Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies.
Adolescent
Adult
Child
Child, Preschool
Epilepsies, Partial
/ genetics
Female
GTPase-Activating Proteins
/ genetics
Genetic Predisposition to Disease
Genomic Structural Variation
/ genetics
Humans
Infant
Male
Mechanistic Target of Rapamycin Complex 1
/ genetics
Middle Aged
Multiprotein Complexes
/ genetics
Signal Transduction
Tuberous Sclerosis Complex 1 Protein
/ genetics
Tuberous Sclerosis Complex 2 Protein
/ genetics
Exome Sequencing
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
17
09
2018
revised:
07
12
2018
accepted:
08
12
2018
entrez:
27
3
2019
pubmed:
27
3
2019
medline:
27
3
2019
Statut:
epublish
Résumé
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). 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. We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients ( 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.
Identifiants
pubmed: 30911571
doi: 10.1002/acn3.722
pii: ACN3722
pmc: PMC6414475
doi:
Substances chimiques
DEPDC5 protein, human
0
GTPase-Activating Proteins
0
Multiprotein Complexes
0
TSC1 protein, human
0
TSC2 protein, human
0
Tuberous Sclerosis Complex 1 Protein
0
Tuberous Sclerosis Complex 2 Protein
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
475-485Subventions
Organisme : NINDS NIH HHS
ID : R01 NS069605
Pays : United States
Investigateurs
Amedeo Bianchi
(A)
Pasquale Striano
(P)
Antonio Gambardella
(A)
Stefano Meletti
(S)
Roberto Dilena
(R)
Margherita Santucci
(M)
Carla Marini
(C)
Aglaia Vignoli
(A)
Giuseppe Gobbi
(G)
Eleonora Briatore
(E)
Massimo Mastrangelo
(M)
Déclaration de conflit d'intérêts
The authors report no disclosures.
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