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Clinical Application of Whole-Exome Sequencing:  A Novel Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Sequence Variation in a Child With Ataxia

Wendy K. M. Liew, MBChB, MRCPCH; Tawfeg Ben-Omran, MD, FRCPC, FCCMG; Basil T. Darras, MD; Sanjay P. Prabhu, MBBS, MRCPCH, FRCR; Darryl C. De Vivo, MD; Matteo Vatta, PhD; Yaping Yang, PhD; Christine M. Eng, MD; Wendy K. Chung, MD, PhD
JAMA Neurol. 2013;70(6):788-791. doi:10.1001/jamaneurol.2013.247.
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Importance Ataxia in children is a diagnostic challenge. Besides the more common acquired causes of ataxia, there are more than 50 inherited disorders associated with ataxia. Our objective was to highlight whole-exome sequencing as a rapidly evolving clinical tool for diagnosis of mendelian disorders, and we illustrate this in the report of a single case of a novel sequence variation in the SACS gene.

Observations A 4-year-old girl presented with delayed gross motor development, ataxia, and polyneuropathy. Results of initial testing for the common causes of inherited and acquired ataxia were unrevealing. Whole-exome sequencing showed a novel frameshift homozygous sequence variation in the SACS gene, consistent with the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Conclusions Whole-exome sequencing is a powerful clinical tool that has been increasingly used to assist in the diagnosis of mendelian disorders. It provides a cost-effective, efficient, and expedited approach to making a clinical diagnosis and, in some cases, may be the only way to make a diagnosis.

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Figures

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Figure 1. Pedigree. The affected proband (P) is indicated by an arrow. The question mark indicates that the zygosity of the twins is unknown.

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Figure 2. Axial T2-weighted magnetic resonance image shows linear hypointensities (arrow) in the region of the pyramidal tract in the pons.

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Figure 3. Sagittal magnetization-prepared rapid acquisition gradient echo magnetic resonance image demonstrates mild cerebellar atrophy (arrow), predominantly of the superior vermis.

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Figure 4. Sanger confirmation of the sequence variation (arrows) with sequencing chromatograms.

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