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

Cerebellar Ataxia Cohort Studies DNA Copy Number Variations / genetics Genomics Humans Peroxins Receptors, Cytoplasmic and Nuclear United States Exome Sequencing

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
11 2021
Historique:
received: 05 03 2021
accepted: 08 06 2021
revised: 08 06 2021
pubmed: 9 7 2021
medline: 12 11 2021
entrez: 8 7 2021
Statut: ppublish

Résumé

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. 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. 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. 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.

Identifiants

DOI: 10.1038/s41436-021-01250-6 PMID: 34234304
pubmed: 34234304
doi: 10.1038/s41436-021-01250-6
pii: S1098-3600(21)05176-5
doi:

Substances chimiques

PEX10 protein, human 0
Peroxins 0
Receptors, Cytoplasmic and Nuclear 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2160-2170

Informations de copyright

© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Références

Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366:636–646. https://doi.org/10.1056/NEJMra1006610 .
doi: 10.1056/NEJMra1006610 pubmed: 22335741
Synofzik M, Németh AH. Recessive ataxias. Handb Clin Neurol. 2018;155:73–89. https://doi.org/10.1016/B978-0-444-64189-2.00005-6 .
doi: 10.1016/B978-0-444-64189-2.00005-6 pubmed: 29891078
Sullivan R, Yau WY, O’Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266:533–544. https://doi.org/10.1007/s00415-018-9076-4 .
doi: 10.1007/s00415-018-9076-4 pubmed: 30284037
Marras C, et al. Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436–457. https://doi.org/10.1002/mds.26527 .
doi: 10.1002/mds.26527 pubmed: 27079681
Rossi M, et al. The genetic nomenclature of recessive cerebellar ataxias. Mov Disord. 2018;33:1056–1076. https://doi.org/10.1002/mds.27415 .
doi: 10.1002/mds.27415 pubmed: 29756227
Ayrignac X, et al. Two neurologic facets of CTLA4-related haploinsufficiency. Neurol Neuroimmunol neuroinflammation. 2020;7:1–6. https://doi.org/10.1212/NXI.0000000000000751 .
doi: 10.1212/NXI.0000000000000751
Marelli C, et al. Plasma oxysterols: Biomarkers for diagnosis and treatment in spastic paraplegia type 5. Brain. 2018;141:72–84. https://doi.org/10.1093/brain/awx297 .
doi: 10.1093/brain/awx297 pubmed: 29228183
Guissart C, et al. ATP8A2-related disorders as recessive cerebellar ataxia. J Neurol. 2020;267:203–213. https://doi.org/10.1007/s00415-019-09579-4 .
doi: 10.1007/s00415-019-09579-4 pubmed: 31612321
Marelli C, Hamel C, Quiles M, Carlander B. ACO2 mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia. Neurol Genet. 2018;0:2–5. https://doi.org/10.1212/NXG.0000000000000225 .
Roubertie A, et al. AP4 deficiency: a novel form of neurodegeneration with brain iron accumulation? Neurol Genet. 2018;4:1–6. https://doi.org/10.1212/NXG.0000000000000217 .
doi: 10.1212/NXG.0000000000000217
Marelli C, et al. Autosomal dominant SPG9: intrafamilial variability and onset during pregnancy. Neurol Sci. 2020;41(Jul):1931–1933. https://doi.org/10.1007/s10072-020-04341-5 .
doi: 10.1007/s10072-020-04341-5 pubmed: 32221810
Guissart C, et al. Dual molecular effects of dominant RORA mutations cause two variants of syndromic intellectual disability with either autism or cerebellar ataxia. Am J Hum Genet. 2018;102:744–759. https://doi.org/10.1016/j.ajhg.2018.02.021 .
doi: 10.1016/j.ajhg.2018.02.021 pubmed: 29656859 pmcid: 5986661
Marelli C, et al. Mini-exome coupled to read-depth based copy number variation analysis in patients with inherited ataxias. Hum Mutat. 2016;37:1340–1353. https://doi.org/10.1002/humu.23063 .
doi: 10.1002/humu.23063 pubmed: 27528516
Ravel J-M, Benkirane M, Calmels N, Marelli C, Ory-Magne F, Ewenczyk C. Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia. J Neurol. (in press).
Baux D, Van Goethem C, Ardouin O, Guignard T, Roux MKA. MobiDetails: online DNA variants interpretation. Eur J Hum Genet. 2020. https://doi.org/10.1038/s41431-020-00755-z .
Klebe S, et al. Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy. Brain. 2012;135:2980–2993. https://doi.org/10.1093/brain/aws240 .
doi: 10.1093/brain/aws240 pubmed: 23065789 pmcid: 3470714
Sánchez-Ferrero E, et al. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet. 2013;83:257–262. https://doi.org/10.1111/j.1399-0004.2012.01896.x .
doi: 10.1111/j.1399-0004.2012.01896.x pubmed: 22571692
Najmabadi H, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63. https://doi.org/10.1038/nature10423 .
doi: 10.1038/nature10423 pubmed: 21937992
Stevanin G. Mutation in the catalytic domain of protein kinase. Arch Neurol. 2004;61:1242–1248.
Navarro-Sastre A, et al. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe–S proteins. Am J Hum Genet. 2011;89:656–667. https://doi.org/10.1016/j.ajhg.2011.10.005 .
