Vergult Sarah, Van Binsbergen Ellen, Sante Tom, Nowak Silke, Vanakker Olivier, Claes Kathleen, Poppe Bruce, Van der Aa Nathalie, van Roosmalen Markus J, Duran Karen, Tavakoli-Yaraki Masoumeh, Swinkels Marielle, van den Boogaard Marie-José, van Haelst Mieke, Roelens Filip, Speleman Frank, Cuppen Edwin, Mortier Geert, Kloosterman Wigard P, Menten Björn
Center for Medical Genetics, Ghent University, Ghent, Belgium.
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Eur J Hum Genet. 2014 May;22(5):652-9. doi: 10.1038/ejhg.2013.220. Epub 2013 Oct 9.
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.
最近，在许多实验室中，微阵列已取代核型分析，成为对患有特发性智力残疾和/或多种先天性异常（ID/MCA）患者进行的一级检测。尽管在约14%-18%的此类患者中可检测到具有临床意义的DNA拷贝数变异（CNV），但微阵列的缺点是会遗漏平衡重排，并且无法提供有关重复和复杂重排等结构变异（SV）的基因组结构信息。此类信息可能有助于更好地解读SV的临床意义。在本研究中，对配对末端新一代测序在50例ID/MCA患者基因组中结构变异的检测及进一步特征分析方面的临床应用进行了评估。其中30例患者携带先前通过阵列比较基因组杂交（array CGH）或核型分析检测到的染色体畸变，且怀疑具有致病性。在其余20例患者中未发现致病的SV，通过传统技术仅检测到良性畸变。对配对末端数据进行聚类和覆盖分析相结合，可实现精确的断点检测，并进一步细化先前鉴定出的平衡和（复杂）不平衡畸变，为部分患者确定致病基因。我们得出结论，配对末端测序是一项强大的技术，可对患者基因组中的不平衡和平衡SV进行快速且明确的特征分析，对于某些SV的临床解读至关重要。
