PMID- 30911571
OWN - NLM
STAT- MEDLINE
DCOM- 20200320
LR  - 20221207
IS  - 2328-9503 (Print)
IS  - 2328-9503 (Electronic)
IS  - 2328-9503 (Linking)
VI  - 6
IP  - 3
DP  - 2019 Mar
TI  - Contribution of ultrarare variants in mTOR pathway genes to sporadic focal 
      epilepsies.
PG  - 475-485
LID - 10.1002/acn3.722 [doi]
AB  - 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.
FAU - Pippucci, Tommaso
AU  - Pippucci T
AD  - Medical Genetics Unit Polyclinic Sant'Orsola-Malpighi University Hospital Bologna 
      Italy.
FAU - Licchetta, Laura
AU  - Licchetta L
AD  - IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
AD  - Department of Biomedical and Neuromotor Sciences (DIBINEM) University of Bologna 
      Bologna Italy.
FAU - Baldassari, Sara
AU  - Baldassari S
AD  - Department of Biomedical and Surgical Sciences (DIMEC) University of Bologna 
      Bologna Italy.
FAU - Marconi, Caterina
AU  - Marconi C
AD  - Department of Biomedical and Surgical Sciences (DIMEC) University of Bologna 
      Bologna Italy.
FAU - De Luise, Monica
AU  - De Luise M
AD  - Department of Biomedical and Surgical Sciences (DIMEC) University of Bologna 
      Bologna Italy.
FAU - Myers, Candace
AU  - Myers C
AD  - Division of Genetic Medicine Department of Pediatrics University of Washington 
      Seattle Washington.
FAU - Nardi, Elena
AU  - Nardi E
AD  - Department of Statistical Sciences "Paolo Fortunati" University of Bologna 
      Bologna Italy.
FAU - Provini, Federica
AU  - Provini F
AD  - IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
AD  - Department of Biomedical and Neuromotor Sciences (DIBINEM) University of Bologna 
      Bologna Italy.
FAU - Cameli, Cinzia
AU  - Cameli C
AD  - Department of Pharmacy and Biotechnology University of Bologna Bologna Italy.
FAU - Minardi, Raffaella
AU  - Minardi R
AD  - IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
AD  - Department of Biomedical and Neuromotor Sciences (DIBINEM) University of Bologna 
      Bologna Italy.
FAU - Bacchelli, Elena
AU  - Bacchelli E
AD  - Department of Pharmacy and Biotechnology University of Bologna Bologna Italy.
FAU - Giordano, Lucio
AU  - Giordano L
AD  - Neuropsychiatric Department Spedali Civili Brescia Italy.
FAU - Crichiutti, Giovanni
AU  - Crichiutti G
AD  - Division of Pediatrics Department of Medicine University of Udine Udine Italy.
FAU - d'Orsi, Giuseppe
AU  - d'Orsi G
AD  - Epilepsy Center Clinic of Nervous System Diseases University of Foggia Riuniti 
      Hospital Foggia Italy.
FAU - Seri, Marco
AU  - Seri M
AD  - Medical Genetics Unit Polyclinic Sant'Orsola-Malpighi University Hospital Bologna 
      Italy.
AD  - Department of Biomedical and Surgical Sciences (DIMEC) University of Bologna 
      Bologna Italy.
FAU - Gasparre, Giuseppe
AU  - Gasparre G
AD  - Department of Biomedical and Surgical Sciences (DIMEC) University of Bologna 
      Bologna Italy.
FAU - Mefford, Heather C
AU  - Mefford HC
AD  - Division of Genetic Medicine Department of Pediatrics University of Washington 
      Seattle Washington.
FAU - Tinuper, Paolo
AU  - Tinuper P
AD  - IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
AD  - Department of Biomedical and Neuromotor Sciences (DIBINEM) University of Bologna 
      Bologna Italy.
FAU - Bisulli, Francesca
AU  - Bisulli F
AD  - IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.
AD  - Department of Biomedical and Neuromotor Sciences (DIBINEM) University of Bologna 
      Bologna Italy.
CN  - Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Commission
LA  - eng
GR  - R01 NS069605/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190225
PL  - United States
TA  - Ann Clin Transl Neurol
JT  - Annals of clinical and translational neurology
JID - 101623278
RN  - 0 (DEPDC5 protein, human)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
MH  - Adolescent
MH  - Adult
MH  - Child
MH  - Child, Preschool
MH  - Epilepsies, Partial/*genetics
MH  - Female
MH  - GTPase-Activating Proteins/genetics
MH  - Genetic Predisposition to Disease
MH  - Genomic Structural Variation/*genetics
MH  - Humans
MH  - Infant
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*genetics
MH  - Middle Aged
MH  - Multiprotein Complexes/genetics
MH  - Signal Transduction
MH  - Tuberous Sclerosis Complex 1 Protein/genetics
MH  - Tuberous Sclerosis Complex 2 Protein/genetics
MH  - Exome Sequencing
PMC - PMC6414475
COIS- The authors report no disclosures.
FIR - Bianchi, Amedeo
IR  - Bianchi A
FIR - Striano, Pasquale
IR  - Striano P
FIR - Gambardella, Antonio
IR  - Gambardella A
FIR - Meletti, Stefano
IR  - Meletti S
FIR - Dilena, Roberto
IR  - Dilena R
FIR - Santucci, Margherita
IR  - Santucci M
FIR - Marini, Carla
IR  - Marini C
FIR - Vignoli, Aglaia
IR  - Vignoli A
FIR - Gobbi, Giuseppe
IR  - Gobbi G
FIR - Briatore, Eleonora
IR  - Briatore E
FIR - Mastrangelo, Massimo
IR  - Mastrangelo M
EDAT- 2019/03/27 06:00
MHDA- 2019/03/27 06:01
PMCR- 2019/02/25
CRDT- 2019/03/27 06:00
PHST- 2018/09/17 00:00 [received]
PHST- 2018/12/07 00:00 [revised]
PHST- 2018/12/08 00:00 [accepted]
PHST- 2019/03/27 06:00 [entrez]
PHST- 2019/03/27 06:00 [pubmed]
PHST- 2019/03/27 06:01 [medline]
PHST- 2019/02/25 00:00 [pmc-release]
AID - ACN3722 [pii]
AID - 10.1002/acn3.722 [doi]
PST - epublish
SO  - Ann Clin Transl Neurol. 2019 Feb 25;6(3):475-485. doi: 10.1002/acn3.722. 
      eCollection 2019 Mar.