Thomas Wirth1, Christine Tranchant2, Nathalie Drouot3, Boris Keren4, Cyril Mignot5, Laura Cif6, Romain Lefaucheur7, Laurence Lion-François8, Aurélie Méneret9, Domitille Gras10, Emmanuel Roze9, Cécile Laroche11, Pierre Burbaud12, Stéphanie Bannier13, Ouhaid Lagha-Boukbiza14, Marie-Aude Spitz15, Vincent Laugel15, Matthieu Bereau16, Emmanuelle Ollivier17, Patrick Nitschke17, Diane Doummar18, Gabrielle Rudolf2, Mathieu Anheim2, Jamel Chelly19. 1. Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Unit of Functional Neurosurgery, National Hospital for Neurology and Neurosurgery, London, United Kingdom; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. Electronic address: thomas.wirth@etu.unistra.fr. 2. Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. 3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. 4. APHP, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Centre de Référence Déficience Intellectuelle de Causes Rares, GRC UPMC «Déficience Intellectuelle et Autisme», Paris, France. 5. APHP, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Centre de Référence Déficience Intellectuelle de Causes Rares, GRC UPMC «Déficience Intellectuelle et Autisme», Paris, France; Faculté de Médecine de Sorbonne Université, INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. 6. Département de Neurochirurgie, Centre Hospitalier Régional Montpellier, Montpellier, France. 7. Département de neurologie, Hôpitaux Universitaires de Rouen, Rouen, France. 8. Service de Neuropédiatrie, Hospices Civils de Lyon, Lyon, France. 9. Faculté de Médecine de Sorbonne Université, INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Paris, France. 10. Service de Neuropédiatrie, Hôpital Robert Debré, AP-HP, Paris, France. 11. Département de pédiatrie, hôpital mère enfant, Limoges, France. 12. CHU de Bordeaux, Service d'explorations Fonctionnelles du système nerveux, Bordeaux, France. 13. Service de neurologie, Centre hospitalier de la Côte Basque, Bayonne, France. 14. Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 15. Service de pédiatrie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 16. Service de Neurologie, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France. 17. Institut IMAGINE, IMAGINE Bioinformatics Platform, Université Paris Descartes, Paris, France. 18. Service de Neuropédiatrie, CHU Paris Est-Hôpital Armand-Trousseau, Paris, France. 19. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Abstract
INTRODUCTION: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing. MATERIAL AND METHODS: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature. RESULTS: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002). CONCLUSION: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.
INTRODUCTION: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonicpatients without diagnosis despite gene panel sequencing. MATERIAL AND METHODS: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature. RESULTS: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002). CONCLUSION: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.
Authors: Lazzaro di Biase; Alessandro Di Santo; Maria Letizia Caminiti; Pasquale Maria Pecoraro; Vincenzo Di Lazzaro Journal: Life (Basel) Date: 2022-01-29