Authors :
Presenting Author: mathilde chipaux-Raffo, MD, PhD – Rothschild Foundation Hospital, Paris, France
Lina Sami, student – ICM, Paris
Christine Bulteau, MD,PhD – Rothschild Foundation Hospital, Paris, France
Emmanuel Raffo, MD, PhD – Rothschild Foundation Hospital, Paris, France
Sarah D. Rosenberg, MD – Rothschild Foundation Hospital, Paris, France
Georg Dorfmüller, MD – Rothschild Foundation Hospital, Paris, France
Rayann Checri, MD – Rothschild Foundation Hospital, Paris, France
Homa Adle-Biassette, MD – Lariboisiere hospital
sara Baldassari, PhD – ICM, Paris
stephanie Baulac, PhD – ICM, Paris
Sarah Ferrand-Sorbets, MD – Rothschild Foundation Hospital, Paris, France
Rationale:
Hypothalamic hamartomas (HHs) are rare developmental brain lesions associated with drug resistant epilepsy and often subjected to epilepsy surgery. Brain somatic mutations 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 mutations were investigated using high-depth whole-exome sequencing
Results:
Pathogenic somatic mutations in known HH genes (GLI3, OFD1, and PRKACA) were identified in 7 of the 9 cases. In addition, a two-hit mutation 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.
Conclusions:
Our findings reinforce the role of somatic mutations 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.
Funding: No funding