Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy

Am J Hum Genet. 2016 Aug 4;99(2):423-9. doi: 10.1016/j.ajhg.2016.05.031. Epub 2016 Jul 21.


Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CREB-Binding Protein / genetics
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics
  • Epilepsies, Partial / genetics*
  • Exome / genetics
  • Female
  • Hamartoma / genetics*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Hypothalamic Diseases / genetics*
  • Kruppel-Like Transcription Factors / genetics
  • Loss of Heterozygosity
  • Male
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / genetics
  • Signal Transduction / genetics*
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3


  • GLI2 protein, human
  • GLI3 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • SHH protein, human
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • CREB-Binding Protein
  • CREBBP protein, human
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human

Supplementary concepts

  • Hypothalamic hamartomas