Mehdi Benkirane1, Cecilia Marelli2, Claire Guissart1, Agathe Roubertie3,4, Elizabeth Ollagnon5, Ariane Choumert6, Frédérique Fluchère7, Fabienne Ory Magne8, Yosra Halleb1, Mathilde Renaud9, Lise Larrieu1, David Baux1, Olivier Patat10, Idriss Bousquet5, Jean-Marie Ravel9, Danielle Cuntz-Shadfar3, Catherine Sarret11, Xavier Ayrignac12, Anne Rolland3, Raoul Morales12, Morgane Pointaux1, Cathy Lieutard-Haag1, Brice Laurens13, Caroline Tillikete14, Emilien Bernard14,15, Martial Mallaret16, Clarisse Carra-Dallière12, Christine Tranchant17, Pierre Meyer3,18, Lena Damaj19, Laurent Pasquier19, Cecile Acquaviva20, Annabelle Chaussenot21, Bertrand Isidor22, Karine Nguyen7, William Camu12, Alexandre Eusebio7, Nicolas Carrière23, Audrey Riquet24, Eric Thouvenot25, Victoria Gonzales12, Emilie Carme3, Shahram Attarian7, Sylvie Odent19, Anna Castrioto16, Claire Ewenczyk26, Perrine Charles26, Laurent Kremer7, Samira Sissaoui27, Nadia Bahi-Buisson27, Elsa Kaphan7, Adrian Degardin23, Bérénice Doray28, Sophie Julia10, Ganaëlle Remerand29, Valerie Fraix16, Lydia Abou Haidar3, Leila Lazaro30, Vincent Laugel31, Frederic Villega32, Cyril Charlin6, Solène Frismand9, Marinha Costa Moreira3, Tatiana Witjas7, Christine Francannet11, Ulrike Walther-Louvier3, Mélanie Fradin19, Brigitte Chabrol33, Joel Fluss34, Eric Bieth10, Giovanni Castelnovo25, Sylvain Vergnet13, Isabelle Meunier4,35, Alain Verloes36, Elise Brischoux-Boucher37, Christine Coubes38, David Geneviève38, Nicolas Lebouc39, Jean Phillipe Azulay7, Mathieu Anheim17, Cyril Goizet40, François Rivier3,18, Pierre Labauge12, Patrick Calvas10, Michel Koenig41. 1. PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France. 2. Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic Diseases, Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier; Molecular Mechanisms of Neurodegenerative Dementia (MMDN), EPHE, INSERM, Université de Montpellier, Montpellier, France. 3. Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France. 4. INSERM, Institut des Neurosciences de Montpellier, Montpellier, France. 5. Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France. 6. Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France. 7. Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France. 8. Department of Neurology, Purpan Hospital, CHU de Toulouse, Toulouse, France. 9. Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France. 10. Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France. 11. Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France. 12. Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France. 13. Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France. 14. Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France. 15. Institut NeuroMyoGène, INSERM-CNRS-UMR, Université Claude Bernard, Lyon, France. 16. Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France. 17. Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France. 18. PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France. 19. Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France. 20. Department of Hereditary Metabolic Diseases, Centre de Biologie et Pathologie Est, CHU de Lyon et UMR, Bron, France. 21. Department of Medical Genetics, National Centre for Mitochondrial Diseases, CHU de Nice, Nice, France. 22. Department of Medical Genetics, CHU de Nantes, Nantes, France. 23. Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France. 24. Department of Pediatrics Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France. 25. Department of Neurology, CHU de Nîmes, Nîmes, France. 26. Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France. 27. Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 28. Department of Medical Genetics, CHU de la Réunion, Saint-Denis, France. 29. Department of Neonatology, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France. 30. Department of Pediatrics, CH de la Côte Basque-Bayonne, Bayonne, France. 31. Department of Pediatrics, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France. 32. Department of Pediatrics, Groupe Hospitalier Pellegrin, CHU de Bordeaux; Institute for Interdisciplinary Neurosciences (IINS), CNRS -UMR, Université de Bordeaux, Bordeaux, France. 33. Departement of Pediatrics, La Timone Hospital, CHU de Marseille, Marseille, France. 34. Pediatric Neurology Unit, Geneva Children's Hospital, Genève, Switzerland. 35. Genetics of Sensory Diseases, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France. 36. Federation of Genetics, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 37. Department of Medical Genetics, Hôpital Saint-Jacques, CHU de Besançon, Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France. 38. Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France. 39. Department of Neuroradiology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France. 40. Department of Medical Genetics, Pellegrin Hospital, CHU de Bordeaux, Bordeaux, France. 41. PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France. michel.koenig@inserm.fr.
