Parietal foramina

Summary

Parietal foramina (MONDO:0018953) is a disease caused by MSX2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: MSX2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.7	Worldwide	Validated
Point prevalence	1-9 / 100 000	4.3	Europe	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0002697	Parietal foramina	Very frequent (80-99%)
HP:0000932	Abnormality of the posterior cranial fossa	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0012721	Venous malformation	Occasional (5-29%)
HP:0100809	Scalp tenderness	Occasional (5-29%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0000894	Short clavicles	Very rare (<1-4%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001363	Craniosynostosis	Very rare (<1-4%)
HP:0002085	Occipital encephalocele	Very rare (<1-4%)
HP:0002475	Myelomeningocele	Very rare (<1-4%)
HP:0002762	Multiple exostoses	Very rare (<1-4%)
HP:0007385	Aplasia cutis congenita of scalp	Very rare (<1-4%)
HP:0008497	Congenital craniofacial dysostosis	Very rare (<1-4%)
HP:0011304	Broad thumb	Very rare (<1-4%)
HP:0012480	Abnormality of cerebral veins	Very rare (<1-4%)
HP:0040197	Encephalomalacia	Very rare (<1-4%)
HP:0410030	Cleft lip	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	parietal foramina
Mondo ID	MONDO:0018953
MeSH	C566826
OMIM	168500
Orphanet	60015
DOID	DOID:0060285
ICD-11	905361904
SNOMED CT	718099006
GARD	0016662
Is cancer (heuristic)	no

Also known as: catlin marks · enlarged parietal foramina · fenestrae parietales symmetricae · foramina parietalia permagna · hereditary cranium bifidum · parietal foramina · symmetric parietal foramina

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › neural tube defect › parietal foramina

Related subtypes (11): Chiari malformation type I, lateral meningocele syndrome, diastematomyelia, lipomyelomeningocele, sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome, leptomyelolipoma, primary tethered cord syndrome, neurenteric cyst, isolated amyelia, caudal regression sequence, iniencephaly

Subtypes (3): parietal foramina 1, parietal foramina 3, parietal foramina 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

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684631	Single allele	LOC126862799	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · 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
ALX4	Definitive	Autosomal dominant	parietal foramina 2	11
MSX2	Definitive	Autosomal dominant	parietal foramina	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALX4	Orphanet:228390	Frontonasal dysplasia-alopecia-genital anomalies syndrome
ALX4	Orphanet:35093	Non-syndromic sagittal craniosynostosis
ALX4	Orphanet:52022	Potocki-Shaffer syndrome
ALX4	Orphanet:60015	Enlarged parietal foramina
MSX2	Orphanet:1541	Craniosynostosis, Boston type
MSX2	Orphanet:251290	Parietal foramina with clavicular hypoplasia
MSX2	Orphanet:60015	Enlarged parietal foramina

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
ALX4	HGNC:450	ENSG00000052850	Q9H161	Homeobox protein aristaless-like 4	gencc
MSX2	HGNC:7392	ENSG00000120149	P35548	Homeobox protein MSX-2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALX4	Homeobox protein aristaless-like 4	Transcription factor involved in skull and limb development.
MSX2	Homeobox protein MSX-2	Acts as a transcriptional regulator in bone development.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALX4	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cranial nerve II	1
primordial germ cell in gonad	1
endometrium epithelium	1
placenta	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALX4	82	broad	yes	primordial germ cell in gonad, buccal mucosa cell, cranial nerve II
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
ALX4	1,162

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALX4	Q9H161	4

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 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.

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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic hindlimb morphogenesis	2	581.1×	9e-05	ALX4, MSX2
embryonic forelimb morphogenesis	2	495.6×	9e-05	ALX4, MSX2
anterior/posterior pattern specification	2	181.2×	5e-04	ALX4, MSX2
cell surface receptor signaling pathway involved in heart development	1	4213.0×	0.002	MSX2
positive regulation of timing of catagen	1	2808.7×	0.002	MSX2
frontal suture morphogenesis	1	2808.7×	0.002	MSX2
positive regulation of mesenchymal cell apoptotic process	1	2808.7×	0.002	MSX2
activation of meiosis	1	2106.5×	0.003	MSX2
embryonic nail plate morphogenesis	1	1685.2×	0.003	MSX2
cranial suture morphogenesis	1	1404.3×	0.003	MSX2
bone trabecula formation	1	1053.2×	0.004	MSX2
endochondral bone growth	1	842.6×	0.004	MSX2
negative regulation of keratinocyte differentiation	1	842.6×	0.004	MSX2
embryonic morphogenesis	1	766.0×	0.004	MSX2
mesenchymal cell apoptotic process	1	766.0×	0.004	MSX2
epithelial to mesenchymal transition involved in endocardial cushion formation	1	702.2×	0.004	MSX2
branching involved in mammary gland duct morphogenesis	1	702.2×	0.004	MSX2
enamel mineralization	1	601.9×	0.004	MSX2
cardiac conduction system development	1	526.6×	0.004	MSX2
wound healing, spreading of epidermal cells	1	526.6×	0.004	MSX2
osteoblast development	1	495.6×	0.004	MSX2
chondrocyte development	1	468.1×	0.004	MSX2
signal transduction involved in regulation of gene expression	1	351.1×	0.006	MSX2
outflow tract septum morphogenesis	1	324.1×	0.006	MSX2
digestive tract development	1	263.3×	0.007	ALX4
positive regulation of BMP signaling pathway	1	227.7×	0.008	MSX2
cellular response to estradiol stimulus	1	205.5×	0.008	MSX2
embryonic skeletal system morphogenesis	1	195.9×	0.008	ALX4
hair follicle development	1	191.5×	0.008	ALX4
negative regulation of fat cell differentiation	1	156.0×	0.010	MSX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
ALX4	0	0
MSX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	ALX4, MSX2

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)
ALX4	0	—
MSX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.