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

Abstract

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.

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

“…This includes (i) the lack of any growth on serial MRI or reported regrowth, even following incomplete resection, (ii) no overt increase in cellularity or conspicuous mitotic activity, (iii) lack of expansive or infiltrative growth patterns with nodules ‘sitting’ in an undisturbed laminar cortex, (iv) comparable localizations in deep cortex/subcortical region in reported cases, (v) retained expression of immature, developmentally regulated proteins as SOX2, TBR1, OTX1, KCC1 and GFAP∂, (vi) absence of any of the known genetic abnormalities of LEATs following NGS, including BRAF V600E, MYB and FGFR1 mutations and (vii) NGS in the present study showing recurring synonymous SNPs in SMO and DEPDC5 in common with cortical dysplasia (FCD IIB) and NPRL3 SNPs noted frequently in MNVT and FCD but not other glioneuronal tumors. Copy number variations in SMO a receptor in the Shh pathway have been recently shown in hypothalamic hamartoma associated with gelastic seizures and DEPDC5 and NPRL3 mutations reported in FCDII . Further histological features in common between MVNT and FCD IIB include the striking hypomyelination of involved white matter which may relate to deficiencies in oligodendroglial lineages .…”

Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series

“…Sporadic cases are proposed to result from somatic mutations leading to the abnormal regulation of early hypothalamic development. Genotyping of surgically resected hypothalamic hamartoma tissue has demonstrated mutations in sonic hedgehog pathway genes in up to 40% of sporadic cases, a quarter of which share the germ‐line abnormality GLI3 gene found in Pallister–Hall syndrome …”

Hypothalamic hamartoma: Neuropathology and epileptogenesis

“…Utilizing a candidate gene approach, somatic (tumor‐only) mutations in GLI3 have been identified in up to 20% of sporadic HH lesions undergoing surgical resection . More recently, whole‐exome sequencing has extended that observation, with the discovery of multiple mutations within genes comprising the sonic hedgehog pathway (including GLI3 ), so that now somatic mutations are associated with up to 37% of sporadic HH cases . At least at this time, genotyping of HH tissue lacks clinical utility and is not routinely recommended.…”