title: Identification of a heterozygous genomic deletion in the spatacsin gene in SPG11 patients using high-resolution comparative genomic hybridization.
abstract: Mutations in the spatacsin gene have recently been identified as the genetic cause of autosomal-recessive spastic paraplegia (SPG) with thin corpus callosum, mapping to chromosome 15p13-21. While several nonsense and frameshift mutations as well as splice mutations have been identified, large genomic deletions have not yet been found, potentially due to the absence of an efficient analysis tool. After complete sequencing of 12 autosomal recessive hereditary spastic paraplegia patients with suggestive clinical signs, we were able to define nine SPG11 cases but were left with three patients in which only one SPG11 mutation could be identified by direct sequencing. In these patients, we performed high-resolution comparative genomic hybridization using a predesigned human chromosome 15 tiling array with an average spacing of 100 bp. Data analysis suggested heterozygous genomic deletion within the spatacsin gene in all three patients. In one patient, a relatively small genomic deletion (8.2 kb) could be validated by quantitative polymerase chain reaction (PCR) and long-range PCR, allowing the diagnosis of the deletion of exons 31 through 34. For two patients, quantitative PCR validation could not confirm a genomic deletion. As high density tiling arrays are available for the entire human genome, we suggest this approach for the screening of heterozygous genomic deletions in candidate genes down to a few kilobases.
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany. peter.bauer@med.uni-tuebingen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Claudia
authors.initials: C
authors.lastname: Bauer
authors.forename: Veronika
authors.initials: V
authors.lastname: Häfele
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Karle
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ringer
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
mesh_terms: D000293:Adolescent; D000328:Adult; D055028:Comparative Genomic Hybridization / Q000706:statistics & numerical data; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
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