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Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2006 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, no 1, 28-38 p.Article in journal (Refereed) Published
Abstract [en]

Background: Segmental duplications flanking the neurofibromatosis type 1 ( NF1) genelocus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report theconstruction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11,using a non- redundant approach for array design. The average resolution of analysis for the array is similar to 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1gene. Methods: We performed a comprehensive array- CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in26 cases, whereas 13 samples showed atypical deletion profiles. Results: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of thedeletion. The deletions identified by array- CGH were independently confirmed using multiplex ligation- dependent probe amplification. Bioinformatic analysis of the entire locus identified 33segmental duplications. Conclusions: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.

Place, publisher, year, edition, pages
2006. Vol. 43, no 1, 28-38 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92897DOI: 10.1136/jmg.2005.033795ISI: 000234406700004OAI: oai:DiVA.org:uu-92897DiVA: diva2:166211
Available from: 2005-04-25 Created: 2005-04-25 Last updated: 2013-09-17Bibliographically approved
In thesis
1. Microarray-Based Comparative Genomic Hybridization in Neurofibromatoses and DiGeorge Syndrome
Open this publication in new window or tab >>Microarray-Based Comparative Genomic Hybridization in Neurofibromatoses and DiGeorge Syndrome
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Microarray-based comparative genomic hybridization (array-CGH) has emerged as a versatile platform with a wide range of applications in molecular genetics. This thesis focuses on the development of array-CGH with a specific aim to approach disease-related questions through improved strategies in array construction and enhanced resolution of analysis. In paper I, we applied an array covering 11 Mb of 22q, encompassing the NF2 locus, for deletion detection in sporadic schwannoma. Hemizygous deletions and tumor heterogeneity were identified. Array-CGH was established as a reliable platform for detection of DNA dosage alterations. Paper II described the construction of the NF2 gene-specific microarray for high-resolution scanning of deletions in the NF2 locus. We report a novel PCR-based non-redundant strategy for microarray fabrication, which considerably improved the sensitivity and reliability of deletion detection. Paper III reported the first tiling-path array comprehensively covering a human chromosome. The usefulness of the 22q-array was demonstrated by applying it to detect DNA dosage-alterations in 22q-associated disorders. In paper IV, we optimized array-CGH protocols for deletion detection in 22q11 deletion-syndrome. We showed that genomic and cDNA clones are not optimal for analysis of 22q11 locus and that PCR-based non-redundant strategy is reliable for deletion detection in such regions. In paper V, we utilized the 22q-array for understanding the genetic basis of schwannomatosis. Two commonly deleted regions were identified within the IGL and the GSTT1/CABIN1 loci. Further investigations using high-resolution arrays, bioinformatic analysis and mutational screening were performed. Missense mutations, specific to the schwannomatosis- and NF2 samples, were identified in the CABIN1 gene. Paper VI described the first array-CGH study for comprehensive and high-resolution profiling of deletions spanning the 17q11 locus. Both typical and atypical deletions were identified in NF1 samples. Bioinformatic analysis revealed novel segmental duplications, which can potentially mediate 17q11 deletions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 70 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 26
Genetics, array-CGH, neurofibromatoses, neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, DiGeorge syndrome, 22q11 syndrome, chromosome 22, genomic microarrays, DNA copy number, Genetik
National Category
Medical Genetics
urn:nbn:se:uu:diva-5743 (URN)91-554-6212-X (ISBN)
Public defence
2005-05-17, Rudbecksalen, Rudbeck laboratory, Uppsala University, Uppsala, 13:15
Available from: 2005-04-25 Created: 2005-04-25Bibliographically approved

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Thuresson, Ann-CharlotteDahl, NiklasDumanski, Jan P
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