Background: Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging.
Objectives: To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions.
Methods: A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada.
Results: A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses.
Conclusions: We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions.
Keywords: ataxia, cerebellar atrophy, channelopathies, exome sequencing.
© 2020 International Parkinson and Movement Disorder Society.