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A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes

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Abstract

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50–60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.

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Acknowledgments

We thank the German Network of Hereditary Movement Disorders (GeNe Move) and the Agence National pour la Recherche for funding support, as well as Anna Sowa for language editing.

Ethical standards

The authors declare that the experiments comply with current laws in Germany.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Genetics, Eberhard-Karls-University, Tübingen, Germany

    Claudia Dufke, Nina Schlipf & Peter Bauer

  2. Department of Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany

    Rebecca Schüle, Andrea Seibel & Ludger Schöls

  3. Microarray Facility, Eberhard-Karls-University, Tübingen, Germany

    Michael Bonin & Sven Poths

  4. Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria

    Michaela Auer-Grumbach

  5. APHP, Department of Genetics and Cytogenetics, Pitié-Salpêtrière Hospital, 75013, Paris, France

    Giovanni Stevanin, Christel Depienne & Stephan Klebe

  6. Department of Neurology, University of Ulm, Ulm, Germany

    Jan Kassubek

  7. CR–ICM (INSERM/UPMC UMR 975, CNRS 7225), Pitié-Salpêtrière Hospital, 75013, Paris, France

    Giovanni Stevanin, Christel Depienne & Stephan Klebe

  8. Department of Neurology, Johannes-Gutenberg-University, Mainz, Germany

    Sven Klimpe

  9. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany

    Thomas Klopstock

  10. Department of Neurology, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany

    Susanne Otto

  11. Department of Neurology, Ev.-Luth. Diakonissenanstalt, Flensburg, Germany

    Henning Stolze

  12. Institute for Human Genetics, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Andreas Gal

  13. German Center of Neurodegenerative Diseases, Eberhard-Karls-University, Tübingen, Germany

    Ludger Schöls

  14. Department of Neurology, University Hospital of Würzburg, Würzburg, Germany

    Stephan Klebe

  15. Department of Medical Genetics, University of Tübingen, Calwerstrasse 7, 72076, Tübingen, Germany

    Peter Bauer

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  1. Claudia Dufke
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  2. Nina Schlipf
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  15. Henning Stolze
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  16. Andreas Gal
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Correspondence to Peter Bauer.

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Claudia Dufke and Nina Schlipf contributed equally to this work.

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Dufke, C., Schlipf, N., Schüle, R. et al. A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes. Neurogenetics 13, 215–227 (2012). https://doi.org/10.1007/s10048-012-0329-6

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