EMX2

protein-coding

empty spiracles homeobox 2, the group of NKL subclass homeoboxes and pseudogenes

Gene summary

This gene encodes a homeobox-containing transcription factor that is the homolog to the 'empty spiracles' gene in Drosophila. Research on this gene in humans has focused on its expression in three tissues: dorsal telencephalon, olfactory neuroepithelium, and urogenetial system. It is expressed in the dorsal telencephalon during development in a low rostral-lateral to high caudal-medial gradient and is proposed to pattern the neocortex into defined functional areas. It is also expressed in embryonic and adult olfactory neuroepithelia where it complexes with eukaryotic translation initiation factor 4E (eIF4E) and possibly regulates mRNA transport or translation. In the developing urogenital system, it is expressed in epithelial tissues and is negatively regulated by HOXA10. Alternative splicing results in multiple transcript variants encoding distinct proteins.[provided by RefSeq, Sep 2009]

MANE transcript

NM_004098.4

Inheritance

ClinVar variants

P:6U:31B:21

Top phenotype

Schizencephaly

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr10:117,542,445-117,549,546

External References & Databases

Ensembl (ENSG00000170370)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

schizencephalyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010011

Submitter: Ambry Genetics

schizencephalyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0010011

Submitter: G2P

schizencephalyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0010011

Submitter: PanelApp Australia

schizencephalyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010011

Submitter: Labcorp Genetics (formerly Invitae)

schizencephalyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010011

Submitter: ClinGen

*EMX2* was first reported in relation to autosomal dominant (AD) schizencephaly in 1996, reporting 3 patients with schizencephaly (Brunelli et al., PMID: 8528262). The same group reported 2 additional patients with schizencephaly in 1997, harboring a heterozygous germline variant in *EMX2* (PMID: 9359037) and suggested that this was a common cause of schizencephaly. However, subsequent reports and case series screening for variants in *EMX2* in cohorts of individuals with schizencephaly did not reveal any additional cases, calling into question the true rate of contribution of this gene to disease (PMID: 17506092, 18409201, 20157829). Overall, 4 variants (a missense, a frameshift, and two 3’ splice site mutations) have been reported in 4 probands across 2 publications (PMID: 8528262, 9359037). In summary, there is limited evidence to support this gene-disease relationship with individuals having a complex neurodevelopmental phenotype and seizures/epilepsy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy GCEP on September 3, 2024 (SOP v.11).

Clinical Genomic Database (CGD)

SchizencephalyAD

Manifestation: Neurologic

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

Refs: 8528262; 9359037; 17506092; 18409201

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EMX2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 28

not providedTotal: 14

not specifiedTotal: 12

SchizencephalyTotal: 9

Congenital hypogonadotropic hypogonadismTotal: 8

EMX2-related disorderTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004098.4. 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			1 clinvar	14 clinvar	1 clinvar	16
missense	2 clinvar	1 clinvar	29 clinvar	6 clinvar		38
nonsense	1 clinvar					1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	5	1	31	20	1	58

Highest pathogenic variant AF is 0.0000059237614

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004098.4	RefSeq	NP_004089.1	3	MANE Select
ENST00000553456.5	Ensembl	ENSP00000450962.3	3	MANE Select
NM_001165924.2	RefSeq	NP_001159396.1	2	Standard
ENST00000442245.5	Ensembl	ENSP00000474874.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
emx2	Danio rerio	Structure: neuromast hair cell Quality: orientation abnormal

Gene / Model

Organism

Observed Phenotype

emx2

Danio rerio

Structure: neuromast hair cell

Quality: orientation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
anterior/posterior pattern specification
dentate gyrus development
cerebral cortex regionalization
cell proliferation in forebrain

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
protein binding
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000553456
Coding exons: 3
Length: 7102
Individuals with no LoFs: 113689
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 113690
p: 0.00000440

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.57	94	148	0.637	0.00000676	1608
Missense (PolyPhen)		18	41.449	0.43427		486
Synonymous	0.503	63	68.3	0.923	0.00000342	523
Loss of Function	2.85	0	9.47	0.00	4.33e-7	96

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)	0.000021	0.000010	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor, which in cooperation with EMX2, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combinations with OTX1/2 to specify cell fates in the developing central nervous system.;

Recessive Scores

pRec: 0.315

Intolerance Scores

RVIS EVS: -0.1
RVIS percentile EVS: 46.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.772

Gene Damage Prediction

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