Abstract
PURPOSE: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. METHODS: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. CONCLUSION: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
PURPOSE: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. METHODS: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. CONCLUSION: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Authors: Claire Guissart; Xenia Latypova; Paul Rollier; Tahir N Khan; Hannah Stamberger; Kirsty McWalter; Megan T Cho; Susanne Kjaergaard; Sarah Weckhuysen; Gaetan Lesca; Thomas Besnard; Katrin Õunap; Lynn Schema; Andreas G Chiocchetti; Marie McDonald; Julitta de Bellescize; Marie Vincent; Hilde Van Esch; Shannon Sattler; Irman Forghani; Isabelle Thiffault; Christine M Freitag; Deborah Sara Barbouth; Maxime Cadieux-Dion; Rebecca Willaert; Maria J Guillen Sacoto; Nicole P Safina; Christèle Dubourg; Lauren Grote; Wilfrid Carré; Carol Saunders; Sander Pajusalu; Emily Farrow; Anne Boland; Danielle Hays Karlowicz; Jean-François Deleuze; Monica H Wojcik; Rena Pressman; Bertrand Isidor; Annick Vogels; Wim Van Paesschen; Lihadh Al-Gazali; Aisha Mohamed Al Shamsi; Mireille Claustres; Aurora Pujol; Stephan J Sanders; François Rivier; Nicolas Leboucq; Benjamin Cogné; Souphatta Sasorith; Damien Sanlaville; Kyle Retterer; Sylvie Odent; Nicholas Katsanis; Stéphane Bézieau; Michel Koenig; Erica E Davis; Laurent Pasquier; Sébastien Küry Journal: Am J Hum Genet Date: 2018-04-12 Impact factor: 11.025
Authors: Claire Guissart; Alexander N Harrison; Mehdi Benkirane; Ibrahim Oncel; Elif Acar Arslan; Anna K Chassevent; Kristin Baraῆano; Lise Larrieu; Maria Iascone; Romano Tenconi; Mireille Claustres; Nesibe Eroglu-Ertugrul; Patrick Calvas; Haluk Topaloglu; Robert S Molday; Michel Koenig Journal: J Neurol Date: 2019-10-14 Impact factor: 4.849
Authors: C Marelli; S Badiou; S Genestet; L Larrieu; P Damier; W Camu; M Planes; M Koenig; C Guissart Journal: Neurol Sci Date: 2020-03-28 Impact factor: 3.307
Authors: Connie Marras; Anthony Lang; Bart P van de Warrenburg; Carolyn M Sue; Sarah J Tabrizi; Lars Bertram; Saadet Mercimek-Mahmutoglu; Darius Ebrahimi-Fakhari; Thomas T Warner; Alexandra Durr; Birgit Assmann; Katja Lohmann; Vladimir Kostic; Christine Klein Journal: Mov Disord Date: 2016-04 Impact factor: 10.338
Authors: Lorenzo Nanetti; Daniela Di Bella; Stefania Magri; Mario Fichera; Elisa Sarto; Anna Castaldo; Alessia Mongelli; Silvia Baratta; Silvia Fenu; Marco Moscatelli; Maria Teresa Bonati; Andrea Martinuzzi; Caterina Mariotti; Franco Taroni Journal: Front Neurol Date: 2022-01-06 Impact factor: 4.003