1. Panels
  2. Fetal anomalies
  3. EMX2
Genes in panel
Prev Next

Fetal anomalies

Gene: EMX2

Green List (high evidence)
EMX2 (empty spiracles homeobox 2)
EnsemblGeneIds (GRCh38): ENSG00000170370
EnsemblGeneIds (GRCh37): ENSG00000170370
OMIM: 600035, Gene2Phenotype
EMX2 is in 5 panels

4 reviews

Ida Ertmanska (Genomics England Curator)

I don't know

Comment on list classification: There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the 1996-1997 studies are limited by their sequencing method (targeted gene sequencing). Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations (PMIDs: 17506092, 18409201, 20157829).
No other schizencephaly cases with EMX2 variants were published in literature since 1997. Other genes, such as SIX3 and SHH, have been putatively linked to schizencephaly (PMID: 20157829). Furthermore, schizencephaly may stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more (PMID: 18409201). Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Fetal anomalies.
Created: 1 Oct 2025, 8:11 a.m. | Last Modified: 1 Oct 2025, 8:11 a.m.
Panel Version: 6.90
There are at least 4 unrelated families where individuals harbouring de novo variants in EMX2 have schizencephaly (SCH) - a rare severe brain malformation, leading to neurologic deficits and developmental delay (PMIDs: 8528262, 9153481, 9359037). However, the articles, published in 1996-1997, are limited by their sequencing method (EMX2 targeted gene sequencing):

PMID: 8528262 Brunelli et al., 1996
Method: SSCP analysis on PCR amplification products of 4 genes: EMX1, EMX2, OTX1, OTX2. No variants were detected in EMX1, OTX1, or OTX2. 7/8 schizencephaly patients harboured heterozygous EMX2 variants, of which 3 were de novo and predicted to be pathogenic:
c.407-4G>T – spliceAI benign, 1 allele reported in European population in gnomAD v4.1
c.407-1G>A – spliceAI splice-altering Strong, not in gnomAD v4.1
c.575_576insA p.(Ser192Argfs*41) – not in gnomAD v4.1

PMID: 9153481 Granata et al., 1997 - two brothers aged 8 and 10 with severe bilateral schizencephaly, carrying an identical point mutation in EMX2. Phenotype: severe neurologic deficits and mental retardation. No access to full article
PMID: 9359037 Faiella et al., 1997 – same two brothers? Variant c.407G>T (p.Gly136Val) – Revel score 0.46 (Uncertain); not in gnomAD v4.1

Supporting evidence: https://iamg.in/genetic_clinics/full_textdfc6.html?id=212 – Clinical Vignette, Indian Academy of Medical Genetics – NO PMID.
Case report: 7 year old boy, bilateral schizencephaly, non-consanguineous parents; heterozygous for a de novo EMX2 variant: c.473G>A, (p.Arg158Gln) – Revel score 0.63, not found in gnomAD v4.1; method: trio sequencing of EMX2 exons only.
Phenotype: Severe developmental delay noticed at age 3-4 months. At 5 years old, the developmental age was 4 months. No meaningful speech was present. History of seizures since 4 years of age. Microcornea, widely spaced teeth, severe spasticity in all limbs.

CONTRADICTING EVIDENCE:
Subsequent studies of 3 different schizencephaly patient cohorts showed that none of the 175 affected individuals carried pathogenic EMX2 mutations:

PMID: 17506092 Tietjen et al., 2007
EMX2 genotyping of 84 affected probands with Schizencephaly – no EMX2 mutations detected.

PMID: 18409201 Merello et al., 2008
EMX2 sequencing in 39 SCH patients detected no pathogenic mutations. Schizencephaly may also stem from non-genetic causes, such as in utero viral infections, teratogen exposure, maternal trauma, and more. Thus, authors claimed that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.

PMID: 20157829 – Hehr et al., 2010
52 patients with SCH, no EMX2 mutations detected. Sequenced EMX2 (all 52 cases) as well SHH, SIX3 and ZIC2 in some of the individuals. SIX3 and SHH variants are reported as causative instead.

EMX2 is associated with Schizencephaly in OMIM (269160, accessed 29th Sep 2025) & classified as Limited for Schizencephaly in ClinGen (Epilepsy GCEP, 2024).

No other cases with EMX2 variants were published in literature since 1997. Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Fetal anomalies.
Created: 1 Oct 2025, 8:10 a.m. | Last Modified: 1 Oct 2025, 8:10 a.m.
Panel Version: 6.90

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011

Publications

Created: 1 Oct 2025, 8:10 a.m.
Last Modified: 1 Oct 2025, 8:10 a.m.
Panel version: 6.90

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Created: 30 Sep 2025, 2:21 p.m. | Last Modified: 30 Sep 2025, 2:21 p.m.
Panel Version: 6.89
Created: 30 Sep 2025, 2:21 p.m.
Last Modified: 30 Sep 2025, 2:21 p.m.
Panel version: 6.89

Arina Puzriakova (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 3 Mar 2022, 11:19 a.m. | Last Modified: 3 Mar 2022, 11:19 a.m.
Panel Version: 1.836
Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Created: 1 Feb 2021, 12:36 p.m. | Last Modified: 1 Feb 2021, 12:36 p.m.
Panel Version: 1.399
Created: 1 Feb 2021, 12:36 p.m.
Last Modified: 1 Feb 2021, 12:36 p.m.
Panel version: 1.836

Rhiannon Mellis (Great Ormond Street Hospital)

Green List (high evidence)

This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Cerebral malformations; Malformations of cortical development
Sources: Expert list
Created: 29 Jan 2021, 9:55 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Schizencephaly, 269160

Created: 29 Jan 2021, 9:55 a.m.

Panel version: 1.215

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Schizencephaly, OMIM:269160
  • schizencephaly, MONDO:0010011
Tags
Q3_25_expert_review Q3_25_demote_amber
OMIM
600035
Clinvar variants
Variants in EMX2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

30 Sep 2025, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: EMX2.

30 Sep 2025, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: EMX2 were changed from Schizencephaly, 269160 to Schizencephaly, OMIM:269160; schizencephaly, MONDO:0010011

30 Sep 2025, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: EMX2 were set to

30 Sep 2025, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_demote_amber tag was added to gene: EMX2.

3 Mar 2022, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: EMX2.

3 Mar 2022, Gel status: 3

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Green was added to EMX2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

1 Feb 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: emx2 has been classified as Amber List (Moderate Evidence).

1 Feb 2021, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: EMX2.

29 Jan 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Rhiannon Mellis (Great Ormond Street Hospital)

gene: EMX2 was added gene: EMX2 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: EMX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: EMX2 were set to Schizencephaly, 269160 Review for gene: EMX2 was set to GREEN