No major role for the EMX2 gene in schizencephaly

Abstract

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.

Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum

“…The diverticulumlike pouch in V:2 was initially considered to resemble schizencephaly, which is defined as true clefts formed in the brain as the result of failure of development of the cerebral mantle in the zones of cleavage of the primary cerebral fissures, which must be lined by abnormal gray matter (microgyria) [Leventer et al, 2008]. Mutations in EMX2 , which is also involved in Wnt signalling, was reported to cause schizencephaly in 1996, however, this association has not since been confirmed [Merello et al, 2008]. Nevertheless, we sequenced CCDC88C in 58 patients with a radiological diagnosis of schizencephaly with or without reported associated brain malformations, but could not detect any mutation, underscoring that the brain malformation observed in the presented consanguineous family is distinct from schizencephaly.…”

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

“…Similarly, EMX2 and PAX6 may be expressed in gradients during neural development in human subjects (21), and individuals with protein coding mutations in PAX6 (22, 23) exhibit cortical malformations. In addition, EMX2 mutations have been associated with schizencephaly, a rare cortical developmental disorder (24,25), although these mutations likely explain a small fraction of this disease burden (26,27). Finally, mutations in the laminin gene LAMC3 have been associated with cortical malformations solely within the occipital lobe (28), providing additional evidence for genetic control over regional cortical development.…”

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

“…Several studies evidenced data suggesting that EMX2 gene may be involved in the modulation of cell proliferation of cortical neuroblasts and/or cell migration of postmitotic neurons, as it is known that these cells reach their final destination in the mature cortex according to their generation date. On the other hand recent data demonstrate that EMX2 gene has no major role in schizencephaly (42).…”