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Fast and reliable detection of repeat expansions in spinocerebellar ataxia using exomes
  1. Jean-Loup Méreaux1,
  2. Claire-Sophie Davoine1,
  3. Marie Coutelier1,
  4. Léna Guillot-Noël1,
  5. Anna Castrioto2,
  6. Perrine Charles3,
  7. Giulia Coarelli1,
  8. Claire Ewenczyk1,
  9. Stephan Klebe4,
  10. Anna Heinzmann1,
  11. Aurélie Méneret5,
  12. Anne-Laure Fauret-Amsellem6,
  13. Jean-Madeleine de Sainte Agathe6,
  14. Alexis Brice1,
  15. Alexandra Durr1
  1. 1 Sorbonne University, Paris Brain Institute (ICM - Institut du Cerveau), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
  2. 2 Department of Neurology, University Hospital Centre Grenoble Alpes, Grenoble, France
  3. 3 Genetics Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
  4. 4 Department of Neurology, University Hospital Essen, Essen, Germany
  5. 5 Neurology Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
  6. 6 Molecular and Cellular Neurogenetics Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
  1. Correspondence to Professor Alexandra Durr, Sorbonne Université, Paris 75013, France; alexandra.durr{at}


Usually, molecular diagnosis of spinocerebellar ataxia is based on a step-by-step approach with targeted sizing of four repeat expansions accounting for most dominant cases, then targeted sequencing of other genes. Nowadays, genome sequencing allows detection of most pathogenic variants in a single step. The ExpansionHunter tool can detect expansions in short-read genome sequencing data. Recent studies have shown that ExpansionHunter can also be used to identify repeat expansions in exome sequencing data. We tested ExpansionHunter on spinocerebellar ataxia exomes in a research context as a second-line analysis, after exclusion of main CAG repeat expansions in half of the probands. First, we confirmed the detection of expansions in seven known expansion carriers and then, after targeted analysis of ATXN1, 2, 3 and 7, CACNA1A, TBP, ATN1, NOP56, AR and HTT in 498 exomes, we found 22 additional pathogenic expansions. Comparison with capillary migration sizing in 247 individuals and confirmation of all expanded alleles detected by ExpansionHunter demonstrated that for these loci, sensitivity and specificity reached 100%. ExpansionHunter detected but underestimated the repeat size for larger expansions, and the normal alleles distribution at each locus should be taken into account to detect expansions. Exome combined with ExpansionHunter is reliable to detect repeat expansions in selected loci as first-line analysis in spinocerebellar ataxia.

  • Genetics
  • Neurodegenerative Diseases
  • High-Throughput Nucleotide Sequencing
  • Molecular Diagnostic Techniques

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  • Contributors J-LM designed experiments, analysed the data and wrote the manuscript; C-SD and LG-N contributed to exome analysis and provided feedback on the report. MC helped with the analysis and interpretation. AC, PC, GC, CE, SK, AH and AM contributed to clinical details. A-LF-A and J-MdSA provided technical guidance. AB and AD designed the study, provided access to cohorts, wrote the manuscript and provided financial support. All authors reviewed and approved the manuscript.

  • Funding Fondation pour la Recherche Médicale (FRM, France).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.