title: Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.
abstract: We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: M-P
authors.initials: MP
authors.lastname: Dubé
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: G
authors.initials: G
authors.lastname: Asselin
authors.forename: S
authors.initials: S
authors.lastname: Blowers
authors.forename: S
authors.initials: S
authors.lastname: Evans
authors.forename: M
authors.initials: M
authors.lastname: Ferguson
authors.forename: C
authors.initials: C
authors.lastname: Macgillivray
authors.forename: M
authors.initials: M
authors.lastname: Matsuoka
authors.forename: M
authors.initials: M
authors.lastname: Nightingale
authors.forename: A
authors.initials: A
authors.lastname: Rideout
authors.forename: M
authors.initials: M
authors.lastname: Delatycki
authors.forename: A
authors.initials: A
authors.lastname: Orr
authors.forename: M
authors.initials: M
authors.lastname: Ludman
authors.forename: J
authors.initials: J
authors.lastname: Dooley
authors.forename: C
authors.initials: C
authors.lastname: Riddell
authors.forename: M E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000453:epidemiology / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human; D004247:DNA