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Original Investigation
February 26, 2018

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes

Author Affiliations
  • 1Institut National de la Santé et de la Recherche Medicale (INSERM) U1127, Paris, France
  • 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 7225, Paris, France
  • 3Unité Mixte de Recherche en Santé 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, Paris, France
  • 4Institut du Cerveau et de la Moelle Epinière, Paris, France
  • 5Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
  • 6Ecole Pratique des Hautes Etudes, Paris Sciences et Lettres Research University, Paris, France
  • 7Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 8Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
  • 9Service de Neurologie, Hopital Gui de Chauliac, Centre Hospitalier Universitaire (CHU) de Montpellier, Montpellier, France
  • 10Service de Génétique, Service de Neurologie, INSERM U1079, Rouen University Hospital, Rouen, France
  • 11UMR 1169, INSERM and University Paris Saclay, Le Kremlin Bicêtre, France
  • 12Medical Genetics Unit, Centre Hospitalier Sud-Francilien, Corbeil Essonnes, France
  • 13Service de Génétique, Centre Hospitalier Universitaire de Tours, INSERM U930, Faculté de Médecine, Université François Rabelais, Tours, France
  • 14Service de Pédiatrie 1, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  • 15Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
  • 16Service de Neurologie C, Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon, Bron, France
  • 17Centre de Neurosciences Cognitives, Centre National de la Recherche Scientifique (CNRS)–UMR 5229, Bron, France
  • 18Université de Lyon, Université Claude-Bernard-Lyon I, Villeurbanne, France
  • 19Service de Génétique et Centre de Référence Pour les Malformations et les Maladies Congénitales du Cervelet, AP-HP, Paris, France
  • 20Département de Neurologie, Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France
  • 21Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964, CNRS-UMR 7104, Université de Strasbourg, Illkirch, France
  • 22Service de Génétique Médicale, CHU de Toulouse, Hôpital Purpan, Toulouse, France
  • 23Service de Neurologie, CHU Caremeau, Nîmes, France
  • 24Service de Neurologie, Centre Hospitalier de Saint-Denis, Saint-Denis, France
  • 25Département des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
  • 26Service de Neurologie, Fondation Ophtalmologique A. de Rothschild, Paris, France
  • 27private practice, Chelles, France
  • 28currently affiliated with Department of Neurology, Oslo University Hospital; and Faculty of Medicine, Oslo University, Oslo, Norway
  • 29Département de Génétique and Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France
  • 30Laboratoire Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
  • 31Service de Génétique Médicale, CHU Pellegrin, Bordeaux, France
  • 32Service de Neurogénétique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
  • 33Centre de Référence des Maladies Neuromusculaires et de la Sclérose Latérale Amyotrophique, Assistance Publique–Hôpitaux de Marseille, Aix Marseille Université, Hôpital de La Timone, Marseille, France
JAMA Neurol. Published online February 26, 2018. doi:10.1001/jamaneurol.2017.5121
Key Points

Questions  Is exome-targeted capture sequencing able to detect mutations in genes broadly linked to ataxia, and what is the prevalence of such mutations in a large cohort of undiagnosed patients with various phenotypic presentations?

Findings  This cohort study of 319 patients with undiagnosed cerebellar ataxia used a sequencing approach that allowed the identification of genetically relevant variants in known genes in 91 (28.5%). This approach had the highest success rate for patients with spastic ataxia or a cerebellar ataxia with oculomotor apraxia–like phenotype; SPG7, SACS, SETX, SYNE1, and CACNA1A were the most frequently mutated genes.

Meaning  Mutations were identified in a broad range of genes implicated in ataxia and related neurologic diseases, even in cohorts that underwent previous extensive screening.


Importance  Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion.

Objectives  To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence.

Design, Setting, and Participants  Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations.

Main Outcomes and Measures  Identification of variants in genes broadly linked to CA, classified in pathogenicity groups.

Results  The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia–like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants.

Conclusions and Relevance  Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.