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

Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, UK.
Neurology (Impact Factor: 8.29). 06/2012; 79(2):127-31. DOI: 10.1212/WNL.0b013e31825f048e
Source: PubMed


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.
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.
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.
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.

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    • "Some of these may be because a nongenetic cause of ataxia is responsible for the clinical presentation. Others may be due, in part, to the limitations of WES which can include poor coverage of certain regions, and an inability to detect noncoding mutations, trinucleotide repeats in known [Sailer et al., 2012] and unknown genes, and large chromosomal rearrangements. However, a significant factor is that there remain a large number of variants in novel genes in the unsolved families that cannot be further validated at this time given the limited size of the current cohort and may represent rare and new causes of ataxia. "
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    ABSTRACT: Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing (WES). We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggests that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative.
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    • "It is, however, increasingly being used as a diagnostic tool to replace Sanger sequencing on a gene-by-gene basis in disorders that display genetic heterogeneity. Exome sequencing allows rapid screening of a large number of candidate genes and at a cost which is no longer prohibitive, it may also be a cost effective diagnostic screening tool [4]. Our study confirms the potential of exome sequencing; however, it also highlights the difficulties associated with the finding of a novel mutation. "
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