A new study highlights an intriguing role for somatic mutations restricted to the brain in a developmental brain disorder, hemimegalencephaly (HMG) (Neuron 74, 41–48).

HMG is an epileptic brain disorder characterized by the enlargement and malformation of one hemisphere of the brain. Given this regional selectivity of the deformation, it has been suggested that HMG may be caused by a somatic mutation limited to the brain, and Annapurna Poduri et al. now provide evidence to support this hypothesis.

The authors analyzed resected brain tissue samples from eight individuals with HMG and found that two of the samples showed trisomy of chromosome 1q, but, in one of the individuals, the blood sample did not show this genetic aberration. Of the genes on chromosome 1q, Poduri et al. suggest AKT3 as a strong candidate gene for HMG, because AKT3 deletions have been previously associated with microcephaly in humans and mice. Moreover, somatic activating mutations in the related genes AKT1 and AKT2 have been associated with human overgrowth syndromes. The authors also found a somatic activating mutation of AKT3 (E17K) in the brain of one individual with HMG.

These results suggest that somatic mutations in the brain could have an important role in neurogenetic disease, although the mechanisms by which they occur remain to be determined. They also bring up an interesting parallel between somatic mutations in cancer and in brain disease: somatic AKT3 mutations have also been identified in cancer, but none of the individuals studied by Poduri et al. had any form of cancer, suggesting that AKT3 mutations may result in different outcomes in different cellular contexts.