Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes

M. Coutelier, M.B. Hammer, G. Stevanin, M.-L. Monin, C.-S. Davoine, F. Mochel, P. Labauge, C. Ewenczyk, J. Ding, J.R. Gibbs, D. Hannequin, J. Melki, A. Toutain, V. Laugel, S. Forlani, P. Charles, E. Broussolle, S. Thobois, A. Afenjar, M. AnheimP. Calvas, G. Castelnovo, T. De Broucker, M. Vidailhet, A. Moulignier, R.T. Ghnassia, C. Tallaksen, C. Mignot, C. Goizet, I. Le Ber, E. Ollagnon-Roman, J. Pouget, A. Brice, A. Singleton, A. Durr, S. Belarabi, A. Hamri, M. Tazir, S. Boesch, M. Pandolfo, U. Ullmann, L. Jardim, V. Guergueltcheva, I. Tournev, B.-W. Soong, O.L.P. Linarès, J.E. Nielsen, K. Svenstrup, M. Zaki, J.-P. Azulay, G. Banneau, O. Boesfplug-Tanguy, A. Burgo, C. Cazeneuve, F. Darios, C. Depienne, C. Duyckaerts, B. Fontaine, J. Hazan, M. Koenig, C. Marelli, K. N'guyen, D. Rodriguez, A. Sittler, C. Verny, P. Bauer, L. Schöls, R. Schüle, G. Koutsis, A. Lossos, A. Antenora, M.T. Bassi, M. Basso, E. Bertini, A. Brusco, C. Casali, G. Casari, C. Criscuolo, A. Filla, M. Lieto, L. Orsi, F.M. Santorelli, E.M. Valente, M. Vavla, G. Vazza, A. Megarbane, A. Benomar, R. Roxburgh, A.K. Erichsen, I. Alonso, P. Coutinho, J.L. Loureiro, J. Sequeiros, M. Salih, V.S. Kostic, I.R. Axpe, S. Roumani, B. Kremer, W. Van Roon-Mom, A. Boukhris, C. Mhiri, A. Karabay, S. Nethisinghe, C. Okane, M. Oliva, E. Reid, T. Warner, N. Wood, Spastic Paraplegia, Ataxia Network

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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. © 2018 American Medical Association. All rights reserved.
Original languageEnglish
Pages (from-to)591-599
Number of pages9
JournalJAMA Neurology
Issue number5
Publication statusPublished - 2018


  • adult
  • apraxia
  • Article
  • autosomal recessive disorder
  • CACNA1A gene
  • cerebellar ataxia
  • clinical effectiveness
  • cohort analysis
  • consanguinity
  • controlled study
  • diagnostic test
  • disease transmission
  • DNA determination
  • ERCC5 gene
  • exome
  • eye movement disorder
  • female
  • France
  • gene
  • gene frequency
  • gene identification
  • gene mutation
  • gene sequence
  • gene targeting
  • genetic association
  • genetic variability
  • genotype
  • heterozygote
  • human
  • KCND3 gene
  • major clinical study
  • male
  • molecular pathology
  • mutational analysis
  • onset age
  • pathogenicity
  • patient coding
  • phenotype
  • prevalence
  • priority journal
  • pyramidal sign
  • SETX gene
  • sex ratio
  • SPG7 gene
  • SYNE1 gene

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