title: Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy.
abstract: BACKGROUND
  Multiple system atrophy (MSA) is a sporadic disease. Its pathogenesis may involve multiple genetic and nongenetic factors, but its etiology remains largely unknown. We hypothesized that the genome of a patient with MSA would demonstrate copy number variations (CNVs) in the genes or genomic regions of interest. To identify genomic alterations increasing the risk for MSA, we examined a pair of monozygotic (MZ) twins discordant for the MSA phenotype and 32 patients with MSA.
  
  
  RESULTS
  By whole-genome CNV analysis using a combination of CNV beadchip and comparative genomic hybridization (CGH)-based CNV microarrays followed by region-targeting, high-density, custom-made oligonucleotide tiling microarray analysis, we identified disease-specific copy number loss of the (Src homology 2 domain containing)-transforming protein 2 (SHC2) gene in the distal 350-kb subtelomeric region of 19p13.3 in the affected MZ twin and 10 of the 31 patients with MSA but not in 2 independent control populations (p = 1.04 × 10-8, odds ratio = 89.8, Pearson's chi-square test).
  
  
  CONCLUSIONS
  Copy number loss of SHC2 strongly indicates a causal link to MSA. CNV analysis of phenotypically discordant MZ twins is a powerful tool for identifying disease-predisposing loci. Our results would enable the identification of novel diagnostic measure, therapeutic targets and better understanding of the etiology of MSA.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. h-isasak@med.hokudai.ac.jp
authors.forename: Hidenao
authors.initials: H
authors.lastname: Sasaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iijima
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.forename: Hidenori
authors.initials: H
authors.lastname: Sato
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yabe
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
authors.forename: Jun
authors.initials: J
authors.lastname: Utsumi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D018628:Gene Dosage; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D055765:Shc Signaling Adaptor Proteins; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C099021:SHC2 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2