title: Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus.
abstract: Hypothalamic hamartomas (HH) are rare, benign congenital tumors associated with intractable epilepsy. Most cases are sporadic and nonsyndromic. 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 in GLI3. 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 (LOH) and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue with Affymetrix 10K SNP microarrays. Additionally, resequencing and fine mapping with SNP genotyping were completed for the GLI3 gene with comparisons between peripheral blood and HH tissue pairs. By analyzing chromosomal copy-number data for paired samples on the Affymetrix 10K array, we identified a somatic chromosomal abnormality on chromosome 7p in one HH tissue sample. Resequencing of GLI3 did not identify causative germline mutations but did identify LOH within the GLI3 gene in the HH tissue samples of three patients. Further genotyping of 28 SNPs within and surrounding GLI3 identified five additional patients exhibiting LOH. Together, these data provide evidence that the development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, nonsyndromic 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 highly variable.
authors.affiliation: The Translational Genomics Research Institute, Neurogenomics Division, Phoenix, AZ 85004, USA. dcraig@tgen.org
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Abraham
authors.initials: A
authors.lastname: Itty
authors.forename: Corrie
authors.initials: C
authors.lastname: Panganiban
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Aswin
authors.initials: A
authors.lastname: Sekar
authors.forename: David
authors.initials: D
authors.lastname: Reiman
authors.forename: Vinodh
authors.initials: V
authors.lastname: Narayanan
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: John F
authors.initials: JF
authors.lastname: Kerrigan
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005838:Genotype; D006222:Hamartoma / Q000235:genetics*; D006801:Humans; D007027:Hypothalamic Diseases / Q000235:genetics*; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000074290:Zinc Finger Protein Gli3
chemical_list: D017931:DNA Primers; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3