Stéphanie Valence1,2,3,4, Emmanuelle Cochet2,5, Christelle Rougeot2,6, Catherine Garel2,3,7, Sandra Chantot-Bastaraud2,3,5, Elodie Lainey8,9, Alexandra Afenjar2,3,5, Marie-Anne Barthez10, Nathalie Bednarek11, Diane Doummar1,2,3, Laurence Faivre12,13,14, Cyril Goizet15,16, Damien Haye2,3,5, Bénédicte Heron1,2,3, Isabelle Kemlin1, Didier Lacombe15,16, Mathieu Milh17,18, Marie-Laure Moutard1,2,3, Florence Riant19, Stéphanie Robin20, Agathe Roubertie21,22, Pierre Sarda23, Annick Toutain24,25, Laurent Villard17,26, Dorothée Ville27, Thierry Billette de Villemeur1,2,3, Diana Rodriguez1,2,3,4, Lydie Burglen28,29,30,31. 1. APHP, GHUEP, Hôpital Armand Trousseau, Service de Neurologie Pédiatrique, Paris, France. 2. Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", Paris-Lyon-Lille, France. 3. Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, APHP, Hôpital Armand Trousseau, F-75012, Paris, France. 4. INSERM U1141, Université Paris Diderot, Paris, France. 5. APHP, GHUEP, Hôpital Armand Trousseau, Département de Génétique Médicale, Paris, France. 6. Département de Neurologie Pédiatrique et Centre de Référence Déficiences Intellectuelles, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Centre Hospitalier Universitaire de Lyon, Lyon, France. 7. APHP, GHUEP, Hôpital Armand Trousseau, Service de Radiologie Pédiatrique, Paris, France. 8. APHP, Hôpital Robert Debré, Service d'Hématologie Biologique, Paris, France. 9. Université Paris Diderot, UMRS_1131, Institut Universitaire d'Hématologie Paris, Paris, France. 10. Service de Neuropédiatrie et Handicaps, Hôpital Gatien de Clocheville, CHU Tours, France. 11. Service de Néonatologie, Institut Alix de Champagne, CHU Reims, Reims, France. 12. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon, France. 13. Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), Centre Hospitalier Universitaire de Dijon, Dijon, France. 14. INSERM UMR1231, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France. 15. Centre de référence Neurogénétique, Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. 16. Maladies Rares, Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux, Bordeaux, France. 17. Aix Marseille Univ, INSERM, UMR-S 1251, MMG, Marseille, France. 18. AP-HM, Département de Neurologie Pédiatrique, Hôpital de la Timone, Marseille, France. 19. AP-HP, Groupe Hospitalier Lariboisière-Fernand Widal, Laboratoire de Génétique, Paris, France. 20. Service de Pédiatrie, CHU de la Réunion - Hôpital Félix Guyon, Saint-Denis, France. 21. CHU Gui de Chauliac, Service de Neurologie Pédiatrique, Montpellier, France. 22. Institut des Neurosciences de Montpellier, INSERM U1051, Université de Montpellier, Montpellier, France. 23. Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France. 24. Centre Hospitalier Universitaire de Tours, Service de Génétique, Tours, France. 25. UMR 1253, iBrain, Université de Tours, Inserm, Tours, France. 26. AP-HM, Département de Génétique Médicale, Hôpital de la Timone, Marseille, France. 27. Département de Neurologie Pédiatrique et Centre de Référence des Epilepsies Rares, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Centre Hospitalier Universitaire de Lyon, Lyon, France. 28. Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", Paris-Lyon-Lille, France. lydie.burglen@aphp.fr. 29. Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, APHP, Hôpital Armand Trousseau, F-75012, Paris, France. lydie.burglen@aphp.fr. 30. INSERM U1141, Université Paris Diderot, Paris, France. lydie.burglen@aphp.fr. 31. APHP, GHUEP, Hôpital Armand Trousseau, Département de Génétique Médicale, Paris, France. lydie.burglen@aphp.fr.
Abstract
PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).
PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).
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