Abstracts

Rationale: Hypothalamic hamartoma (HH) and gelastic epilepsy is a well-recognized drug-resistant epileptic syndrome of early life. A variety of surgical approaches to resect or ablate HH have been reported with variable efficacy and morbidity. Despite improvement in prognosis for HH patients over the last 20 years only 52% to 66% of surgical patients achieve seizure-freedom. This suggests we do not fully understand the pathological mechanisms that underlie development of these tumors, nor their effect on the brain.Methods: Here we report the results of a genome-wide scan for somatic mutations using exome sequencing of 15 paired hamartoma- and leuckocyte-derived DNA samples.Results: Consistent with previous studies, we identified novel somatic mutations in GLI3, a key regulator of sonic-hedgehog (Shh) signalling, in the hamartoma tissue of two patients. Remarkably, we identified somatic mutations involving four new genes that also regulate the Shh pathway in the hamartoma tissue of four of the other 13 patients studied. In two patients we found somatic mutations of the cAMP-dependent protein kinase (PRKACA) gene, in one patient a brain-tissue specific deletion of the q-arm of chromosome 7 encompassing the sonic hedgehog (SHH) and smoothened, frizzled classed receptor (SMO) genes, and in another patient a somatic deletion of the p-arm of chromosome 16 deleting the CREB binding protein (CREBBP) gene.Conclusions: We are now interrogating new cases by both array CGH and targeted gene resequencing to provide additional diagnoses. Taken together our data implicate perturbation of the Shh pathway in a striking proportion of HH and gelastic epilepsy cases (6/15; 40%), supporting the idea that this is a rare ‘pathway’ brain disease.