title: Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis.
abstract: BACKGROUND
  Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance.
  
  
  METHODS
  In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999 bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate.
  
  
  RESULTS
  In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r = 0.6590, p = 0.0104; linear regression analysis r = 0.6577, p = 0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype.
  
  
  CONCLUSIONS
  The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.
authors.affiliation: Section of Medical Genetics, Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy. fla@unife.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
authors.forename: Matteo
authors.initials: M
authors.lastname: Bovolenta
authors.forename: Marcella
authors.initials: M
authors.lastname: Neri
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balboni
authors.forename: Anton
authors.initials: A
authors.lastname: Yuryev
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Salvi
authors.forename: Donato
authors.initials: D
authors.lastname: Gemmati
authors.forename: Alberto
authors.initials: A
authors.lastname: Liboni
authors.forename: Paolo
authors.initials: P
authors.lastname: Zamboni
mesh_terms: D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D055028:Comparative Genomic Hybridization; D005091:Exons / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007438:Introns / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D014680:Veins / Q000002:abnormalities*
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains