title: Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing.
abstract: Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.
authors: INSERM, U 1127, 75013, Paris, France. marie.coutelier@icm-institute.org.|CNRS, UMR 7225, 75013, Paris, France. marie.coutelier@icm-institute.org.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France. marie.coutelier@icm-institute.org.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France. marie.coutelier@icm-institute.org.|Ecole Pratique des Hautes Etudes, 75014, Paris, France. marie.coutelier@icm-institute.org.|Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium. marie.coutelier@icm-institute.org.
authors: Marie
authors: M
authors: Coutelier
authors: INSERM, U 1127, 75013, Paris, France.|CNRS, UMR 7225, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.|Ecole Pratique des Hautes Etudes, 75014, Paris, France.|APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié- Salpêtrière, 75013, Paris, France.
authors: Giovanni
authors: G
authors: Stevanin
authors: INSERM, U 1127, 75013, Paris, France. alexis.brice@upmc.fr.|CNRS, UMR 7225, 75013, Paris, France. alexis.brice@upmc.fr.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1127, 75013, Paris, France. alexis.brice@upmc.fr.|Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France. alexis.brice@upmc.fr.|APHP, Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié- Salpêtrière, 75013, Paris, France. alexis.brice@upmc.fr.
authors: Alexis
authors: A
authors: Brice
mesh_terms: D056726:Genetic Association Studies; D006801:Humans; D017422:Sequence Analysis, DNA; D020754:Spinocerebellar Ataxias / Q000235:genetics*
keywords: Genotype-phenotype delineation; Next generation sequencing; Novel genes; Pathways; Spinocerebellar ataxia