NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening
- 407 Downloads
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.
KeywordsAtaxia Recessive ataxia Early onset ataxia Genetics Lysosomal storage diseases Prevalence
Chronic external ophthalmoplegia
Exome sequencing project
Exome variant server
Frontotemporal lobar degeneration
Minor allele frequency
Niemann pick type C
Progressive supranuclear gaze palsy
Vertical supranuclear gaze palsy
Variant of uncertain significance
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.
Compliance with ethical standards
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.
- 2.Bauer P, Balding DJ, Klunemann HH, Linden DE, Ory DS, Pineda M, Priller J, Sedel F, Muller A, Chadha-Boreham H, Welford RW, Strasser DS, Patterson MC (2013) Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study. Hum Mol Genet 22:4349–4356PubMedCentralCrossRefPubMedGoogle Scholar
- 6.Ottinger EA, Kao ML, Carrillo-Carrasco N, Yanjanin N, Shankar RK, Janssen M, Brewster M, Scott I, Xu X, Cradock J, Terse P, Dehdashti SJ, Marugan J, Zheng W, Portilla L, Hubbs A, Pavan WJ, Heiss J, HV C, Walkley SU, Ory DS, Silber SA, Porter FD, Austin CP, McKew JC (2014) Collaborative development of 2-hydroxypropyl-beta-cyclodextrin for the treatment of Niemann-Pick type C1 disease. Curr top Med Chem 14:330–339PubMedCentralCrossRefPubMedGoogle Scholar
- 9.Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, Hogervorst FB, Hoogerbrugge N, Spurdle AB, Tavtigian SV (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29:1282–1291PubMedCentralCrossRefPubMedGoogle Scholar
- 12.Synofzik M, Schöls L, Rieß O (2013) Hereditäre Ataxien. Aktuelle Übersicht und diagnostische Strategien Medizinische Genetik:235–248Google Scholar
- 15.Wassif CA, Cross JL, Iben J, Sanchez-Pulido L, Cougnoux A, Platt FM, Ory DS, Ponting CP, Bailey-Wilson JE, Biesecker LG, Porter FD (2015) High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet MedGoogle Scholar
- 17.Zech M, Nubling G, Castrop F, Jochim A, Schulte EC, Mollenhauer B, Lichtner P, Peters A, Gieger C, Marquardt T, Vanier MT, Latour P, Klunemann H, Trenkwalder C, Diehl-Schmid J, Perneczky R, Meitinger T, Oexle K, Haslinger B, Lorenzl S, Winkelmann J (2013) Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. PLoS One 8:e82879PubMedCentralCrossRefPubMedGoogle Scholar