Craniosynostosis 2

Summary

Craniosynostosis 2 (MONDO:0011481) is a disease caused by MSX2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MSX2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 67

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	craniosynostosis 2
Mondo ID	MONDO:0011481
OMIM	604757
Orphanet	1541
DOID	DOID:0061009
SNOMED CT	720817008
UMLS	C1858160
MedGen	346753
GARD	0005538
Is cancer (heuristic)	no

Also known as: craniosynostosis 2 · craniosynostosis type 2 · craniosynostosis Warman type · craniosynostosis, Warman type · CRS2 · MSX2-related craniosynostosis · Warman Mulliken Hayward syndrome · Warman-Mulliken-Hayward syndrome

Data availability: 67 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › craniosynostosis 2

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, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, 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

67 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 22 benign, 3 pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16961	NM_002449.5(MSX2):c.443C>A (p.Pro148His)	MSX2	Pathogenic	criteria provided, single submitter
219192	NM_002449.5(MSX2):c.443C>T (p.Pro148Leu)	MSX2	Pathogenic	criteria provided, single submitter
2664282	NM_002449.5(MSX2):c.441_442dup (p.Pro148fs)	MSX2	Pathogenic	no assertion criteria provided
3591944	NM_002449.5(MSX2):c.380-2A>T	MSX2	Likely pathogenic	criteria provided, single submitter
352839	NM_002449.5(MSX2):c.*46G>T	MSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904830	NM_002449.5(MSX2):c.286G>T (p.Val96Leu)	MSX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1424628	NM_002449.5(MSX2):c.712G>A (p.Ala238Thr)	MSX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3234015	NM_002449.5(MSX2):c.764_772del (p.Tyr255_Pro258delinsSer)	MSX2	Uncertain significance	criteria provided, single submitter
3254818	NM_002449.5(MSX2):c.44A>G (p.Glu15Gly)	MSX2	Uncertain significance	criteria provided, single submitter
352834	NM_002449.5(MSX2):c.-50C>T	MSX2	Uncertain significance	criteria provided, single submitter
352837	NM_002449.5(MSX2):c.635C>G (p.Ala212Gly)	MSX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
352840	NM_002449.5(MSX2):c.*102C>T	MSX2	Uncertain significance	criteria provided, single submitter
352841	NM_002449.5(MSX2):c.*144C>T	MSX2	Uncertain significance	criteria provided, single submitter
352844	NM_002449.5(MSX2):c.*289A>G	MSX2	Uncertain significance	criteria provided, single submitter
352845	NM_002449.5(MSX2):c.*306G>T	MSX2	Uncertain significance	criteria provided, single submitter
352847	NM_002449.5(MSX2):c.*363A>G	MSX2	Uncertain significance	criteria provided, single submitter
352850	NM_002449.5(MSX2):c.*526T>C	MSX2	Uncertain significance	criteria provided, single submitter
352851	NM_002449.5(MSX2):c.*530A>G	MSX2	Uncertain significance	criteria provided, single submitter
352852	NM_002449.5(MSX2):c.*601C>T	MSX2	Uncertain significance	criteria provided, single submitter
352853	NM_002449.5(MSX2):c.*647C>T	MSX2	Uncertain significance	criteria provided, single submitter
352856	NM_002449.5(MSX2):c.*863A>G	MSX2	Uncertain significance	criteria provided, single submitter
352857	NM_002449.5(MSX2):c.*946T>G	MSX2	Uncertain significance	criteria provided, single submitter
352861	NM_002449.5(MSX2):c.*1096A>G	MSX2	Uncertain significance	criteria provided, single submitter
352866	NM_002449.5(MSX2):c.*1312A>G	MSX2	Uncertain significance	criteria provided, single submitter
904118	NM_002449.5(MSX2):c.*106C>T	MSX2	Uncertain significance	criteria provided, single submitter
904119	NM_002449.5(MSX2):c.*126T>C	MSX2	Uncertain significance	criteria provided, single submitter
904177	NM_002449.5(MSX2):c.*512G>T	MSX2	Uncertain significance	criteria provided, single submitter
904178	NM_002449.5(MSX2):c.*516A>G	MSX2	Uncertain significance	criteria provided, single submitter
904233	NM_002449.5(MSX2):c.*1064A>G	MSX2	Uncertain significance	criteria provided, single submitter
904829	NM_002449.5(MSX2):c.122A>T (p.Lys41Met)	MSX2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · 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
MSX2	Definitive	Autosomal dominant	craniosynostosis 2	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSX2	Orphanet:1541	Craniosynostosis, Boston type
MSX2	Orphanet:251290	Parietal foramina with clavicular hypoplasia
MSX2	Orphanet:60015	Enlarged parietal foramina

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
MSX2	HGNC:7392	ENSG00000120149	P35548	Homeobox protein MSX-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSX2	Homeobox protein MSX-2	Acts as a transcriptional regulator in bone development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
endometrium epithelium	1
placenta	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSX2	175	ubiquitous	marker	placenta, endometrium epithelium, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSX2	2,322

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MSX2	P35548	68.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Transcriptional regulation by RUNX2	1	253.8×	0.014	MSX2
Regulation of RUNX2 expression and activity	1	181.3×	0.014	MSX2
RNA Polymerase II Transcription	1	22.5×	0.066	MSX2
Gene expression (Transcription)	1	17.8×	0.066	MSX2
Generic Transcription Pathway	1	15.1×	0.066	MSX2

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
cell surface receptor signaling pathway involved in heart development	1	8426.0×	0.002	MSX2
positive regulation of timing of catagen	1	5617.3×	0.002	MSX2
frontal suture morphogenesis	1	5617.3×	0.002	MSX2
positive regulation of mesenchymal cell apoptotic process	1	5617.3×	0.002	MSX2
activation of meiosis	1	4213.0×	0.002	MSX2
embryonic nail plate morphogenesis	1	3370.4×	0.002	MSX2
cranial suture morphogenesis	1	2808.7×	0.002	MSX2
bone trabecula formation	1	2106.5×	0.002	MSX2
endochondral bone growth	1	1685.2×	0.002	MSX2
negative regulation of keratinocyte differentiation	1	1685.2×	0.002	MSX2
embryonic morphogenesis	1	1532.0×	0.002	MSX2
mesenchymal cell apoptotic process	1	1532.0×	0.002	MSX2
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	MSX2
branching involved in mammary gland duct morphogenesis	1	1404.3×	0.002	MSX2
enamel mineralization	1	1203.7×	0.002	MSX2
cardiac conduction system development	1	1053.2×	0.002	MSX2
wound healing, spreading of epidermal cells	1	1053.2×	0.002	MSX2
osteoblast development	1	991.3×	0.002	MSX2
chondrocyte development	1	936.2×	0.002	MSX2
signal transduction involved in regulation of gene expression	1	702.2×	0.003	MSX2
outflow tract septum morphogenesis	1	648.1×	0.003	MSX2
embryonic hindlimb morphogenesis	1	581.1×	0.003	MSX2
embryonic forelimb morphogenesis	1	495.6×	0.003	MSX2
positive regulation of BMP signaling pathway	1	455.5×	0.003	MSX2
cellular response to estradiol stimulus	1	411.0×	0.004	MSX2
negative regulation of fat cell differentiation	1	312.1×	0.004	MSX2
stem cell differentiation	1	300.9×	0.004	MSX2
positive regulation of osteoblast differentiation	1	224.7×	0.006	MSX2
BMP signaling pathway	1	200.6×	0.006	MSX2
anterior/posterior pattern specification	1	181.2×	0.007	MSX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MSX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	MSX2

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)
MSX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.