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Late-Onset Sacsinopathy Diagnosed by Exome Sequencing and Comparative Genomic Hybridization

Lookup NU author(s): Dr Angela Pyle, Dr Helen GriffinORCiD, Dr Jennifer Duff, Shona Bennett, Dr Simon Zwolinski, Tania Smertenko, Dr Patrick Yu Wai Man, Dr Mauro Santibanez Koref, Professor Rita HorvathORCiD, Professor Patrick Chinnery


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The molecular diagnosis of adult-onset autosomal recessive cerebellar ataxias remains challenging because of genetic heterogeneity. However, recently developed molecular genetic techniques will potentially revolutionize the diagnostic approach. Here we set out to defi ne the genetic basis of the ataxia in two brothers with no molecular diagnosis. Clinical evaluation was followed by whole-exome second-generation sequencing and comparative genomic hybridization to determine the diagnosis. Whole-exome sequencing identifi ed a hemizygous novel spastic ataxia of Charlevoix-Saguenay (SACS) stop-codon mutation in both brothers (c.13048G -> T, p.E4350*) that was present in the mother, but not the father. Comparative genomic hybridization revealed a 0.7-Mb deletion on chromosome 13q12.12 in both brothers, which included SACS and was heterozygous in the asymptomatic father. The milder phenotype, caused by a whole-gene deletion and a stop-codon mutation in SACS, indicates a loss-of-function mechanism in late-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and illustrates the importance of chromosomal rearrangements in the investigation of adult-onset ataxia.

Publication metadata

Author(s): Pyle A, Griffin H, Duff J, Bennett S, Zwolinski S, Smertenko T, Yu-Wai-Man P, Santibanez-Koref M, Horvath R, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Journal of Neurogenetics

Year: 2013

Volume: 27

Issue: 4

Pages: 176-182

Print publication date: 01/12/2013

ISSN (print): 0167-7063

ISSN (electronic): 1563-5260

Publisher: Informa Healthcare


DOI: 10.3109/01677063.2013.831094


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Funder referenceFunder name
Association Franaise contre les Myopathies
European Research Council (ERC)
Newcastle University
Medical Research Council (UK) Centre for Translational Muscle Disease Research
NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
Wellcome Trust
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research
G1001799Medical Research Council
WT095219MAMedical Research Council