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Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations

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Abstract
Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.
Keywords
mate pair sequencing, intellectual disability, array CGH, structural variation, COPY NUMBER VARIATION, DE-NOVO MUTATIONS, STRUCTURAL VARIATION, MENTAL-RETARDATION, HUMAN GENOME, DEVELOPMENTAL DELAY, GENETIC-DISEASE, REARRANGEMENTS, DIAGNOSTICS, CHROMOTHRIPSIS

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Chicago
Vergult, Sarah, Ellen Van Binsbergen, Tom Sante, Silke Nowak, Olivier Vanakker, Kathleen Claes, Bruce Poppe, et al. 2014. “Mate Pair Sequencing for the Detection of Chromosomal Aberrations in Patients with Intellectual Disability and Congenital Malformations.” European Journal of Human Genetics 22 (5): 652–659.
APA
Vergult, S., Van Binsbergen, E., Sante, T., Nowak, S., Vanakker, O., Claes, K., Poppe, B., et al. (2014). Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations. EUROPEAN JOURNAL OF HUMAN GENETICS, 22(5), 652–659.
Vancouver
1.
Vergult S, Van Binsbergen E, Sante T, Nowak S, Vanakker O, Claes K, et al. Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations. EUROPEAN JOURNAL OF HUMAN GENETICS. 2014;22(5):652–9.
MLA
Vergult, Sarah, Ellen Van Binsbergen, Tom Sante, et al. “Mate Pair Sequencing for the Detection of Chromosomal Aberrations in Patients with Intellectual Disability and Congenital Malformations.” EUROPEAN JOURNAL OF HUMAN GENETICS 22.5 (2014): 652–659. Print.
@article{4180284,
  abstract     = {Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18\% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.},
  author       = {Vergult, Sarah and Van Binsbergen, Ellen and Sante, Tom and Nowak, Silke and Vanakker, Olivier and Claes, Kathleen and Poppe, Bruce and Van der Aa, Nathalie and van Roosmalen, Markus J and Duran, Karen and Tavakoli-Yaraki, Masoumeh and Swinkels, Marielle and van den Boogaard, Marie-Jos{\'e} and van Haelst, Mieke and Roelens, Filip and Speleman, Franki and Cuppen, Edwin and Mortier, Geert and Kloosterman, Wigard P and Menten, Bj{\"o}rn},
  issn         = {1018-4813},
  journal      = {EUROPEAN JOURNAL OF HUMAN GENETICS},
  language     = {eng},
  number       = {5},
  pages        = {652--659},
  title        = {Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations},
  url          = {http://dx.doi.org/10.1038/ejhg.2013.220},
  volume       = {22},
  year         = {2014},
}

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