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

Abstract

Objective-The molecular diagnosis of adult-onset autosomal recessive cerebellar ataxias remains challenging because of genetic heterogeneity. However, recently developed molecular genetic techniques will potentially revolutionise the diagnostic approach. Here we set out to define the genetic basis of the ataxia in two brothers with no molecular diagnosis.Methods-Clinical evaluation followed by whole exome second generation sequencing and comparative genomic hybridisation.Results-Whole exome sequencing identified a hemizygous novel spastic ataxia of CharlevoixSaguenay (SACS) stop-codon mutation in both brothers (c.13048G>T, p.E4350X) which was present in the mother, but not the father. Comparative genomic hybridisation revealed a 0.7Mb deletion on chromosome 13q12.12 in both brothers, which included SACs and was heterozygous in the asymptomatic father.Conclusions-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.

Exome sequencing in undiagnosed inherited and sporadic ataxias

“…Confirmed pathogenic variants were found in 9/22 probands (41%) ( Table 1 and Supplementary Table 4 ). Three families had novel compound SACS mutations, each found in two affected siblings, including a full deletion of SACS detected from exome coverage ( Pyle et al , 2012 , 2013 ). Known compound heterozygous SPG7 mutations were found in three affected individuals from one family with no spasticity ( Casari et al , 1998 ).…”

“… s Segregation analysis performed in the family. Two have been reported previously ( Pyle et al , 2012 , 2013 ). …”

Abnormal retinal thickening is a common feature among patients with ARSACS-related phenotypes: Table 1

“…The molecular genetic characterisation of these four patients with next-generation whole exome sequencing has been previously reported 4 5. All the patients presented with progressive gait ataxia and they were severely disabled, requiring the use of a wheelchair for ambulation.…”

“…4 5 Topographic analysis of the optic disc was performed with the Spectralis optical coherence tomography (OCT) platform (Heidelberg Engineering, Heidelberg, Germany).…”

Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix‐Saguenay, ARSACS, in a Finnish family

“…The patients harboring two founder mutations identified in Quebec have manifested with the uniform presentation of unsteadiness and ataxia in early childhood, followed by spasticity during childhood and neuropathy during the teens [1][2][3]. In other populations with different pathogenic mutations, the phenotype is still quite constant, although occasional later onset and atypical forms have been identified [4][5][6][7][8][9]14]. The age of onset and the presenting symptoms as well as the rate of progression varied in our family.…”