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Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes
  1. Martin Krenn1,
  2. Matias Wagner2,3,
  3. Christoph Hotzy1,
  4. Elisabeth Graf4,
  5. Sandrina Weber4,
  6. Theresa Brunet2,
  7. Bettina Lorenz-Depiereux4,
  8. Gregor Kasprian5,
  9. Susanne Aull-Watschinger1,
  10. Ekaterina Pataraia1,
  11. Elisabeth Stogmann1,
  12. Alexander Zimprich1,
  13. Tim M Strom2,4,
  14. Thomas Meitinger2,4,
  15. Fritz Zimprich1
  1. 1Department of Neurology, Medical University of Vienna, Vienna, Austria
  2. 2Institute of Human Genetics, Technical University Munich, Munich, Bayern, Germany
  3. 3Institute of Neurogenomics, Helmholtz Center Munich, Neuherberg, Bayern, Germany
  4. 4Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Bayern, Germany
  5. 5Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Fritz Zimprich, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; friedrich.zimprich{at}


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.

  • epilepsy and seizures
  • genetics
  • diagnostics
  • neurology
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  • Contributors FZ designed and supervised the study. MK analysed exome data and wrote the manuscript. TM supervised the genetic analyses. TMS was responsible for the bioinformatic pipeline. MW and AZ were involved in genetic data analysis. CH was responsible for DNA preparation and quality check. EG, SW and BL-D were involved in the sequencing pipeline. TB was responsible for the secondary confirmation of copy number variants. GK re-evaluated patient MRIs. EP, SA-W and ES were involved in the clinical diagnosis of patients.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the ethics committee of the Medical University of Vienna (ethics approval number: 2051/2016).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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