Genetic Insights Into Hypothalamic Hamartoma: Unraveling Somatic Variants.

Autor:	Sami L; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Chipaux M; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Ferrand-Sorbets S; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Doladilhe M; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Bulteau C; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Raffo E; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Rosenberg S; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Dorfmuller G; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Checri R; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., De Sainte Agathe JM; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Leguern E; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Adle-Biassette H; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Baldassari S; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France., Baulac S; From the Institut du Cerveau-Paris Brain Institute-ICM (L.S., M.D., J.-M.D.S.A., E.L., Sara Baldassari, Stephanie Baulac), Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière; Department of Pediatric Neurosurgery (M.C., S.F.-S., C.B., E.R., S.R., G.D., R.C.), Rothschild Foundation Hospital EPICARE; Department of Medical Genetics (J.-M.D.S.A., E.L.), AP-HP, Sorbonne Université, Hôpital de la Pitié Salpêtrière; and Université de Paris Cité (H.A.-B.), service d'Anatomie Pathologique, AP-HP, Hôpital Lariboisière, DMU DREAM, Biobank BB-0033-00064, UMR 1141, INSERM, Paris, France.
Jazyk:	angličtina
Zdroj:	Neurology. Genetics [Neurol Genet] 2024 Sep 04; Vol. 10 (5), pp. e200180. Date of Electronic Publication: 2024 Sep 04 (Print Publication: 2024).
DOI:	10.1212/NXG.0000000000200180
Abstrakt:	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.)
Databáze:	MEDLINE
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