title: SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.
abstract: Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.
authors.affiliation: Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.|Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Choquet
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.|McGill University and Genome Quebec Innovation Center, Montreal, Québec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Yang
authors.affiliation: Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
authors.forename: Roberta
authors.initials: R
authors.lastname: La Piana
authors.affiliation: Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dicaire
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Vanstone
authors.affiliation: Complexe Hospitalier de la Sagamie et Faculté de Médecine et des Sciences de la Santé de l'Université de Sherbrooke, Jonquière, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Mathieu
authors.affiliation: Hôpital Enfant-Jésus, CHU de Québec et Département des Sciences Neurologiques, Faculté de Médecine de l'Université Laval, Québec, Québec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke - Hôpital Fleurimont, Sherbrooke, Québec, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Rioux
authors.affiliation: Montreal Neurological Institute and Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.|McGill University and Genome Quebec Innovation Center, Montreal, Québec, Canada.
authors.forename: Jacek
authors.identifier: 0000-0003-3572-9558
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.|Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000328:Adult; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D009128:Muscle Spasticity / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015995:Prevalence; D011792:Quebec; D020754:Spinocerebellar Ataxias / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities