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NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening

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Abstract

Niemann–Pick disease type C (NP-C) is a rare autosomal-recessive neurodegenerative disease featuring pleiotropic neurological, psychiatric and visceral manifestations. Since many of the adult manifestations can be non-specific or missed, NP-C often goes undetected in adult-onset patients. Here we hypothesized that targeted high-throughput sequencing allows identifying NP-C patients among subjects with unexplained early-onset ataxia (EOA) and, moreover, that this population is enriched for NPC1 mutations. From 204 consecutive EOA patients, all 108 subjects with an established diagnosis were removed (including 4 NPC1 patients), yielding a target cohort of 96 subjects with unexplained EOA, but without primary suspicion of NP-C. This cohort was investigated for NPC1/NPC2 mutations using a high-coverage HaloPlex gene panel including 122 ataxia genes. Among 96 samples, we identified 4 known NPC1 mutations, 3 novel NPC1 missense variants of uncertain significance (VUS) and 1 novel NPC2 missense VUS. The total mutant allele frequency (8/192 = 4.17 %) was significantly enriched compared with control population data (1.57 %; p = 0.011). Two NPC1-positive patients were identified (both with non-specific incipient clinical features), giving a NPC1 patient frequency of 2/96 = 2.1 % in unexplained EOA and of 6/204 = 2.9 % in the total EOA series. NPC1 mutations are substantially enriched in unexplained EOA, demonstrating EOA as a risk-group for NP-C disease. Targeted high-throughput sequencing allows to identify also those NP-C patients with non-specific conditions where the diagnosis has initially been missed. This method does not require having considered NP-C during differential diagnosis, but allows identification of NP-C as part of the default analysis.

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Abbreviations

cPEO:

Chronic external ophthalmoplegia

ESP:

Exome sequencing project

EVS:

Exome variant server

FTLD:

Frontotemporal lobar degeneration

MAF:

Minor allele frequency

NP-C:

Niemann pick type C

PD:

Parkinson’s disease

PSP:

Progressive supranuclear gaze palsy

VSGP:

Vertical supranuclear gaze palsy

VUS:

Variant of uncertain significance

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Acknowledgments

This study was supported by the Interdisciplinary Center for Clinical Research IZKF Tübingen (Grant 2191-0-0 to MS), the European Union (Grant F5-2012-305121 “NEUROMICS” to LS), and E-RARE grants of the German Ministry for Education and Research (BMBF) to the EUROSCAR project (grant 01GM1206) (to LS and PB). We are thankful to Professor Dr. Heiko Runz for his support on the updated Niemann–Pick type C disease variation database.

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    Authors and Affiliations

    1. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany

      Matthis Synofzik, Jennifer Müller vom Hagen & Ludger Schöls

    2. German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

      Matthis Synofzik, Jennifer Müller vom Hagen & Ludger Schöls

    3. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

      Florian Harmuth, Miriam Stampfer & Peter Bauer

    Authors
    1. Matthis Synofzik
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    2. Florian Harmuth
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    3. Miriam Stampfer
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    4. Jennifer Müller vom Hagen
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    5. Ludger Schöls
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    6. Peter Bauer
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    Correspondence to Matthis Synofzik.

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    Conflicts of interest

    M. Sy, M. St, J. MvH and P. B. have each received travel expenses and presentation honoraria from Actelion Pharmaceuticals Ltd. The preparation of this manuscript (but not the initiation and the performance of the study) was sponsored by Actelion Pharmaceuticals Ltd. Matthew Reilly Ph.D. at InTouch Medical Ltd provided medical writing support in the preparation of this manuscript, paid for by Actelion Pharmaceuticals.

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    M. Synofzik and F. Harmuth contributed equally to this work.

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    Synofzik, M., Harmuth, F., Stampfer, M. et al. NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening. J Neurol 262, 2557–2563 (2015). https://doi.org/10.1007/s00415-015-7889-y

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    • DOI: https://doi.org/10.1007/s00415-015-7889-y

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