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Intellectual disability

Gene: EMX2

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

7 reviews

Arina Puzriakova (Genomics England Curator)

I don't know

The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.
Created: 12 Mar 2026, 1:33 p.m. | Last Modified: 12 Mar 2026, 1:33 p.m.
Panel Version: 9.299
Created: 12 Mar 2026, 1:33 p.m.
Last Modified: 12 Mar 2026, 1:33 p.m.
Panel version: 9.299

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: OMIM phenotype accessed on 29th September 2025
Created: 30 Sep 2025, 2:10 p.m. | Last Modified: 30 Sep 2025, 2:10 p.m.
Panel Version: 9.104
Created: 30 Sep 2025, 2:10 p.m.
Last Modified: 30 Sep 2025, 2:10 p.m.
Panel version: 9.104

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 Due to outdated / conflicting evidence, this gene should be downgraded to Amber for Intellectual disability.
Created: 29 Sep 2025, 12:26 p.m. | Last Modified: 29 Sep 2025, 12:37 p.m.
Panel Version: 9.99
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 Intellectual disability.
Created: 29 Sep 2025, 12:12 p.m. | Last Modified: 29 Sep 2025, 12:26 p.m.
Panel Version: 9.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

Created: 29 Sep 2025, 12:12 p.m.
Last Modified: 29 Sep 2025, 12:37 p.m.
Panel version: 9.99

Helen Brittain (Genomics England Curator)

Comment when marking as ready: Sufficient cases; phenotype is of structural brain abnormality with variable ID. Although cases may be excluded on the MRI findings, on balance there is sufficient evidence for a gene:phenotype match.
Created: 13 Nov 2017, 3:07 p.m.
Created: 13 Nov 2017, 3:07 p.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.80

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
FAMILIAL SCHIZENCEPHALY, EMX2-RELATED

Publications

  • 0

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Ellen McDonagh (Genomics England Curator)

Green List (high evidence)

Possible DD gene for FAMILIAL SCHIZENCEPHALY, EMX2-RELATED in Gene2Phenotype.
Created: 27 Oct 2017, 2:46 p.m.

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

Phenotypes
Schizencephaly 269160

Publications

Created: 27 Oct 2017, 2:46 p.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.2

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:08 a.m.

Panel version: 0.306

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • NHS GMS
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Schizencephaly, OMIM:269160
  • schizencephaly, MONDO:0010011
OMIM
600035
Clinvar variants
Variants in EMX2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

12 Mar 2026, Gel status: 2

Removed Tag, Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_expert_review was removed from gene: EMX2. Tag Q3_25_NHS_review was removed from gene: EMX2. Tag Q3_25_demote_amber was removed from gene: EMX2.

12 Mar 2026, Gel status: 2

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

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

30 Oct 2025, Gel status: 3

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_expert_review tag was added to gene: EMX2.

30 Sep 2025, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_NHS_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 9359037; 24975717; 27125467; 9153481

30 Sep 2025, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q3_25_demote_amber tag was added to gene: EMX2.

11 Feb 2021, Gel status: 3

Clear Sources

Ivone Leong (Genomics England Curator)

Source: Expert Review Red was removed from gene: EMX2

12 Mar 2018, Gel status: 4

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

29 Nov 2017, Gel status: 4

Added New Source, Set mode of inheritance, Set publications

Ellen McDonagh (Genomics England Curator)

Expert Review Green was added to EMX2. Panel: Intellectual disability Model of inheritance for gene EMX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene EMX2 was set to ['9359037', '24975717', '27125467', '9153481']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 1

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

EMX2 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene EMX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

EMX2 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen