• 1
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
MSX2 (HGNC:7392) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
msh homeobox 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
PFM1
Alias symbols
CRS2, FPP, HOX8, MSH, PFM
%HI
1.48(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.26(Read more about gnomAD pLI score)
LOEUF
0.82(Read more about gnomAD LOEUF score)
Cytoband
5q35.2
Genomic Coordinates
GRCh37/hg19: chr5:174151585-174157899 NCBI Ensembl UCSC
GRCh38/hg38: chr5:174724582-174730896 NCBI Ensembl UCSC
MANE Select Transcript
NM_002449.5 ENST00000239243.7 (Read more about MANE Select)
Function
Acts as a transcriptional regulator in bone development. Represses the ALPL promoter activity and antagonizes the stimulatory effect of DLX5 on ALPL expression during osteoblast differentiation. Probable morphogenetic role. May play a role in limb-pattern formation. In osteoblasts, suppresses transcription driven by the osteocalcin FGF response element (OCFRE). Binds to the homeodomain-response element of the ALPL promoter. {ECO:0000269|PubMed:12145306}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-36545
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
06/28/2023

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 14571277
    Garcia-Minaur et al (2003) sequenced exons 1 and 2 of the MSX2 gene in a family presenting with parietal foramina with cleidocranial dysplasia (PFMCCD). Analysis identified a frameshift variant in exon 2 of the MSX2 gene (c.505_508dupATTG, p.A170fsX245). The variant was observed to segregate with four affected family members over three generations. In addition, an ALX4 variant was observed in both the proband and unaffected mother.
  • PUBMED: 16319823
    Mavrogiannis et al (2006) sequenced the MSX2 and ALX4 genes in eleven unrelated families presenting with enlarged parietal foramina (PFM) and cranium bifidum (CB). A frameshift variant in MSX2 (c.417_418del, p.H139QfsX105) was detected in the father of family 12 which, according to the authors, “presumably, had been transmitted to his affected son”. A second frameshift variant in MSX2 (c.456_465dup, p.A156fsX92) was detected in family 13 in which the variant was found in the mother presenting with isolated PFM and her two children who both presented with a central parietal defect at birth.
  • PUBMED: 16642368
    Ghassibe et al (2006) identified a frameshift variant (c.468_484dup, p.R162PfsX24) in a family with eight affected members showing cranial foramina associated with flash headaches and venous malformation. The variant was observed in all seven tested affected individuals. The variant was not observed in five tested unaffected individuals.
  • PUBMED: 10767351
    Wuyts et al (2000) sequenced exons 1 and 2 of the MSX2 gene in five families presenting with isolated autosomal dominant foramina parietalia permagna (FPP). A nonsense variant was identified in two families (family 3: p.W115X and family 5: p.A89X). Family 3 had three individuals affected by FPP while family 5 had six affected individuals. Per the authors, exons 1 and 2 of the MSX2 gene were sequenced in "two members from every family." It is unclear which two individuals from each family were sequenced and whether or not the two individuals presented with FPP. Due to this uncertainty, segregation information cannot accurately be assessed.
  • PUBMED: 16222674
    Spruijt et al (2005) describes a female proband with bilateral symmetrical foramina. The father of the proband was identified to have bilateral skull defects at the same posterior position of the skull as his daughter. Sequencing exons 1 and 2 of the MSX2 gene in the father identified a frameshift variant (c.548del8, p. Q1833fsX59). Sequencing of the proband was not performed.
  • PUBMED: 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.
HI Evidence Comments:
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.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
PMID 18000908: Bernardini et al (2007) observed a complex derivative chromosome 5 resulting in a gain of the MSX2 gene in a 6 month old female with multiple sutural synostosis and prenatal onset growth deficiency, developmental delay, facial dysmorphism, congenital heart defect, and inguinal hernia. Using chromosome analysis, mBAND, locus specific FISH, and array-CGH the authors identified at least nine breakpoints along chromosome 5, leading to three paracentric inversions, two between-arm insertions, and partial trisomy of the distal 5q segment. It is unclear if the complex rearrangement disrupts other genes along chromosome 5. It is also unclear how large the duplication is and if it includes additional genes as breakpoints were not provided. PMID 17955513: Wang et al (2007) reported two unrelated probands with craniosynostosis and unbalanced translocations leading to a gain of the long arm of chromosome 5 [46,XY,der(10)t(5;10)(q33;q26.3) and 46,XX,der(17)t(5;17)(q35.1;p13.3)]. Array-CGH confirmed the chromosome findings, but it is unclear if the gains, which include MSX2 include additional genes as breakpoints were not provided. The authors review 22 previously reported individuals presenting with microcephaly and/or abnormal skull shape with gains of the long arm of chromosome 5 which include MSX2. However, similar to the probands presented above it is unclear if the gains include genes in addition to MSX2. PMID 2466290: Plaisancie et al (2015) used multiplex ligation probes amplification (MLPA), quantitative PCR, and 180K microarray on a proband with developmental eye defects and craniosynostosis. The authors did not find variants in the genes typically associated with craniosynostosis or cranial suture fusion (FGFR1, FGFR2, FGFR3, TWIST1, TWISTNB, EFNB1, ALX1, ALX3, ALX4, and RUNX2). However, a whole gene duplication of MSX2 was identified, and this variant was confirmed de novo. It is unclear if the gain includes genes in addition to MSX2 as breakpoints were not provided. Due to the currently available evidence triplosensitivity can not be evaluated for MSX2.

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)