ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 23 citations in OpenAlex.
- Review
- Article
- AP4B1 hypomorphic variants cause autosomal recessive adult-onset ataxia.Journal of neurology · 2025Article
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- Compound Heterozygous WARS2 Variants Including a Hypomorphic Allele Cause a Milder Phenotype of Complex Dopa Responsive Dystonia: Case Report and Review of the Literature.Cerebellum (London, England) · 2024Review
- SpliceVarDB: A comprehensive database of experimentally validated human splicing variants.American journal of human genetics · 2024Article
- Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement.Protein & cell · 2024Article
- Genetic Testing of Movements Disorders: A Review of Clinical Utility.Tremor and other hyperkinetic movements (New York, N.Y.) · 2024Review
- ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization.Genome medicine · 2023Article
- PLP1 gene mutations cause spastic paraplegia type 2 in three families.Annals of clinical and translational neurology · 2023Article
- Genome sequencing with comprehensive variant calling identifies structural variants and repeat expansions in a large fraction of individuals with ataxia and/or neuromuscular disorders.Frontiers in neurology · 2023Article
- Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome.Journal of human genetics · 2022Article
- Splicing Interruption by Intron Variants inFrontiers in neuroscience · 2022Article
- Multifaceted and Age-Dependent Phenotypes Associated With BiallelicFrontiers in neurology · 2021Article
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Authors and funding
85 authors at 20 institutions in 3 countries.
Mehdi BenkiranePhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.ORCID http://orcid.org/0000-0001-6445-6347
Cecilia MarelliExpert 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.
Claire GuissartPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
Agathe RoubertieDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Elizabeth OllagnonDepartment of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.
Ariane ChoumertDepartment of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France.
Frédérique FluchèreDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Fabienne Ory MagneDepartment of Neurology, Purpan Hospital, CHU de Toulouse, Toulouse, France.
Yosra HallebPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
Mathilde RenaudDepartments of Genetics and of Neurology, CHU de Nancy, Nancy, France.
Lise LarrieuPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
David BauxPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
Olivier PatatDepartment of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.
Idriss BousquetDepartment of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.
Jean-Marie RavelDepartments of Genetics and of Neurology, CHU de Nancy, Nancy, France.
Danielle Cuntz-ShadfarDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Catherine SarretDepartment of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Xavier AyrignacDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Anne RollandDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Raoul MoralesDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Morgane PointauxPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
Cathy Lieutard-HaagPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
Brice LaurensDepartement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France.
Caroline TilliketeDepartment of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.
Emilien BernardDepartment of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.
Martial MallaretDepartment of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.
Clarisse Carra-DallièreDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Christine TranchantDepartment of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.
Pierre MeyerDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Lena DamajDepartment of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.
Laurent PasquierDepartment of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.
Cecile AcquavivaDepartment of Hereditary Metabolic Diseases, Centre de Biologie et Pathologie Est, CHU de Lyon et UMR, Bron, France.
Annabelle ChaussenotDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, CHU de Nice, Nice, France.
Bertrand IsidorDepartment of Medical Genetics, CHU de Nantes, Nantes, France.
Karine NguyenDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
William CamuDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Alexandre EusebioDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Nicolas CarrièreDepartment of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.
Audrey RiquetDepartment of Pediatrics Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.
Eric ThouvenotDepartment of Neurology, CHU de Nîmes, Nîmes, France.
Victoria GonzalesDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Emilie CarmeDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Shahram AttarianDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Sylvie OdentDepartment of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.
Anna CastriotoDepartment of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.
Claire EwenczykNeurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France.
Perrine CharlesNeurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France.
Laurent KremerDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Samira SissaouiDepartment of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Nadia Bahi-BuissonDepartment of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Elsa KaphanDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Adrian DegardinDepartment of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.
Bérénice DorayDepartment of Medical Genetics, CHU de la Réunion, Saint-Denis, France.
Sophie JuliaDepartment of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.
Ganaëlle RemerandDepartment of Neonatology, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Valerie FraixDepartment of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.
Lydia Abou HaidarDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Leila LazaroDepartment of Pediatrics, CH de la Côte Basque-Bayonne, Bayonne, France.
Vincent LaugelDepartment of Pediatrics, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.
Frederic VillegaDepartment of Pediatrics, Groupe Hospitalier Pellegrin, CHU de Bordeaux; Institute for Interdisciplinary Neurosciences (IINS), CNRS -UMR, Université de Bordeaux, Bordeaux, France.
Cyril CharlinDepartment of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France.
Solène FrismandDepartments of Genetics and of Neurology, CHU de Nancy, Nancy, France.
Marinha Costa MoreiraDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Tatiana WitjasDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Christine FrancannetDepartment of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
Ulrike Walther-LouvierDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Mélanie FradinDepartment of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.
Brigitte ChabrolDepartement of Pediatrics, La Timone Hospital, CHU de Marseille, Marseille, France.
Joel FlussPediatric Neurology Unit, Geneva Children's Hospital, Genève, Switzerland.
Eric BiethDepartment of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.
Giovanni CastelnovoDepartment of Neurology, CHU de Nîmes, Nîmes, France.
Sylvain VergnetDepartement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France.
Isabelle MeunierINSERM, Institut des Neurosciences de Montpellier, Montpellier, France.
Alain VerloesFederation of Genetics, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Elise Brischoux-BoucherDepartment of Medical Genetics, Hôpital Saint-Jacques, CHU de Besançon, Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
Christine CoubesDepartment of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France.
David GenevièveDepartment of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France.
Nicolas LeboucDepartment of Neuroradiology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Jean Phillipe AzulayDepartment of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.
Mathieu AnheimDepartment of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.
Cyril GoizetDepartment of Medical Genetics, Pellegrin Hospital, CHU de Bordeaux, Bordeaux, France.
François RivierDepartment of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Pierre LabaugeDepartment of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
Patrick CalvasDepartment of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.
Michel KoenigPhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France. michel.koenig@inserm.fr.
Centre Hospitalier Universitaire de Montpellier · FRCentre National de la Recherche Scientifique · FRHôpital de la Timone · FRCentre Hospitalier Universitaire de Toulouse · FRCentre Hospitalier Universitaire de Rennes · FRCentre Hospitalier Régional et Universitaire de Nancy · FRCentre Hospitalier Universitaire de Clermont-Ferrand · FRCentre Hospitalier Universitaire de Grenoble · FRCentre Hospitalier Universitaire de Lille · FRHôpitaux Universitaires de Strasbourg · FRInserm · FRCentre Hospitalier Universitaire de La Réunion · FRCentre Hospitalier Universitaire de Nîmes · FRHôpital de la Croix-Rousse · FRHôpital Necker-Enfants Malades · FRHospices Civils de Lyon · FRSorbonne Université · FRAssistance Publique – Hôpitaux de Paris · FRCentre Hospitalier de la Côte Basque · FRCentre Hospitalier Universitaire de Besançon · FR
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeDiagnosis 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.
methodsWe 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.
resultsWe 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.
conclusionA 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.
Indexed as
Cerebellar AtaxiaGenomicsCohort StudiesDNA Copy Number VariationsExome SequencingHumansPeroxinsReceptors, Cytoplasmic and NuclearUnited StatesPeroxinsPEX10 protein, humanReceptors, Cytoplasmic and Nuclear
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