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Exome Sequencing as a Diagnostic Tool for Pediatric‐Onset Ataxia

2013; Wiley; Volume: 35; Issue: 1 Linguagem: Inglês

10.1002/humu.22451

1098-1004

Sarah L. Sawyer, Jeremy Schwartzentruber, Chandree L. Beaulieu, David A. Dyment, Amanda Smith, Jodi Warman‐Chardon, Grace Yoon, Guy A. Rouleau, Oksana Suchowersky, Victoria Mok Siu, Lisa Murphy, Robert A. Hegele, Christian R. Marshall, Dennis E. Bulman, Jacek Majewski, Mark A. Tarnopolsky, Kym M. Boycott,

Mitochondrial Function and Pathology

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. 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 suggest 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.