Novel SACS Mutations Identified by Whole Exome Sequencing in a Norwegian Family with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

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Abstract

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.Leu4451Pro; c.6890T>G, p.Leu2297Trp) for mutations in the SACS gene establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical features shown by our patients were typical of this disorder with the exception of epilepsy, which is a rare manifestation. This is the first report of ARSACS in Scandinavian patients and our findings expand the genetic and clinical spectrum of this rare disorder. Moreover, we show that exome sequencing is a powerful and cost-effective tool for the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

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Exome sequencing: dual role as a discovery and diagnostic tool.

Nasheen Naidoo, Richie Soong, Constantin Polychronakos … (2011)

Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies have now made exome sequencing a viable approach to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. In addition, exome sequencing is increasingly being employed as a diagnostic tool for specific genetic diseases, particularly in the context of those disorders characterized by significant genetic and phenotypic heterogeneity, for example, Charcot-Marie-Tooth disease and congenital disorders of glycosylation. Such disorders are challenging to interrogate with conventional polymerase chain reaction-Sanger sequencing methods, because of the inherent difficulty in prioritizing candidate genes for diagnostic testing. Here, we explore the value of exome sequencing as a diagnostic tool and discuss whether exome sequencing can come to serve a dual role in diagnosis and discovery. We summarize the current status of exome sequencing, the technical challenges facing it, and its adaptation to diagnostics, and make recommendations for the use of exome sequencing as a routine diagnostic tool. Finally, we discuss pertinent ethical concerns, such as the use of exome sequencing data, originally generated in a diagnostic context, in research investigations. Copyright © 2011 American Neurological Association.

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Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study.

C. M. E. Tallaksen, Anne Kjersti Erichsen, Asbjørg Stray-Pedersen … (2009)

A population-based, cross-sectional study was performed in southeast Norway, between January 2002 and February 2008, to identify subjects with hereditary ataxia and hereditary spastic paraplegia, and to estimate the prevalence of these disorders. Patients were recruited through colleagues, families, searches in computerized hospital archives and the National Patients' Association for Hereditary Ataxia and Spastic Paraplegia. Strict criteria were used for inclusion of familial and isolated subjects. A project neurologist examined all index subjects and clinical and genetic data were registered. The source population on January 1, 2008 was 2.63 million and the prevalence day was set as February 1, 2008. One hundred seventy-one subjects from 87 unrelated families with hereditary ataxia and 194 subjects from 65 unrelated families with hereditary spastic paraplegia were included. The total prevalence was estimated at 13.9/100 000. Hereditary ataxia prevalence in the region was estimated at 6.5/100 000: 4.2/100 000 for autosomal-dominant and 2.3/100 000 for autosomal recessive, 0.15/100 000 for Friedreich's ataxia and 0.4/100 000 for ataxia telangiectasia. Hereditary spastic paraplegia prevalence was 7.4/100 000: 5.5/100 000 for autosomal dominant-hereditary spastic paraplegia, 0.6/100 000 for autosomal recessive-hereditary spastic paraplegia and 1.3/100 000 for isolated subjects. Marked differences were found in the frequencies of hereditary ataxia subtypes compared with other countries, while those of the most common autosomal dominant-hereditary spastic paraplegia genotypes, SPG4, SPG3 and SPG31, were similar to those previously reported. Clear variations between age groups and counties were observed, but no gender differences. Mean age on prevalence day was 48 years, mean age at onset was 24 years. We present the largest population study performed on hereditary ataxia and hereditary spastic paraplegia prevalence and report a higher prevalence than expected. Better inclusion criteria and multiple search strategies may explain the observed differences.

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ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia

Sascha Vermeer, Rowdy P. P. Meijer, Benjamin Pijl … (2008)

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.

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Author and article information

Contributors

Mathias Toft: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 13 June 2013

Volume: 8

Issue: 6

Electronic Location Identifier: e66145

Affiliations

[1 ]Department of Neurology, Haukeland University Hospital, Bergen, Norway

[2 ]Department of Clinical Medicine, University of Bergen, Bergen, Norway

[3 ]Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

[4 ]Department of Biomedicine, University of Bergen, Bergen, Norway

[5 ]K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway

Oslo University Hospital, Norway

Author notes

* E-mail: laurence.bindoff@ 123456helse-bergen.no

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: CT SJ PK BIH HB LAB. Performed the experiments: SJ PK BIH HB. Analyzed the data: CT SJ PK BIH HB LAB. Contributed reagents/materials/analysis tools: SJ PK BIH HB. Wrote the paper: CT SJ PK BIH HB LAB.

Article

Publisher ID: PONE-D-13-04234

DOI: 10.1371/journal.pone.0066145

PMC ID: 3681964

PubMed ID: 23785480

SO-VID: f2d027a7-2cad-4f77-86fc-b6168ad7ff58

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 24 January 2013

Date accepted : 1 May 2013

Page count

Pages: 5

Funding

This work was supported by grants from the Western Norway Health Trust, University of Bergen. Western Norway Regional Health Authority (Helse Vest). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Novel SACS Mutations Identified by Whole Exome Sequencing in a Norwegian Family with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

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Most cited references 21

Exome sequencing: dual role as a discovery and diagnostic tool.

Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study.

ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia

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