title: Genetics of epilepsy: The testimony of twins in the molecular era.
abstract: OBJECTIVE
  Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses.
  
  
  METHODS
  A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable.
  
  
  RESULTS
  Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles.
  
  
  CONCLUSIONS
  Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the "genetic" syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Lata
authors.initials: L
authors.lastname: Vadlamudi
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrence
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Heron
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Jazmin
authors.initials: J
authors.lastname: Eckhaus
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: Keay
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Connellan
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Torn-Broers
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: R Anne
authors.initials: RA
authors.lastname: Howell
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Mulley
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: From the Epilepsy Research Centre, Department of Medicine (Neurology) (L.V., K.L., J.E., D.K., M.C., Y.T.-B., R.A.H., I.E.S., S.F.B.), University of Melbourne, Austin Health; School of Medicine (L.V.), The University of Queensland, Brisbane; Department of Neurology (L.V.), Royal Brisbane and Women's Hospital; Centre for Molecular, Environmental, Analytic and Genetic Epidemiology (R.L.M., J.L.H.), University of Melbourne; School of Pharmacy and Medical Sciences and Sansom Institute for Health Research (S.E.H., L.M.D.), University of South Australia, Adelaide; and the Department of Genetic Medicine, SA Pathology (J.C.M.), Women's and Children's Hospital, North Adelaide, Australia. s.berkovic@unimelb.edu.au.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D015331:Cohort Studies; D004828:Epilepsies, Partial / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D003294:Seizures, Febrile / Q000235:genetics*; D013577:Syndrome; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*
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