Background: Malformations of cortical development are not rare and cause a wide spectrum of neurological diseases based on the affected region in the cerebral cortex. A significant proportion of these malformations could have a genetic basis. However, genetic studies are limited because most cases are sporadic and mendelian forms are rare.
Methods: In order to identify new genetic causes in patients presenting defects of cortical organization, we have performed array-based comparative genomic hybridization (array-CGH) in a cohort of 100 sporadic cases with various types of cortical malformations in search for inframicroscopic chromosomal rearrangements.
Results: In one patient presenting with periventricular nodular heterotopias and marked corpus callosum hypoplasia, we have identified a small (400 kilobases) 17p13.3 deletion involving the YWHAE gene. We show that YWHAE is the only brain-expressed gene in the deleted region and that the other genes in the interval are unlikely to contribute to the brain malformation phenotype of this patient.
Conclusion: Most 17p13.3 deletions reported to date are large, such as the deletions causing Miller-Dieker syndrome, and involve several genes implicated in various steps of brain development. Haploinsufficiency of the mouse ortholog of YWHAE causes a defect of neuronal migration. However, the human counterpart of this phenotype was not known. The case described here represents the smallest reported deletion involving the YWHAE gene and could represent the human counterpart of the abnormal cortical organization phenotype presented by the Ywhae heterozygous knock-out mouse.