EMX2

Gene Facts

• HGNC Symbol: EMX2 (HGNC:3341)
• HGNC Name: empty spiracles homeobox 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: No aliases found
• %HI: 7.32
• pLI: 0.98
• LOEUF: 0.5
• Cytoband: 10q26.11
• Genomic Coordinates:

  GRCh37/hg19:	chr10:119302257-119309057
  GRCh38/hg38:	chr10:117542746-117549546

• MANE Select Transcript: NM_004098.4 ENST00000553456.5
• Function: Transcription factor, which in cooperation with EMX1, acts to generate the boundary between the roof and archipallium in the developing brain. May function in combination with OTX1/2 to specify cell fates in the developing central nervous system. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-8398
• ClinGen Curation ID: CCID:007068
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/09/2021

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• Schizencephaly

HI Evidence

• PUBMED: PMID: 8528262
  Brunelli et al (1996): A report of three de novo variants in patients with schizencephaly. The three variants were listed as: a substitution at position - 4 of the 3' splice of the first intron, a transition G~A at position -1 of the 3' splice of the first intron, fragment change in exon 2 (possible frameshift). The original reports of EMX2 mutations in schizencephaly were published before variant nomenclature was standardized. The three variants were corrected by Merello (2008) to c.407-1G>A, p.R155R, and p.L191fs.
• PUBMED: 9359037
  Faiella et al (1997): The same group also reported on five de novo EMX2 variants in six individuals (two brothers) with schizencephaly. In particular, the two brothers show the same variant affecting the splicing of the first intron, while this variant is absent in their parents and in the two unaffected siblings. The original reports of EMX2 mutations in schizencephaly were published before variant nomenclature was standardized. However, the five variants were corrected by Merello (2008) to p.G136V, p.R157R, p.R155R, c.591+59delG, and c.591+74C>A.
• PUBMED: 18409201
  Merello (2008): The authors provide data from 39 patients with schizencephaly. They did not find any EMX2 variants in their patient series. In addition, they questioned the findings from Brunelli (1996) and Faiella (1997) and reinterpretation of the nine variants published. They acknowledged that there were two clearly loss-of-function (p.L191fs and c.407-1G>A) variants in EMX2 in patients with schizencephaly, but felt the rest were questionable (missense and intronic variants).
• PUBMED: 20157829
  While initial reports suggested that EMX2 variants are a common cause of schizencephaly, more recent evidence suggests that EMX2 variants are not a common cause of this malformation. Hehr et al. (2010) also found no EMX2 variants in 52 patients with schizencephaly, raising doubt about the functional significance of EMX2 variants as a cause.
• PUBMED: 17506092
  To determine the frequency of EMX2 variants in patients with schizencephaly, Tiethen et al (2007) sequenced EMX2 in a cohort of 84 affected probands. No pathologic variants were identified in this cohort, suggesting that EMX2 variants are an uncommon cause of schizencephaly.
• PUBMED: 25577462
  Liu et al. (2015) reported a novel nonsense variant p.E142X in EMX2 in a woman with a didelphic uterus (1 of 517, 0.19%). The results of Western blot analysis confirmed that the variant caused a truncated protein as predicted, and functional studies proved that it resulted in a dominant negative effect. PMID: 33434492. Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina. Chen et al. (2021) sequenced 442 affected subjects and 941 female control subjects, and identified 12 likely pathogenic variants in 7 genes, including EMX2, p.Tyr120Ter.

• HI Evidence Comments: While initial reports suggested that EMX2 variants are a common cause of schizencephaly, more recent evidence suggests that EMX2 variants are not a common cause of this malformation. More recently, limited studies report EMX2 variants in individuals with disrupted uterine development, which is completely different from schizencephaly. Due to the conflicting studies, down grading score from 2 to 1.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity