Schizencephaly (SCH) is a rare disorder of cerebral cortical development, characterized by full thickness clefts spanning the wall of the cerebral hemispheres that are lined and surrounded by polymicrogyric cortex. Based on pathological analysis, SCH was originally considered to have multiple causes including infectious and vascular injuries, and toxic agents. However, a few reports of familial SCH have suggested a possible genetic etiology. Ten years ago two articles identified EMX2 as the first causative gene for human SCH in 13 of 18 patients, although for several putative mutations no pathogenic role was demonstrated. Here, we reinterpret the original articles as showing a significantly lower mutational rate (17%) than originally reported (72%), and provide results of EMX2 sequencing in 39 new SCH patients, detecting no pathogenic mutations. We conclude that the reported association between SCH and EMX2 mutations is not adequately supported by current data, and that diagnostic testing of EMX2 is not justified, as any results would be uninterpretable.
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