Abstracts

Rationale: Hypothalamic hamartomas (HH) are rare, benign congenital tumors associated with intractable epilepsy. Most cases are sporadic and non-syndromic. Approximately 5% of HH cases are associated with Pallister-Hall syndrome (PHS), which is caused by haploinsufficiency of GLI3. We have investigated the possibility that HH pathogenesis in sporadic cases is due to a somatic (tumor-only) mutation of GLI3.Methods: We isolated genomic DNA from peripheral blood and surgically resected HH tissue in 55 patients with sporadic HH and intractable epilepsy. A genome-wide screen for loss of heterozygosity and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue using Affymetrix 10K GeneChip single nucleotide polymorphism (SNP) microarrays (n=21). Additionally, resequencing (n=55) and fine-mapping with SNP genotyping (n=21) was completed for the GLI3 gene with comparison between peripheral blood and HH tissue pairs.Results: By analyzing chromosomal copy number data for paired samples on the Affymetrix 10K GeneChip array a somatic amplification of chromosome 7p was identified in one HH tissue sample. Exons on GLI3 (also present on 7p) were resequenced for paired samples. Resequencing did not identify causative germline mutations, but did identify loss of heterozygosity within the GLI3 gene in the HH tissue samples of 3 patients. Further custom genotyping of 28 SNPs within and surrounding GLI3 identified 5 additional patients exhibiting loss of heterozygosity in HH tissue samples. Conclusions: Taken together, these data provide suggestive evidence that that development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, non-syndromic patients with HH and intractable epilepsy. Chromosomal abnormalities including the GLI3 locus were seen in 8 of 55 (15%) of the resected HH tissue samples. These somatic mutations appear to be variable between the individual cases. (Supported by a grant from the Barrow Neurological Institute Foundation.)