EMX2 – Schizencephaly

EMX2 has been reported in 13 probands with schizencephaly based on heterozygous de novo or sporadic variants, including a recurrent splice‐site mutation segregating in two affected brothers (c.407G>T (p.Gly136Val)) ([PMID:9359037]). These mutations were identified in 7 of 8 initial sporadic cases and in 6 of 10 additional patients, with one family showing intronic splicing disruption in both affected siblings and absence of the variant in unaffected relatives ([PMID:9359037]).

However, multiple subsequent large‐scale sequencing efforts failed to identify pathogenic EMX2 variants in cohorts of 39, 52, and 84 schizencephaly patients ([PMID:18409201]; [PMID:17506092]), suggesting that EMX2 mutations are not a common cause of schizencephaly. No functional assays have demonstrated a mechanistic link between EMX2 variants and cortical cleft formation.

Overall, the initial case reports provided Limited genetic evidence under an Autosomal dominant model with segregation in 2 affected relatives, but the preponderance of negative screening studies leads to a Disputed gene–disease association. Diagnostic testing of EMX2 for schizencephaly is not currently supported.

Key Take-home: EMX2 variants were initially implicated in sporadic and familial schizencephaly but are now considered to lack reproducible pathogenicity and should not be used for clinical diagnosis.

References

• European journal of human genetics • 1997 • A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. PMID:9359037
• American journal of medical genetics. Part A • 2008 • No major role for the EMX2 gene in schizencephaly. PMID:18409201
• American journal of medical genetics. Part A • 2007 • Comprehensive EMX2 genotyping of a large schizencephaly case series. PMID:17506092

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