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

Authors:
Tommaso Pippucci
Tommaso Pippucci
University of Bologna
Italy
Laura Licchetta
Laura Licchetta
University of Bologna
Italy
Sara Baldassari
Sara Baldassari
University of Bologna
Italy
Caterina Marconi
Caterina Marconi
University of Bologna
Italy
Candace Myers
Candace Myers
El Paso | United States
Elena Nardi
Elena Nardi
Laboratory of Biostatistics
Federica Provini
Federica Provini
University of Bologna
Italy

Ann Clin Transl Neurol 2019 Mar 25;6(3):475-485. Epub 2019 Feb 25.

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.

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 ( = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in and 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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http://dx.doi.org/10.1002/acn3.722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414475PMC
March 2019
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References

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Panayiotopoulos CP et al.
2005

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