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MSX2 Gene Curation

MSX2 Gene Curation

Owned by Andrea Oza
2025-03-21
3 min read

Gene-disease assertions not curated here (add link or write note): CURATING FOR LOF MECHANISM ONLY

Disease

parietal foramina

Disease

parietal foramina

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Rapid or full curation?

PARTIAL
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

 

Clinical Validity Scoring Notes and points

CURATING FOR LOF MECHANISM ONLY - VARIANTS FROM HGMD

Dosage curation from ClinGen - Little Evidence for haploinsufficiency https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7392

  • The ClinGen Craniofacial Malformations Gene Curation Expert Panel has definitive evidence demonstrating the relationship between pathogenic variants in MSX2 and autosomal dominant enlarged parietal foramina (PFM) and craniosynostosis 2. However, due to the lack of clear null variants available for evaluation it cannot be definitively concluded that haploinsufficiency of MSX2 is the mechanism leading to PFM or craniosynostosis. In addition, as MSX2 is a two-exon gene it is unclear if the frameshift variants described above lead to nonsense mediated decay and thus loss of function.c.345delG p.(Trp115*) - located w/in last 50bp of exon 1, NMD is not expected

  • p.(Ala89*) - NMD+, reported in PMID: 10767351

    • Variant identified in family 5 with foramina paretalia permagna.

  • Deletion of ~206 kb incl. entire gene in PMID: 10742103

    • Wilkie et al (2000) describes a family (family 1) presenting with enlarged parietal foramina (PFM). A large complex deletion including MSX2 was observed in five individuals with PFM (III-1, III-3, III-4, IV-1, IV-2) identified through PCR and Southern blot analysis. One obligate carrier (II-2) was identified to have the same MSX2 deletion, but with a normal skull radiograph. It is unclear if additional genes in cis to MSX2 are affected by the large deletion.

Source:

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

 

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

Clinical Features

 

Sources:

HPO Terms

https://hpo.jax.org/app/

 

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

 

Case ID, Curator name, Date, Jira ticket link

AO E3860750876 03/21/25

 

 

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