title: EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality.
abstract: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants.
  
  
  
  We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/-KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants.
  
  
  
  Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls.
  
  
  
  NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.|Department of Epidemiology, Fielding School of Public Health, UCLA, Los Angeles, California, USA.
authors.forename: Julia N
authors.identifier: 0000-0003-1556-5904
authors.initials: JN
authors.lastname: Bailey
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.
authors.forename: Christopher
authors.initials: C
authors.lastname: Patterson
authors.affiliation: GENESS International Consortium.|GIGA-Neurosciences, University of Liège, Liège, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: de Nijs
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.|Facultad de Ciencias de la Salud, Universidad Tecnológica Centroamericana (UNITEC), Tegucigalpa, Honduras.
authors.forename: Reyna M
authors.initials: RM
authors.lastname: Durón
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.|Chapman University School of Pharmacy, Irvine, California, USA.
authors.forename: Viet-Huong
authors.initials: VH
authors.lastname: Nguyen
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.|Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Miyabi
authors.identifier: 0000-0003-0469-054X
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: GENESS International Consortium.|National Autonomous University of Honduras, Tegucigalpa, Honduras.
authors.forename: Marco T
authors.initials: MT
authors.lastname: Medina
authors.affiliation: GENESS International Consortium.|National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Jara-Prado
authors.affiliation: GENESS International Consortium.|National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Martínez-Juárez
authors.affiliation: GENESS International Consortium.|National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
authors.forename: Adriana
authors.identifier: 0000-0001-9485-2658
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: GENESS International Consortium.|National Autonomous University of Honduras, Tegucigalpa, Honduras.
authors.forename: Yolli
authors.initials: Y
authors.lastname: Molina
authors.affiliation: GENESS International Consortium.|Neurogenetics Lab, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: GENESS International Consortium.|National Institute of Neurology and Neurosurgery, Mexico City, Mexico.
authors.forename: María E
authors.initials: ME
authors.lastname: Alonso
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Wight
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lin
authors.affiliation: GENESS International Consortium.|Unidade de Pesquisa e Tratamento das Epilepsias (UNIPETE), Universidade Federal de Sao Paulo (UNIFESP-EPM), Sao Paulo, Brazil.
authors.forename: Laura
authors.initials: L
authors.lastname: Guilhoto
authors.affiliation: GENESS International Consortium.|Unidade de Pesquisa e Tratamento das Epilepsias (UNIPETE), Universidade Federal de Sao Paulo (UNIFESP-EPM), Sao Paulo, Brazil.
authors.forename: Elza Marcia
authors.initials: EM
authors.lastname: Targas Yacubian
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.
authors.forename: Jesús
authors.initials: J
authors.lastname: Machado-Salas
authors.affiliation: GENESS International Consortium.|Eugenio Medea Scientific Institute, Conegliano and Dulbecco Telethon Institute, Italy.
authors.forename: Andrea
authors.identifier: 0000-0001-8935-5489
authors.initials: A
authors.lastname: Daga
authors.affiliation: GENESS International Consortium.|Neurogenetics Lab, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Kazuhiro
authors.identifier: 0000-0002-1478-4390
authors.initials: K
authors.lastname: Yamakawa
authors.affiliation: GENESS International Consortium.|GIGA-Neurosciences, University of Liège, Liège, Belgium.
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Grisar
authors.affiliation: GENESS International Consortium.|GIGA-Neurosciences, University of Liège, Liège, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lakaye
authors.affiliation: Epilepsy Genetics/Genomics Lab, Neurology and Research Services, VA GLAHS/UCLA, Los Angeles, California, USA.|GENESS International Consortium.|Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Antonio V
authors.identifier: 0000-0002-1581-6999
authors.initials: AV
authors.lastname: Delgado-Escueta
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D003712:Dendrites / Q000473:pathology; D059472:Exome; D005787:Gene Frequency; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics* / Q000503:physiopathology; D054560:National Human Genome Research Institute (U.S.); D009474:Neurons / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D013569:Synapses / Q000473:pathology; D014481:United States
chemical_list: D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human