Somatic mutations in GLI3 can cause hypothalamic hamartoma and gelastic seizures

Hypothalamic hamartomas are congenital mass lesions consisting of mature neuronal and glial elements that resemble normal gray matter. They are usually sporadic but rarely are associated with Pallister–Hall syndrome (PHS), an autosomal dominant syndrome with additional congenital anomalies including insertional polydactyly, imperforate anus, and bifid epiglottis. PHS is due to mutations in the zinc-finger transcription factor gene GLI3 on chromosome 7p13.1 GLI proteins are involved in downstream regulation of sonic hedgehog-mediated CNS development, where they are the key regulators of target-gene expression.2 Hypothalamic hamartomas are associated with the remarkable phenomenon of gelastic (laughing) seizures often accompanied by a severe and medically refractory epilepsy syndrome. The lesions causing epilepsy are typically in the third ventricle and were previously regarded as inoperable. The development of a safe and effective transcallosal technique to remove these epileptogenic lesions3 allowed us to test the hypothesis that sporadic hypothalamic hamartomas were associated with somatic GLI3 mutations. ### Methods. We obtained hypothalamic hamartoma tissue samples from 15 patients operated on at the Royal Children's Hospital in Melbourne, Australia. All had refractory epilepsy and none had a family history or clinical features of …