Exome-Targeted Capture Sequencing Can Diagnose Previously-Undetected Ataxia

genetic code
genetic code
Exome capture with a targeted analysis may allow for a molecular level diagnosis in patients with cerebellar ataxia.

Exome-targeted capture sequencing followed by targeted analysis can be used for molecular diagnosis of cerebellar ataxia and other highly heterogeneous mendelian disorders, according to results published online in JAMA Neurology.

The exome-targeted capture sequencing identified mutations in a broad range of genes, even in participants who had previously undergone extensive screening.

The study included 319 participants with cerebellar ataxia without a history of dominant transmission. The researchers classified patients into 6 clinical groups. They used exome-targeted capture sequencing to identify variants of genes broadly linked to cerebellar ataxia. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations.

Based on the sequencing, the researchers found very probably or definite diagnoses for 22.6% of participants (n=72), and another 6% (n=19) had possibly pathogenic variants.

The researchers found that the most commonly mutated genes were SPG7 (n=14), SACS (n=8), SETX (n=7), SYNE1 (n=6), and CACNA1A (n=6). Participants with the highest diagnostic rate had autosomal-recessive cerebellar ataxia with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and had onset before 25 years of age (41 of 131 [31.3%]). Participants carrying KCND3 or ERCC5 variants had peculiar phenotypes.

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“Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and [allows] post hoc reanalysis of data as new genes are implicated in the disease,” the researchers wrote.


Marie Coutelier, MD, PhD, reports being the recipient of a fellowship from the Fond National de la Recherche Scientifique (aspirant FNRS). No other disclosures were reported.


Coutelier M, Hammer MB, Stevanin G, et al. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes [published online February 26, 2018]. JAMA Neurol. doi:10.1001/jamaneurol.2017.5121.