF1
protein methylation	1	468.1×	0.004	ETF1
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	234.1×	0.007	ETF1
cell differentiation	1	14.6×	0.090	ERF
negative regulation of transcription by RNA polymerase II	1	8.9×	0.125	ERF
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ERF

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
ERF	0	0
ETF1	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
ETF1	1	Binding:1

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	2	ERF, ETF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERF	0	—
ETF1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.