Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases

Objective: Genetic heterogeneity is common in many neurologic disorders. This is particularly true for the hereditary ataxias where at least 36 disease genes or loci have been described for spinocerebellar ataxia and over 100 genes for neurologic disorders that present primarily with ataxia. Traditional genetic testing of a large number of candidate genes delays diagnosis and is expensive. In contrast, recently developed genomic techniques, such as exome sequencing that targets only the coding portion of the genome, offer an alternative strategy to rapidly sequence all genes in a comprehensive manner. Here we describe the use of exome sequencing to investigate a large, 5-generational British kindred with an autosomal dominant, progressive cerebellar ataxia in which conventional genetic testing had not revealed a causal etiology. Methods: Twenty family members were seen and examined; 2 affected individuals were clinically investigated in detail without a genetic or acquired cause being identified. Exome sequencing was performed in one patient where coverage was comprehensive across the known ataxia genes, excluding the known repeat loci which should be examined using conventional analysis. Results: A novel p.Arg26Gly change in the PRKCG gene, mutated in SCA14, was identified. This variant was confirmed using Sanger sequencing and showed segregation with disease in the entire family. Conclusions: This work demonstrates the utility of exome sequencing to rapidly screen heterogeneous genetic disorders such as the ataxias. Exome sequencing is more comprehensive, faster, and significantly cheaper than conventional Sanger sequencing, and thus represents a superior diagnostic screening tool in clinical practice. Neurology (R) 2012;79:127-131