Exome sequencing potentially valuable in diagnosing familial cerebellar ataxias
1. Clinical exome sequencing (CES) is a method of analyzing the protein-encoding genes of an entire genome.
2. CES may be a high-yield diagnostic method for evaluating the presence of rare ataxia-causing mutations.
Evidence Rating Level: 3 (Average)
Study Rundown: A variety of pathologies may affect the cerebellum, a part of the brain essential for coordination and the phenomena of motor learning referred to colloquially as ‘muscle memory’. Because cerebellar ataxia (incoordination) syndromes are heterogeneous in their etiology, with presentations that often overlap, it is difficult to distinguish between these disorders based solely on their phenotype. This study sought to evaluate the utility of clinical exome sequencing (CES) as a method of whole genome analysis in the workup of cerebellar ataxias. CES is a method of scanning protein-encoding genes only, which are vastly outnumbered by non-protein encoding segments. Because CES sequences a fraction of the genes in a given genome, at locations that are most likely to produce disease when mutated, it is more cost-effective than other methods such as single-gene analysis.
Concerns in this study include most notably the technical limitations of CES as well as our incomplete knowledge of disease-causing mutations and the variability with which these disorders may present. However, this study does make a compelling argument for a role of this diagnostic modality in the workup of patients with cerebellar ataxias, after clinical evaluation and screening for highly prevalent repeat expansion disorders (SCA1, SCA2, SCA3, and Friedreich ataxia) that would not be detected on CES. What role CES will play, and in what patients, are questions that remain to be elucidated.
Click to read the study in JAMA Neurology
Relevant Reading: Genomic medicine enters the neurology clinic
In-Depth [case series]: At the UCLA Ataxia Center, a tertiary referral center, 76 patients were evaluated and subsequently included in the study analysis. Patients were classified based on which of three symptoms were most predominant: ataxia, spasticity, or Parkinsonism. Patients were also categorized based on age of onset and presence of family history. Patients were screened for acquired causes of ataxias well as the most common repeat expansion disorders, including spinocerebellar ataxias 1, 2, 3, 6, 7 and Friedreich ataxia (which represent 40-50% of genetic ataxias worldwide).
All patients received counseling both before and after exome sequencing. In 46 of the 76 patients studied, CES revealed clinically relevant genetic information, either suggesting a diagnosis or definitively identifying a causative mutation. In one case rapid identification of a causative mutation was valuable in initiating treatment. 16% of patients were found to have a pathogenic sequence variation explaining their disease, and 40% were found to have potentially pathogenic sequence variations that merited further follow-up. Pathogenic sequences were those that have been described in the literature as a disease mutation, or those that caused truncation of a protein generated from an established gene implicated in ataxia.
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