MSX2

protein-coding

msh homeobox 2, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

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]

Previous symbols:

PFM1

MANE transcript

NM_002449.5

Inheritance

ClinVar variants

P:14U:106B:52

Top phenotype

Craniosynostosis 2; Parietal foramina with cleidocranial dysplasia; Parietal foramina 1

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr5:174,724,582-174,730,896

External References & Databases

Ensembl (ENSG00000120149)

Transcript & Mutation Effects

hg38 • Region Span ~6.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniosynostosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: Labcorp Genetics (formerly Invitae)

craniosynostosis 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: Orphanet

parietal foramina with cleidocranial dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008198

Submitter: G2P

craniosynostosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: ClinGen

MSX2 was first associated with autosomal dominant craniosynostosis by Warman et al. in 1993 (PMID: 8357019). The large family originally described was studied in Boston thus their phenotype has since been referred to as "craniosynostosis, Boston type" or "craniosynostosis, Warman type" (PMID: 23949913, 23918290). At least 3 unique missense variants have been identified in patients with craniosynostosis (PMIDs: 8357019, 23918290, 23949913, 27884935, 28808027). Notably, all variants are at the Pro148 codon in exon 2. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental evidence. Two mouse models have been generated, thus reaching the maximum score of 4 pts has been reached for animal models (PMIDs: 9917362, 7597092). In summary, MSX2 is definitively associated with autosomal dominant craniosynostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

parietal foramina 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008197

Submitter: Ambry Genetics

parietal foraminaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018953

Submitter: ClinGen

The relationship between MSX2 and Enlarged parietal foramina (PFM) was described by Wilkie et al. in 2000 (PMID: 10742103). Parietal foramina are oval defects of the parietal bones caused by deficient ossification around the parietal notch (PMID: 10742103). Notably, MSX2 has also been evaluated by the ClinGen Craniofacial Malformations Gene Curation Expert panel for MSX2-related Craniosynostosis and found it to have a definitive association. At least 8 unique variants (missense, nonsense, frameshift etc.) have been identified in MSX2 in patients with PFM. Evidence supporting this gene-disease relationship includes case-level and experimental evidence. In summary, MSX2 is definitively associated with autosomal dominant Enlarged parietal foramina. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on 7/8/2020 (SOP Version 7).

parietal foraminaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018953

Submitter: Orphanet

craniosynostosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: G2P

parietal foraminaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018953

Submitter: PanelApp Australia

parietal foramina with cleidocranial dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008198

Submitter: Orphanet

craniosynostosis 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: Ambry Genetics

parietal foramina 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008197

Submitter: Labcorp Genetics (formerly Invitae)

parietal foramina with cleidocranial dysplasiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008198

Submitter: Labcorp Genetics (formerly Invitae)

craniosynostosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011481

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Craniosynostosis 2; Parietal foramina with cleidocranial dysplasia; Parietal foramina 1AD

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Upstream microduplications have been described as causing Cleidocranial dysplasia

Refs: 8106171; 8357019; 10742103; 14571277; 16222674; 16319823; 16642368; 17955513; 18000908; 19533795; 21082653

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MSX2 variants in ClinVar

8 Conditions Cataloged

Cranium bifidum occultumTotal: 132

Inborn genetic diseasesTotal: 34

not providedTotal: 32

not specifiedTotal: 20

Craniosynostosis 2Total: 16

MSX2-related disorderTotal: 15

Parietal foramina 1Total: 15

Parietal foramina with cleidocranial dysplasiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002449.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	38 clinvar	4 clinvar	44
missense	2 clinvar	1 clinvar	101 clinvar	10 clinvar		114
nonsense	1 clinvar	2 clinvar	1 clinvar			4
start loss		1 clinvar	1 clinvar			2
frameshift	4 clinvar	2 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	7	7	106	48	4	172

Highest pathogenic variant AF is 0.0000066446064

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002449.5	RefSeq	NP_002440.2	2	MANE Select
ENST00000239243.7	Ensembl	ENSP00000239243.5	2	MANE Select
NM_001363626.2	RefSeq	NP_001350555.1	1	Standard
ENST00000507785.2	Ensembl	ENSP00000427425.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HTLV-I infection - Homo sapiens (human)
Neural Crest Differentiation
Hair Follicle Development- Induction (Part 1 of 3)
Transcriptional regulation by RUNX2
Gene expression (Transcription)

Biological Process

negative regulation of transcription by RNA polymerase II
osteoblast differentiation
chondrocyte development
osteoblast development
outflow tract septum morphogenesis

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
transcription coregulator activity
protein binding

Cellular Component

nucleus
cytosol
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000239243
Coding exons: 2
Length: 6361
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125734
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.471	141	158	0.894	0.00000816	1669
Missense (PolyPhen)		41	52.295	0.78401		582
Synonymous	0.181	70	72.0	0.973	0.00000388	582
Loss of Function	1.90	2	7.68	0.260	3.84e-7	88

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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}.;
Disease: DISEASE: Parietal foramina 1 (PFM1) [MIM:168500]: Autosomal dominant disease characterized by oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. {ECO:0000269|PubMed:10742103, ECO:0000269|PubMed:10767351}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parietal foramina with cleidocranial dysplasia (PFMCCD) [MIM:168550]: Combines skull defects in the form of enlarged parietal foramina and deficient ossification of the clavicles. {ECO:0000269|PubMed:14571277}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniosynostosis 2 (CRS2) [MIM:604757]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. CRS2 is characterized by either fronto-orbital recession, or frontal bossing, or turribrachycephaly, or cloverleaf skull. Associated features include severe headache, high incidence of visual problems (myopia or hyperopia), and short first metatarsals. Intelligence is normal. {ECO:0000269|PubMed:23918290, ECO:0000269|PubMed:23949913, ECO:0000269|PubMed:8106171}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.342

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.426

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium