1. Genetic Insights Into Hypothalamic Hamartoma: Unraveling Somatic Variants.
- Author
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Sami L, Chipaux M, Ferrand-Sorbets S, Doladilhe M, Bulteau C, Raffo E, Rosenberg S, Dorfmuller G, Checri R, De Sainte Agathe JM, Leguern E, Adle-Biassette H, Baldassari S, and Baulac S
- Abstract
Objectives: Hypothalamic hamartomas (HHs) are rare developmental brain lesions associated with drug-resistant epilepsy and often subjected to epilepsy surgery. Brain somatic variants in genes affecting the Sonic hedgehog (Shh) and primary cilia signaling pathways have been implicated in approximately 50% of nonsyndromic HH cases. This study aims to characterize a new cohort of 9 HH cases and elucidate their genetic etiology., Methods: We recruited 9 HH cases including 8 nonsyndromic cases of which 4 were type IV HH. Genomic DNA was extracted from peripheral blood and surgical brain tissues, and somatic variants were investigated using high-depth whole-exome sequencing., Results: Pathogenic somatic variants in known HH genes ( GLI3 , OFD1 , and PRKACA) were identified in 7 of the 9 cases. In addition, a 2-hit mutational event comprising a germline variant (predicted to impair kinase activity) and a somatic loss-of-heterozygosity was identified in TNK2 , a gene encoding a brain-expressed tyrosine kinase., Discussion: Our findings reinforce the role of somatic variants in Shh and cilia genes in HH cases while also shedding light on TNK2 as a potential novel disease-causing gene. This study emphasizes the increasing importance of brain mosaicism in epilepsy disorders and underscores the critical role of genetic diagnosis derived from resected brain tissue., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2024
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