Michael Zech1,2, Sylvia Boesch3, Angela Jochim2, Sandrina Weber1, Tobias Meindl2, Barbara Schormair1, Thomas Wieland4, Christian Lunetta5, Valeria Sansone6,7, Michael Messner8, Joerg Mueller3,9, Andres Ceballos-Baumann2,8, Tim M Strom4,10, Roberto Colombo11,12, Werner Poewe3, Bernhard Haslinger2, Juliane Winkelmann1,2,13,14. 1. Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany. 2. Klinik und Poliklinik für Neurologie, Klinikum rechts der lsar, Technische Universität München, Munich, Germany. 3. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 4. Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany. 5. Neuromuscular Omnicentre Sud (NEMO SUD), Fondazione Aurora Onlus, Messina, Italy. 6. Neuromuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milan, Italy. 7. Department of Biochemical Sciences for Health, University of Milan, Milan, Italy. 8. Schön Klinik München Schwabing, Munich, Germany. 9. Vivantes Klinikum Spandau, Berlin, Germany. 10. Institut für Humangenetik, Technische Universität München, Munich, Germany. 11. Institute of Clinical Biochemistry, Catholic University, Rome, Italy. 12. Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy. 13. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. 14. Institute of Human Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Abstract
BACKGROUND: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought.
BACKGROUND:Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. METHODS: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. RESULTS: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. CONCLUSIONS: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought.
Authors: Michael Zech; Robert Jech; Matias Wagner; Tobias Mantel; Sylvia Boesch; Michael Nocker; Angela Jochim; Riccardo Berutti; Petra Havránková; Anna Fečíková; David Kemlink; Jan Roth; Tim M Strom; Werner Poewe; Evžen Růžička; Bernhard Haslinger; Juliane Winkelmann Journal: Neurogenetics Date: 2017-08-28 Impact factor: 2.660
Authors: Michael Zech; Sylvia Boesch; Esther M Maier; Ingo Borggraefe; Katharina Vill; Franco Laccone; Veronika Pilshofer; Andres Ceballos-Baumann; Bader Alhaddad; Riccardo Berutti; Werner Poewe; Tobias B Haack; Bernhard Haslinger; Tim M Strom; Juliane Winkelmann Journal: Am J Hum Genet Date: 2016-11-10 Impact factor: 11.025
Authors: Michael Zech; Robert Jech; Sylvia Boesch; Matej Škorvánek; Sandrina Weber; Matias Wagner; Chen Zhao; Angela Jochim; Ján Necpál; Yasemin Dincer; Katharina Vill; Felix Distelmaier; Malgorzata Stoklosa; Martin Krenn; Stephan Grunwald; Tobias Bock-Bierbaum; Anna Fečíková; Petra Havránková; Jan Roth; Iva Příhodová; Miriam Adamovičová; Olga Ulmanová; Karel Bechyně; Pavlína Danhofer; Branislav Veselý; Vladimír Haň; Petra Pavelekova; Zuzana Gdovinová; Tobias Mantel; Tobias Meindl; Alexandra Sitzberger; Sebastian Schröder; Astrid Blaschek; Timo Roser; Michaela V Bonfert; Edda Haberlandt; Barbara Plecko; Birgit Leineweber; Steffen Berweck; Thomas Herberhold; Berthold Langguth; Jana Švantnerová; Michal Minár; Gonzalo Alonso Ramos-Rivera; Monica H Wojcik; Sander Pajusalu; Katrin Õunap; Ulrich A Schatz; Laura Pölsler; Ivan Milenkovic; Franco Laccone; Veronika Pilshofer; Roberto Colombo; Steffi Patzer; Arcangela Iuso; Julia Vera; Monica Troncoso; Fang Fang; Holger Prokisch; Friederike Wilbert; Matthias Eckenweiler; Elisabeth Graf; Dominik S Westphal; Korbinian M Riedhammer; Theresa Brunet; Bader Alhaddad; Riccardo Berutti; Tim M Strom; Martin Hecht; Matthias Baumann; Marc Wolf; Aida Telegrafi; Richard E Person; Francisca Millan Zamora; Lindsay B Henderson; David Weise; Thomas Musacchio; Jens Volkmann; Anna Szuto; Jessica Becker; Kirsten Cremer; Thomas Sycha; Fritz Zimprich; Verena Kraus; Christine Makowski; Pedro Gonzalez-Alegre; Tanya M Bardakjian; Laurie J Ozelius; Annalisa Vetro; Renzo Guerrini; Esther Maier; Ingo Borggraefe; Alice Kuster; Saskia B Wortmann; Annette Hackenberg; Robert Steinfeld; Birgit Assmann; Christian Staufner; Thomas Opladen; Evžen Růžička; Ronald D Cohn; David Dyment; Wendy K Chung; Hartmut Engels; Andres Ceballos-Baumann; Rafal Ploski; Oliver Daumke; Bernhard Haslinger; Volker Mall; Konrad Oexle; Juliane Winkelmann Journal: Lancet Neurol Date: 2020-11 Impact factor: 44.182
Authors: Tanya M Bardakjian; Ingo Helbig; Colin Quinn; Lauren B Elman; Leo F McCluskey; Steven S Scherer; Pedro Gonzalez-Alegre Journal: Neurogenetics Date: 2018-03-28 Impact factor: 2.660