Laurence Gauquelin1,2, Taila Hartley3, Mark Tarnopolsky4, David A Dyment3, Bernard Brais5,6, Michael T Geraghty3, Martine Tétreault6,7, Sohnee Ahmed1, Samantha Rojas3, Karine Choquet5, Jacek Majewski6, François Bernier8, Allan Micheil Innes8, Guy Rouleau5, Oksana Suchowersky9, Kym M Boycott3, Grace Yoon1,2. 1. Division of Clinical and Metabolic Genetics, Department of Paediatrics The Hospital for Sick Children, University of Toronto Toronto Ontario Canada. 2. Division of Paediatric Neurology, Department of Paediatrics The Hospital for Sick Children, University of Toronto Toronto Ontario Canada. 3. Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada. 4. Department of Paediatrics McMaster University Medical Centre Hamilton Ontario Canada. 5. Department of Neurology and Neurosurgery McGill University, Montreal Neurological Institute Montreal Qubec Canada. 6. Department of Human Genetics McGill University Montreal Qubec Canada. 7. Department of Neuroscience Université de Montréal CHUM, Montreal Qubec Canada. 8. Department of Medical Genetics University of Calgary Calgary Alberta Canada. 9. Department of Medicine Division of Neurology, University of Alberta Edmonton Alberta Canada.
Abstract
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.
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.
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