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
Neurology. 2014 Jun 3;82(22):1999-2002. doi: 10.1212/WNL.0000000000000477. Epub 2014 May 7.
We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51.
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.
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).
Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.
我们在大量先天性镜像运动（CMM）个体中筛选出两个已确定的致病基因 DCC 和 RAD51 的突变。
我们研究了 6 个家族性和 20 个单纯性 CMM 病例。每位患者均进行了标准化的神经评估。DCC 和 RAD51 编码区的分析包括 Sanger 测序和一种定量方法，可检测微重排。然后，我们比较了我们人群中由 PolyPhen-2 或 SIFT 算法预测为致病性的罕见变异的频率，以及 Exome Variant Server 上 4300 名欧洲起源的对照。
我们在 6 个家族中的 4 个中发现了与 CMM 分离的 DCC 的 3 个新的截断突变。在 20 个单纯性病例中，我们发现了一个 DCC 的外显子缺失，一个导致移码的 DCC 突变，5 个 DCC 的错义变异，以及 2 个 RAD51 的错义变异。所有 7 个错义变异均由一种或两种算法预测为致病性。统计学分析显示，患者和对照组之间预测为有害的变异频率存在显著差异（RAD51 和 DCC 均为 p<0.001）。
DCC 和 RAD51 的突变和变异与 CMM 密切相关，但仍有待发现导致 CMM 的其他基因。