doi: 10.1016/j.ajhg.2011.10.005 pubmed: 22077971 pmcid: 3213398
Berg T, et al. Spectrum of mutations in a -mannosidosis. Am. J. Hum Genet. 1999;64:77–88.
Ogilvie I, Kennaway NG, Shoubridge EA. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest. 2005;115:2784–2792. https://doi.org/10.1172/JCI26020 .
doi: 10.1172/JCI26020 pubmed: 16200211 pmcid: 1236688
Hoefs SJ, et al. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009;30:728–736. https://doi.org/10.1002/humu.21037 .
doi: 10.1002/humu.21037
Ebberink MS, et al. A novel defect of peroxisome division due to a homozygous nonsense mutation in the PEX11β gene. J Med Genet. 2012;49:307–313. https://doi.org/10.1136/jmedgenet-2012-100778 .
doi: 10.1136/jmedgenet-2012-100778 pubmed: 22581968
Coutelier M, et al. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018;75:591–599. https://doi.org/10.1001/jamaneurol.2017.5121 .
doi: 10.1001/jamaneurol.2017.5121 pubmed: 29482223 pmcid: 5885259
Sun M, et al. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. Genet Med. 2019;21:195–206. https://doi.org/10.1038/s41436-018-0007-7 .
doi: 10.1038/s41436-018-0007-7 pubmed: 29915382
Fogel BL, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71:1237–1246. https://doi.org/10.1001/jamaneurol.2014.1944 .
doi: 10.1001/jamaneurol.2014.1944 pubmed: 25133958 pmcid: 4324730
Ngo KJ, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Hum Mutat. 2020;41:487–501. https://doi.org/10.1002/humu.23946 .
doi: 10.1002/humu.23946 pubmed: 31692161
Chemin J, et al. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain. 2018;141:1998–2013. https://doi.org/10.1093/brain/awy145 .
doi: 10.1093/brain/awy145 pubmed: 29878067
Coutelier M, et al. A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am J Hum Genet. 2015;97:726–737. https://doi.org/10.1016/j.ajhg.2015.09.007 .
doi: 10.1016/j.ajhg.2015.09.007 pubmed: 26456284 pmcid: 4667105
Ikeda Y, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006;38:184–190. https://doi.org/10.1038/ng1728 .
doi: 10.1038/ng1728 pubmed: 16429157
Lise S, et al. Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development. PLoS Genet. 2012;8:e1003074. https://doi.org/10.1371/journal.pgen.1003074 .
doi: 10.1371/journal.pgen.1003074 pubmed: 23236289 pmcid: 3516553
Lieto M, et al. The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families. Eur J Neurol. 2020;27:498–505. https://doi.org/10.1111/ene.14094 .
doi: 10.1111/ene.14094 pubmed: 31571321
Depondt C, et al. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations. Neurology. 2014;82:1749–1750. https://doi.org/10.1212/WNL.0000000000000416 .
Synofzik M, et al. Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts. Orphanet J Rare Dis. 2014;9:1–8. https://doi.org/10.1186/1750-1172-9-57 .
doi: 10.1186/1750-1172-9-57
Minnerop M et al. Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain. 2017;140:1561–1578. https://doi.org/10.1093/brain/awx095 .
Paolacci S et al. Specific combinations of biallelic POLR3A variants cause Wiedemann–Rautenstrauch syndrome. J Med Genet. 2018;55:1–10. https://doi.org/10.1136/jmedgenet-2018-105528 .
Coppieters F, Lefever S, Leroy BP, De Baere E. CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Hum Mutat. 2010;31:1097–1108. https://doi.org/10.1002/humu.21337 .
Frank V, et al. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat. 2008;29:45–52. https://doi.org/10.1002/humu.20614 .
doi: 10.1002/humu.20614 pubmed: 17705300
Régal L, et al. Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol. 2010;68:259–263. https://doi.org/10.1002/ana.22035 .
doi: 10.1002/ana.22035 pubmed: 20695019
Yamashita T, et al. Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype. J Neurol Sci. 2017;375:424–429. https://doi.org/10.1016/j.jns.2017.02.058 .
doi: 10.1016/j.jns.2017.02.058 pubmed: 28320181
Yoo DH, et al. Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome. Mitochondrion. 2017;35:54–58. https://doi.org/10.1016/j.mito.2017.05.005 .
doi: 10.1016/j.mito.2017.05.005 pubmed: 28499982
Ghezzi D, et al. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome C oxidase deficiency. Am J Hum Genet. 2008;83:415–423. https://doi.org/10.1016/j.ajhg.2008.08.009 .
doi: 10.1016/j.ajhg.2008.08.009 pubmed: 18771761 pmcid: 2556431
Wei X, et al. Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency. Hum Mutat. 2020;41:961–972. https://doi.org/10.1002/humu.23985 .
doi: 10.1002/humu.23985 pubmed: 31944455
Popow J, Alleaume AM, Curk T, Schwarzl T, Sauer S, Hentze MW. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. RNA. 2015;21:1873–1884. https://doi.org/10.1261/rna.052365.115 .
doi: 10.1261/rna.052365.115 pubmed: 26370583 pmcid: 4604428

