title: Identification of a VPS13A founder mutation in French Canadian families with chorea-acanthocytosis.
abstract: Mutations in VPS13A cause chorea-acanthocytosis (ChAc), an autosomal recessive neurodegenerative disorder. VPS13A is located in a tail-to-tail arrangement with GNA14 on chromosome 9q21. ChAc shows substantial allelic heterogeneity, with no single VPS13A mutation causing the majority of cases. We examined 11 patients in four French Canadian ChAc pedigrees for mutations in VPS13A. Affected members of three families were homozygous for a 37-kb deletion of the four terminal exons of VPS13A (EX70_EX73del). This deletion also encompasses the two terminal exons of GNA14. Two affected females in family 4 were homozygous for the splicing mutation 4242+1G>T. Remarkably, the affected males in this highly consanguineous pedigree were compound heterozygotes for EX70_EX73del and 4242+1G>T. PCR analysis of the deletion breakpoint junction revealed that an additional patient with French Canadian ancestry was heterozygous for the EX70_EX73del allele. The identification of a common 9q21 haplotype associated with EX70_EX73del in at least four apparently unrelated ChAc families implies that ChAc shows a founder effect in French Canadians, and that routine testing for EX70_EX73del in suspected ChAc cases may therefore be worthwhile in this population. The deletion breakpoint PCR described here will enable rapid identification of both homozygous and heterozygous carriers of EX70_EX73del.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Dobson-Stone
authors.forename: Antonio
authors.initials: A
authors.lastname: Velayos-Baeza
authors.forename: An
authors.initials: A
authors.lastname: Jansen
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.forename: François
authors.initials: F
authors.lastname: Dubeau
authors.forename: Francine
authors.initials: F
authors.lastname: Robert
authors.forename: Anne
authors.initials: A
authors.lastname: Summers
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chouinard
authors.forename: Adrian
authors.initials: A
authors.lastname: Danek
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Monaco
mesh_terms: D017668:Age of Onset; D001483:Base Sequence; D002170:Canada; D002819:Chorea / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D018703:Founder Effect; D005602:France / Q000208:ethnology; D006801:Humans; D007438:Introns; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins; D004247:DNA