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Are Somatic Mutations in Cortical Development the One Bad Apple that Spoils the Bunch?

Commentary Cortical malformations, including double-cortex syndrome, polymicrogyria, periventricular nodular heterotopia, pachygyria, and others, are a common cause of refractory epilepsy (1, 2). These epilepsies are thought to arise from disruptions in cortical development, such as failed cell migration, altered proliferation, or stalled cellular maturation. Cortical malformations have a number of known genetic causes, including mutations in DCX, Lis1, FLNA, Tsc1/2, and others. Many times, however, clear genetic linkages cannot be made. Recent revolutions in genomic technologies are now addressing this issue. Nextgeneration (NextGen) sequencing allows massively parallel sequencing of genes of interest, or even the entire genome, in a high throughput manner (3). The amount of genetic information that can now be accessed in a relatively cost-effective manner is something that would have been impossible even a decade ago. Implementation of this approach has allowed significant advances in understanding the genetics of many diseases, including the epilepsies. The Epi4K project is an example of a powerful application of NextGen sequencing. DNA sequences isolated from leukocytes of more than 200 patients were analyzed, leading to the identification of novel genes linked to epileptic encephalopathies (4). Here, we highlight recent work by Jamuar and colleagues using NextGen sequencing in a different way to investigate the role of somatic mutations in patients with cortical malformations. Somatic mutations are postzygotic events that result in groups of cells with different genetic sequences. If a somatic mutation induces a change in DNA sequence in a single cell early in development, all the cells that subsequently arise from that cell will contain that DNA alteration, whereas all the remaining cells in the body will not. This is a simple example of how a somatic mutation can lead to diversity in the genome of an individual. In reality, the genomic diversity within an individual is much more complex. Recent studies of postmortem brain show an abundance of single-neuron genomic diversity (or mosaicism), including megabase scale Somatic Mutations in Cerebral Cortical Malformations.