Auteurs

Mehdi Benkirane (M)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
ORCID: 0000-0001-6445-6347

Cecilia 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.

Claire Guissart (C)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

Agathe Roubertie (A)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
INSERM, Institut des Neurosciences de Montpellier, Montpellier, France.

Elizabeth Ollagnon (E)

Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.

Ariane Choumert (A)

Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France.

Frédérique Fluchère (F)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Fabienne Ory Magne (FO)

Department of Neurology, Purpan Hospital, CHU de Toulouse, Toulouse, France.

Yosra Halleb (Y)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

Mathilde Renaud (M)

Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France.

Lise Larrieu (L)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

David Baux (D)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

Olivier Patat (O)

Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.

Idriss Bousquet (I)

Department of Medical Genetics and Reference Centre for Neurological and Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.

Jean-Marie Ravel (JM)

Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France.

Danielle Cuntz-Shadfar (D)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Catherine Sarret (C)

Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.

Xavier Ayrignac (X)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Anne Rolland (A)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Raoul Morales (R)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Morgane Pointaux (M)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

Cathy Lieutard-Haag (C)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.

Brice Laurens (B)

Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France.

Caroline Tillikete (C)

Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France.

Emilien 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.

Martial Mallaret (M)

Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.

Clarisse Carra-Dallière (C)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Christine Tranchant (C)

Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.

Pierre Meyer (P)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France.

Lena Damaj (L)

Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.

Laurent Pasquier (L)

Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.

Cecile Acquaviva (C)

Department of Hereditary Metabolic Diseases, Centre de Biologie et Pathologie Est, CHU de Lyon et UMR, Bron, France.

