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Open Access 01-12-2010 | Research article

Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis

Authors: Alessandra Ferlini, Matteo Bovolenta, Marcella Neri, Francesca Gualandi, Alessandra Balboni, Anton Yuryev, Fabrizio Salvi, Donato Gemmati, Alberto Liboni, Paolo Zamboni

Published in: BMC Medical Genetics | Issue 1/2010

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.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/11/64/prepub

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
Authors: Alessandra Ferlini
Matteo Bovolenta
Marcella Neri
Francesca Gualandi
Alessandra Balboni
Anton Yuryev
Fabrizio Salvi
Donato Gemmati
Alberto Liboni
Paolo Zamboni
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2010
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-11-64

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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