MSX2

Chr 5AD

msh homeobox 2

Also known as: CRS2, FPP, HOX8, MSH, PFM, PFM1

NCBI Gene: 4488 ENSG00000120149 UniProt: P35548 OMIM: 123101

The MSX2 protein is a transcriptional repressor that regulates bone development by controlling osteoblast differentiation and has a morphogenetic role in craniofacial development. Mutations cause craniosynostosis type 2, parietal foramina (with or without cleidocranial dysplasia), affecting skull bone formation and closure. The condition follows autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.823 OMIM phenotypes

Clinical Summary— MSX2

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Gene-Disease Validity (ClinGen)

parietal foramina · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.262

Z-score 1.90

OE 0.26 (0.10–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.89 (0.78–1.03)

141 obs / 157.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.10–0.82)

0≤0.351.4

Missense OE?0.89 (0.78–1.03)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 2 / 7.7Missense obs/exp: 141 / 157.6Syn Z: 0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMSX2-related craniosynostosisOTHERAD

definitiveMSX2-related enlarged parietal foramina/cranium bifidumLOFAD

This gene — mechanism propensity

0.6840th %ile

GOF

0.3689th %ile

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFThree different mutations on MSX2 cause parietal foramina by haploinsufficiency.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References