A novel custom high density-comparative genomic hybridization array detects common rearrangements as well as deep intronic mutations in dystrophinopathies

Bovolenta, Matteo; Neri, Marcella; Fini, Sergio; Fabris, M.; Trabanelli, Cecilia; Venturoli, A.; Martoni, E.; Bassi, Elena; Spitali, Pietro; Brioschi, Simona; Falzarano, Maria Sofia; Rimessi, Paola; Ciccone, Roberto; Ashton, Emma; McCauley, Joanne; Yau, Shu; Abbs, Stephen; Muntoni, F.; Merlini, Luciano; Gualandi, Francesca; Ferlini, Alessandra

doi:10.1186/1471-2164-9-572

Cited by 70 publications

(69 citation statements)

References 26 publications

(23 reference statements)

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“…In conclusion, this large survey of 50 patients confirmed the previous observations [10][11][12][13] that array-CGH is a reliable and effective tool in detecting simple and complex DMD rearrangements. This approach offers some advantages over exon-based detection methods as it can identify pure intronic pathogenic events and it allows precise delineation of rearrangements, some of which may affect the splicing process.…”

Section: Discussionsupporting

confidence: 87%

Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene

et al. 2012

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We report on the effectiveness of a custom-designed oligonucleotide-based comparative genomic hybridization microarray (array-CGH) to interrogate copy number across the entire 2.2-Mb genomic region of the DMD gene and its applicability in diagnosis. The high-resolution array-CGH, we developed, successfully detected a series of 42 previously characterized large rearrangements of various size, localization and type (simple or complex deletions, duplications, triplications) and known intronic CNVs/Indels. Moreover, the technique succeeded in identifying a small duplication of only 191 bp in one patient previously negative for DMD mutation. Accurate intronic breakpoints localization by the technique enabled subsequent junction fragments identification by sequencing in 86% of cases (all deletion cases and 62.5% of duplication cases). Sequence examination of the junctions supports a role of microhomology-mediated processes in the occurrence of DMD large rearrangements. In addition, the precise knowledge of the sequence context at the breakpoints and analysis of the resulting consequences on maturation of pre-mRNA contribute to elucidating the cause of discrepancies in phenotype/genotype correlations in some patients. Thereby, the array-CGH proved to be a highly efficient and reliable diagnostic tool, and the new data it provides will have many potential implications in both, clinics and research.

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Section: Discussionsupporting

confidence: 87%

Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene

et al. 2012

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“…Intronic duplications potentially disrupting the splicing machinery have also been reported to be pathogenic. 27 In our study, we found de novo duplications in one s-JIA patient, which involve many important genes for the regulation of the immune system. Other patients without any pathological CNVs in this study may have point mutations of a gene(s) mapped to the duplications, which may lead to upregulated gene expression causative for s-JIA as previously described in a different disease.…”

Section: Discussionmentioning

confidence: 54%

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

et al. 2011

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Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed singlenucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

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“…[7][8][9]). This method uses thousands of oligonucleotides to interrogate copy number across the entire 2.2 MB genomic region of the DMD gene including all exons and introns, and thereby maps rearrangement breakpoints to relatively narrow intervals depending on the spacing of the oligonucleotides at the breakpoints.…”

Section: Testing For Deletions and Duplicationsmentioning

confidence: 99%

“…If a duplication of a single or multiple exons is identified it is important to test all exons for the possibility of additional exons being duplicated, since a number of apparently non-continuous duplications have been reported [9,10].…”

Section: Testing For Deletions and Duplicationsmentioning

confidence: 99%

Best Practice Guidelines on molecular diagnostics in Duchenne/Becker muscular dystrophies

Abbs

Tuffery‐Giraud

Bakker

et al. 2010

Neuromuscular Disorders

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A novel custom high density-comparative genomic hybridization array detects common rearrangements as well as deep intronic mutations in dystrophinopathies

Cited by 70 publications

References 26 publications

Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene

Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

Best Practice Guidelines on molecular diagnostics in Duchenne/Becker muscular dystrophies

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