title: Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2-2q11.2.
abstract: Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between individuals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of individuals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family; eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Lyndal
authors.initials: L
authors.lastname: Henden
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Saskia
authors.initials: S
authors.lastname: Freytag
authors.affiliation: Tel Aviv University Medical School, 69978, Tel Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi-Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Baldassari
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne Austin Health, Melbourne, VIC, 3084, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bisulli
authors.affiliation: Neurophysiopathology and Epilepsy Center, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Canafoglia
authors.affiliation: Division of Genetics and Cell Biology, Università Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
authors.affiliation: Neurology Department, Northern Health, Melbourne, VIC, 3076, Australia.
authors.forename: Douglas Ewan
authors.initials: DE
authors.lastname: Crompton
authors.affiliation: Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.|Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: Robinson Institute and School of Medicine, The University of Adelaide, Adelaide, SA, 5005, Australia.|School of Biological Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.|IRCCS Stella Maris Foundation, Pisa, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Neuropediatrics, Christian-Albrechts-University of Kiel and University Medical Center, Kiel, Schleswig-Holstein, Germany.|Departments of Brain and Cognitive Sciences, Physiology and Cell Biology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Negev, Israel.|Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Medical and Surgical Epilepsy Unit, Hautepierre Hospital, University of Strasbourg, Strasbourg, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Département de Génétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06,UMR S 1127, ICM, 75013, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany.|Department of Neurology, Epilepsy Center Hessen, University Hospitals Giessen and Marburg, Philipps-University Marburg, Marburg, Germany.
authors.forename: Karl Martin
authors.initials: KM
authors.lastname: Klein
authors.affiliation: Department of Neurology, Montpellier University, Gui de Chauliac, 34295, Montpellier, Cedex 5, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06,UMR S 1127, ICM, 75013, Paris, France.|INSERM, U 1127; CNRS, UMR 7225; INSERM UMR 975; Institut du Cerveau et de la Moelle Epinière; and Département de Génétique et de Cytogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux De Paris (AP-HP), Paris, France.|Université Pierre et Marie Curie (Paris 6) (UPMC), UMRS 975, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: LeGuern
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Licchetta
authors.affiliation: Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.affiliation: Département de Génétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06,UMR S 1127, ICM, 75013, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi-Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France.|Department of Neurology, Hautepierre Hospital, University of Strasbourg, Strasbourg, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne Austin Health, Melbourne, VIC, 3084, Australia.|Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, 3084, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, 3052, Australia.
authors.forename: Ingrid Eileen
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Gaslini Institute, Genoa, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.affiliation: Laboratory of Neurogenetics, Department of Neurosciences, Gaslini Institute, Genoa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.affiliation: Robinson Institute and School of Medicine, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, 3052, Australia. bahlo@wehi.edu.au.|Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3010, Australia. bahlo@wehi.edu.au.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018703:Founder Effect; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000503:physiopathology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology