High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.

Autor: Benkirane M; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Marelli C; 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., Guissart C; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Roubertie A; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.; INSERM, Institut des Neurosciences de Montpellier, Montpellier, France., Ollagnon E; Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France., Choumert A; Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France., Fluchère F; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Magne FO; Department of Neurology, Purpan Hospital, CHU de Toulouse, Toulouse, France., Halleb Y; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Renaud M; Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France., Larrieu L; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Baux D; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Patat O; Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France., Bousquet I; Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France., Ravel JM; Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France., Cuntz-Shadfar D; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Sarret C; Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France., Ayrignac X; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Rolland A; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Morales R; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Pointaux M; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Lieutard-Haag C; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France., Laurens B; Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France., Tillikete C; Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France., Bernard E; Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.; Institut NeuroMyoGène, INSERM-CNRS-UMR, Université Claude Bernard, Lyon, France., Mallaret M; Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France., Carra-Dallière C; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Tranchant C; Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France., Meyer P; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.; PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France., Damaj L; Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France., Pasquier L; Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France., Acquaviva C; Department of Hereditary Metabolic Diseases, Centre de Biologie et Pathologie Est, CHU de Lyon et UMR, Bron, France., Chaussenot A; Department of Medical Genetics, National Centre for Mitochondrial Diseases, CHU de Nice, Nice, France., Isidor B; Department of Medical Genetics, CHU de Nantes, Nantes, France., Nguyen K; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Camu W; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Eusebio A; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Carrière N; Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France., Riquet A; Department of Pediatrics Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France., Thouvenot E; Department of Neurology, CHU de Nîmes, Nîmes, France., Gonzales V; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Carme E; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Attarian S; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Odent S; Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France., Castrioto A; Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France., Ewenczyk C; Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France., Charles P; Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France., Kremer L; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Sissaoui S; Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Bahi-Buisson N; Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Kaphan E; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Degardin A; Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France., Doray B; Department of Medical Genetics, CHU de la Réunion, Saint-Denis, France., Julia S; Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France., Remerand G; Department of Neonatology, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France., Fraix V; Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France., Haidar LA; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Lazaro L; Department of Pediatrics, CH de la Côte Basque-Bayonne, Bayonne, France., Laugel V; Department of Pediatrics, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France., Villega F; Department of Pediatrics, Groupe Hospitalier Pellegrin, CHU de Bordeaux; Institute for Interdisciplinary Neurosciences (IINS), CNRS -UMR, Université de Bordeaux, Bordeaux, France., Charlin C; Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France., Frismand S; Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France., Moreira MC; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Witjas T; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Francannet C; Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France., Walther-Louvier U; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Fradin M; Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France., Chabrol B; Departement of Pediatrics, La Timone Hospital, CHU de Marseille, Marseille, France., Fluss J; Pediatric Neurology Unit, Geneva Children's Hospital, Genève, Switzerland., Bieth E; Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France., Castelnovo G; Department of Neurology, CHU de Nîmes, Nîmes, France., Vergnet S; Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France., Meunier I; INSERM, Institut des Neurosciences de Montpellier, Montpellier, France.; Genetics of Sensory Diseases, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Verloes A; Federation of Genetics, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Brischoux-Boucher E; Department of Medical Genetics, Hôpital Saint-Jacques, CHU de Besançon, Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France., Coubes C; Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France., Geneviève D; Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France., Lebouc N; Department of Neuroradiology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Azulay JP; Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France., Anheim M; Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France., Goizet C; Department of Medical Genetics, Pellegrin Hospital, CHU de Bordeaux, Bordeaux, France., Rivier F; Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.; PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France., Labauge P; Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France., Calvas P; Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France., Koenig M; PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France. michel.koenig@inserm.fr.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Nov; Vol. 23 (11), pp. 2160-2170. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1038/s41436-021-01250-6
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
Databáze: MEDLINE
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