Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies. Issue 3 (25th February 2019)

• Record Type: Journal Article
• Authors: Pippucci, Tommaso; Licchetta, Laura; Baldassari, Sara; Marconi, Caterina; De Luise, Monica; Myers, Candace; Nardi, Elena; Provini, Federica; Cameli, Cinzia; Minardi, Raffaella; Bacchelli, Elena; Giordano, Lucio; Crichiutti, Giovanni; d'Orsi, Giuseppe; Seri, Marco; Gasparre, Giuseppe; Mefford, Heather C.; Tinuper, Paolo; Bisulli, Francesca
• Other Names: Bianchi Amedeo investigator.; Striano Pasquale investigator.; Gambardella Antonio investigator.; Meletti Stefano investigator.; Dilena Roberto investigator.; Santucci Margherita investigator.; Marini Carla investigator.; Vignoli Aglaia investigator.; Gobbi Giuseppe investigator.; Briatore Eleonora investigator.; Mastrangelo Massimo investigator.
• Is Part Of: Annals of clinical and translational neurology. Volume 6:Issue 3(2019)
• Page Start: 475
• Page End: 485
• Publication Date: 2019-02-25
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.722
• Languages: English
• ISSNs: 2328-9503

Abstract

Abstract: Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single‐molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed "qualifying" variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients ( P = 0.006; exact unconditional test, one‐tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.