Annabelle Chaussenot (A)

Department of Medical Genetics, National Centre for Mitochondrial Diseases, CHU de Nice, Nice, France.

Bertrand Isidor (B)

Department of Medical Genetics, CHU de Nantes, Nantes, France.

Karine Nguyen (K)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

William Camu (W)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Alexandre Eusebio (A)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Nicolas Carrière (N)

Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.

Audrey Riquet (A)

Department of Pediatrics Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.

Eric Thouvenot (E)

Department of Neurology, CHU de Nîmes, Nîmes, France.

Victoria Gonzales (V)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Emilie Carme (E)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Shahram Attarian (S)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Sylvie Odent (S)

Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.

Anna Castrioto (A)

Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.

Claire Ewenczyk (C)

Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France.

Perrine Charles (P)

Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris (AP-HP), Paris, France.

Laurent Kremer (L)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Samira Sissaoui (S)

Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Nadia Bahi-Buisson (N)

Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Elsa Kaphan (E)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Adrian Degardin (A)

Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille, France.

Bérénice Doray (B)

Department of Medical Genetics, CHU de la Réunion, Saint-Denis, France.

Sophie Julia (S)

Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.

Ganaëlle Remerand (G)

Department of Neonatology, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.

Valerie Fraix (V)

Department of Functional Explorations of the Nervous System, CHU de Grenoble, Grenoble, France.

Lydia Abou Haidar (LA)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Leila Lazaro (L)

Department of Pediatrics, CH de la Côte Basque-Bayonne, Bayonne, France.

Vincent Laugel (V)

Department of Pediatrics, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.

Frederic Villega (F)

Department of Pediatrics, Groupe Hospitalier Pellegrin, CHU de Bordeaux; Institute for Interdisciplinary Neurosciences (IINS), CNRS -UMR, Université de Bordeaux, Bordeaux, France.

Cyril Charlin (C)

Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre, France.

Solène Frismand (S)

Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France.

Marinha Costa Moreira (MC)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Tatiana Witjas (T)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Christine Francannet (C)

Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France.

Ulrike Walther-Louvier (U)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Mélanie Fradin (M)

Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies du Développement, CHU de Rennes, Rennes, France.

Brigitte Chabrol (B)

Departement of Pediatrics, La Timone Hospital, CHU de Marseille, Marseille, France.

Joel Fluss (J)

Pediatric Neurology Unit, Geneva Children's Hospital, Genève, Switzerland.

Eric Bieth (E)

Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.

Giovanni Castelnovo (G)

Department of Neurology, CHU de Nîmes, Nîmes, France.

Sylvain Vergnet (S)

Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux, Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux, Bordeaux, France.

Isabelle Meunier (I)

INSERM, Institut des Neurosciences de Montpellier, Montpellier, France.
Genetics of Sensory Diseases, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Alain Verloes (A)

Federation of Genetics, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Elise Brischoux-Boucher (E)

Department of Medical Genetics, Hôpital Saint-Jacques, CHU de Besançon, Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.

Christine Coubes (C)

Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France.

David Geneviève (D)

Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France.

Nicolas Lebouc (N)

Department of Neuroradiology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Jean Phillipe Azulay (JP)

Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille, France.

Mathieu Anheim (M)

Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg, France.

Cyril Goizet (C)

Department of Medical Genetics, Pellegrin Hospital, CHU de Bordeaux, Bordeaux, France.

François Rivier (F)

Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.
PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France.

Pierre Labauge (P)

Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier, Montpellier, France.

Patrick Calvas (P)

Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, France.

Michel Koenig (M)

PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université de Montpellier, INSERM, CHU de Montpellier, Montpellier, France. michel.koenig@inserm.fr.

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Classifications MeSH

questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Dyskinésies › Ataxie › Ataxie cérébelleuse › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Péroxines › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Régions géographiques › Amériques › Amérique du Nord › États-Unis › High rate of hypomorphic variants as the cause...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › High rate of hypomorphic variants as the cause...