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. 2019 Feb 25;6(3):475-485.
doi: 10.1002/acn3.722. eCollection 2019 Mar.

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Tommaso Pippucci  1 , Laura Licchetta  2   3 , Sara Baldassari  4 , Caterina Marconi  4 , Monica De Luise  4 , Candace Myers  5 , Elena Nardi  6 , Federica Provini  2   3 , Cinzia Cameli  7 , Raffaella Minardi  2   3 , Elena Bacchelli  7 , Lucio Giordano  8 , Giovanni Crichiutti  9 , Giuseppe d'Orsi  10 , Marco Seri  1   4 , Giuseppe Gasparre  4 , Heather C Mefford  5 , Paolo Tinuper  2   3 , Francesca Bisulli  2   3 ; Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission
Collaborators, Affiliations

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies

Tommaso Pippucci et al. Ann Clin Transl Neurol. .

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.

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Conflict of interest statement

The authors report no disclosures.

Figures

Figure 1
Figure 1
Simplified schematic of GATOR and TSC complexes in the mTOR pathway. The number of qualifying variants identified in each analyzed gene is reported. Under each gene name, the number of qualifying variants in cases (left) and controls (right), separated by colon.
Figure 2
Figure 2
Workflow of the case–control gene collapsing analysis.
Figure 3
Figure 3
Functional assessment of mTORC1 activation in human lymphocytes. (A) List of the evaluated variants; (B) densitometric analysis of western blot showing the mean ratio of p‐S6K over total S6K expression in the tested lymphocytes; (C) representative western blot result. In panel (B), asterisks indicate significant P‐values obtained when comparing patients and controls (two‐tailed T‐test): **P‐value < 0.01, ***P‐value < 0.001.
See this image and copyright information in PMC

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