Aurélie Méneret1, Christel Depienne1, Florence Riant1, Oriane Trouillard1, Delphine Bouteiller1, Massimo Cincotta1, Pierre Bitoun1, Julia Wickert1, Isabelle Lagroua1, Ana Westenberger1, Alessandra Borgheresi1, Diane Doummar1, Marcello Romano1, Simone Rossi1, Luc Defebvre1, Linda De Meirleir1, Alberto J Espay1, Simona Fiori1, Stephan Klebe1, Chloé Quélin1, Sabine Rudnik-Schöneborn1, Ghislaine Plessis1, Russell C Dale1, Susan Sklower Brooks1, Karolina Dziezyc1, Pierre Pollak1, Jean-Louis Golmard1, Marie Vidailhet1, Alexis Brice1, Emmanuel Roze1. 1. From INSERM, U 975, and CNRS 7225-CRICM (A.M., C.D., O.T., D.B., I.L., M.V., A.B., E.R.), Département de Neurologie (A.M., M.V., E.R.), Fédération de Génétique, Département de Génétique et de Cytogénétique (C.D., A.B.), Banque d'ADN et de cellules (I.L.), Department of Biostatistics (J.-L.G.), and Centre d'Investigation Clinique Pitié Neurosciences 1422 (E.R.), Hôpital Pitié-Salpêtrière, AP-HP, Paris; Université Pierre et Marie Curie-Paris-6 (A.M., C.D., M.V., A.B., E.R.), UMR_S 975, Paris; Laboratoire de Génétique (F.R.), Groupe hospitalier Lariboisière-Fernand Widal, AP-HP, Paris; INSERM UMR_S740 (F.R.), Université Paris 7 Denis Diderot, Paris, France; Unit of Neurology (M.C., A.B.), Florence Health Authority, Italy; Génétique Médicale (P.B.), CHU Paris Nord, Hôpital Jean Verdier, Bondy, France; Department of Human Genetics (J.W.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Neurogenetics (A.W.), University of Lübeck, Germany; Service de Neuropédiatrie (D.D.), Hôpital Trousseau, AP-HP, Paris, France; Unit of Neurology (M.R.), Villa Sofia-Cervello Hospital, Palermo; Department of Neuroscience (S.R.), Section of Neurology and Clinical Neurophysiology, Azienda Ospedaliera Universitaria of Siena, Italy; Neurologie et Pathologie du Mouvement (L.D.), Neurologie A, Hopital Salengro, Centre Hospitalier Universitaire, EA 1046, Lille, France; Pediatric Neurology and Metabolism (L.D.M.), Universitair Ziekenhuis Brussel, Belgium; James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders (A.J.E.), University of Cincinnati Academic Health Center, Cincinnati, OH; IRCCS Fondazione Stella Maris (S.F.), Calambrone, Pisa, Italy; Department of Neurology (S.K.), University Hospital Würzburg, Germany; Service de Génétique Clinique (C.Q.), Hôpital Sud, Rennes, France; Institute for Human Genetics (S.R.-S.), Uniklinik RWTH Aachen, Germany; Service de Génétique (G.P.), CHU Clémenceau, Caen, F
Abstract
OBJECTIVE: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. METHODS: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. RESULTS: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). CONCLUSION: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.
OBJECTIVE: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. METHODS: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. RESULTS: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). CONCLUSION: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.
Authors: Myriam Srour; Jean-Baptiste Rivière; Jessica M T Pham; Marie-Pierre Dubé; Simon Girard; Steves Morin; Patrick A Dion; Géraldine Asselin; Daniel Rochefort; Pascale Hince; Sabrina Diab; Naser Sharafaddinzadeh; Sylvain Chouinard; Hugo Théoret; Frédéric Charron; Guy A Rouleau Journal: Science Date: 2010-04-30 Impact factor: 47.728
Authors: Jacqueline H Finger; Rod T Bronson; Belinda Harris; Kenneth Johnson; Stefan A Przyborski; Susan L Ackerman Journal: J Neurosci Date: 2002-12-01 Impact factor: 6.167
Authors: C Depienne; M Cincotta; S Billot; D Bouteiller; S Groppa; V Brochard; C Flamand; C Hubsch; S Meunier; F Giovannelli; S Klebe; J C Corvol; M Vidailhet; A Brice; E Roze Journal: Neurology Date: 2011-01-18 Impact factor: 9.910
Authors: Ashley P L Marsh; Delphine Heron; Timothy J Edwards; Angélique Quartier; Charles Galea; Caroline Nava; Agnès Rastetter; Marie-Laure Moutard; Vicki Anderson; Pierre Bitoun; Jens Bunt; Anne Faudet; Catherine Garel; Greta Gillies; Ilan Gobius; Justine Guegan; Solveig Heide; Boris Keren; Fabien Lesne; Vesna Lukic; Simone A Mandelstam; George McGillivray; Alissandra McIlroy; Aurélie Méneret; Cyril Mignot; Laura R Morcom; Sylvie Odent; Annalisa Paolino; Kate Pope; Florence Riant; Gail A Robinson; Megan Spencer-Smith; Myriam Srour; Sarah E M Stephenson; Rick Tankard; Oriane Trouillard; Quentin Welniarz; Amanda Wood; Alexis Brice; Guy Rouleau; Tania Attié-Bitach; Martin B Delatycki; Jean-Louis Mandel; David J Amor; Emmanuel Roze; Amélie Piton; Melanie Bahlo; Thierry Billette de Villemeur; Elliott H Sherr; Richard J Leventer; Linda J Richards; Paul J Lockhart; Christel Depienne Journal: Nat Genet Date: 2017-02-27 Impact factor: 38.330
Authors: Ashley P L Marsh; Timothy J Edwards; Charles Galea; Helen M Cooper; Elizabeth C Engle; Saumya S Jamuar; Aurélie Méneret; Marie-Laure Moutard; Caroline Nava; Agnès Rastetter; Gail Robinson; Guy Rouleau; Emmanuel Roze; Megan Spencer-Smith; Oriane Trouillard; Thierry Billette de Villemeur; Christopher A Walsh; Timothy W Yu; Delphine Heron; Elliott H Sherr; Linda J Richards; Christel Depienne; Richard J Leventer; Paul J Lockhart Journal: Hum Mutat Date: 2017-11-11 Impact factor: 4.878