Annals of clinical and translational neurology · 2019
Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission
Аннотация
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.
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.
Предметные рубрики MeSH
AdolescentAdultChildChild, PreschoolEpilepsies, PartialFemaleGTPase-Activating ProteinsGenetic Predisposition to DiseaseGenomic Structural VariationHumansInfantMaleMechanistic Target of Rapamycin Complex 1Middle AgedMultiprotein ComplexesSignal TransductionTuberous Sclerosis Complex 1 ProteinTuberous Sclerosis Complex 2 ProteinExome Sequencing