PMID- 32086284 OWN - NLM STAT- MEDLINE DCOM- 20210708 LR - 20221207 IS - 1468-6244 (Electronic) IS - 0022-2593 (Linking) VI - 57 IP - 9 DP - 2020 Sep TI - Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes. PG - 624-633 LID - 10.1136/jmedgenet-2019-106658 [doi] AB - BACKGROUND: The genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE. METHODS: 112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE. RESULTS: ES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants. CONCLUSION: This study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years. CI - (c) Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Krenn, Martin AU - Krenn M AUID- ORCID: 0000-0003-3026-3082 AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Wagner, Matias AU - Wagner M AD - Institute of Human Genetics, Technical University Munich, Munich, Bayern, Germany. AD - Institute of Neurogenomics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Hotzy, Christoph AU - Hotzy C AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Graf, Elisabeth AU - Graf E AD - Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Weber, Sandrina AU - Weber S AD - Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Brunet, Theresa AU - Brunet T AD - Institute of Human Genetics, Technical University Munich, Munich, Bayern, Germany. FAU - Lorenz-Depiereux, Bettina AU - Lorenz-Depiereux B AD - Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Kasprian, Gregor AU - Kasprian G AD - Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria. FAU - Aull-Watschinger, Susanne AU - Aull-Watschinger S AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Pataraia, Ekaterina AU - Pataraia E AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Stogmann, Elisabeth AU - Stogmann E AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Zimprich, Alexander AU - Zimprich A AD - Department of Neurology, Medical University of Vienna, Vienna, Austria. FAU - Strom, Tim M AU - Strom TM AD - Institute of Human Genetics, Technical University Munich, Munich, Bayern, Germany. AD - Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Meitinger, Thomas AU - Meitinger T AD - Institute of Human Genetics, Technical University Munich, Munich, Bayern, Germany. AD - Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany. FAU - Zimprich, Fritz AU - Zimprich F AD - Department of Neurology, Medical University of Vienna, Vienna, Austria friedrich.zimprich@meduniwien.ac.at. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200221 PL - England TA - J Med Genet JT - Journal of medical genetics JID - 2985087R RN - 0 (DEPDC5 protein, human) RN - 0 (GTPase-Activating Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (NPRL3 protein, human) RN - 0 (Repressor Proteins) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Child MH - Child, Preschool MH - Epilepsies, Partial/diagnosis/*genetics/pathology MH - Exome/genetics MH - Female MH - GTPase-Activating Proteins/*genetics MH - *Genetic Predisposition to Disease MH - Genetic Variation/genetics MH - Humans MH - Infant MH - Male MH - Middle Aged MH - Multiprotein Complexes/genetics MH - Mutation/genetics MH - Phenotype MH - Repressor Proteins/genetics MH - Signal Transduction/genetics MH - Exome Sequencing MH - Young Adult OTO - NOTNLM OT - diagnostics OT - epilepsy and seizures OT - genetics OT - neurology COIS- Competing interests: None declared. EDAT- 2020/02/23 06:00 MHDA- 2021/07/09 06:00 CRDT- 2020/02/23 06:00 PHST- 2019/10/28 00:00 [received] PHST- 2020/01/17 00:00 [revised] PHST- 2020/01/22 00:00 [accepted] PHST- 2020/02/23 06:00 [pubmed] PHST- 2021/07/09 06:00 [medline] PHST- 2020/02/23 06:00 [entrez] AID - jmedgenet-2019-106658 [pii] AID - 10.1136/jmedgenet-2019-106658 [doi] PST - ppublish SO - J Med Genet. 2020 Sep;57(9):624-633. doi: 10.1136/jmedgenet-2019-106658. Epub 2020 Feb 21.