Parietal foramina 1

Summary

Parietal foramina 1 (MONDO:0008197) is a disease caused by MSX2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MSX2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	parietal foramina 1
Mondo ID	MONDO:0008197
MeSH	C566827
OMIM	168500
UMLS	C1868599
MedGen	401480
GARD	0018051
Is cancer (heuristic)	no

Also known as: MSX2 parietal foramina · parietal foramina · parietal foramina 1 · parietal foramina caused by mutation in MSX2 · PFM · PFM1

Data availability: 67 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › neural tube defect › parietal foramina › parietal foramina 1

Related subtypes (2): 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

67 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 23 benign, 6 pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
16964	NC_000005.10:g.174694600_174931940delinsTATAATATGTGTGTATATAATATATATATTACAATATA	LINC01951	Pathogenic	no assertion criteria provided
16962	NM_002449.5(MSX2):c.475_480del (p.Arg159_Lys160del)	MSX2	Pathogenic	no assertion criteria provided
16963	NM_002449.5(MSX2):c.515G>A (p.Arg172His)	MSX2	Pathogenic	no assertion criteria provided
16965	NM_002449.5(MSX2):c.265_266delinsTA (p.Ala89Ter)	MSX2	Pathogenic	no assertion criteria provided
16966	NM_002449.5(MSX2):c.345del (p.Ala114_Trp115insTer)	MSX2	Pathogenic	no assertion criteria provided
16968	NM_002449.5(MSX2):c.548_555del (p.Glu183fs)	MSX2	Pathogenic	no assertion criteria provided
3591944	NM_002449.5(MSX2):c.380-2A>T	MSX2	Likely pathogenic	criteria provided, single submitter
4294501	NM_002449.5(MSX2):c.473dup (p.Arg159fs)	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
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

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	parietal foramina	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

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MSX2	HGNC:7392	ENSG00000120149	P35548	Homeobox protein MSX-2	gencc,clinvar
LINC01951	HGNC:52774	ENSG00000204754		long intergenic non-protein coding RNA 1951	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: 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSX2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
LINC01951	Other/Unknown	no

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
endometrium epithelium	1
placenta	1
secondary oocyte	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSX2	175	ubiquitous	marker	placenta, endometrium epithelium, secondary oocyte
LINC01951	106		yes	ventricular zone, cortical plate, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSX2	2,322
LINC01951	0

Structural data

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

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 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: 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
MSX2	0	0
LINC01951	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	2	MSX2, LINC01951

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)
MSX2	0	—
LINC01951	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.