Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
Laboratory of Medical Genetics, Cytogenetics Unit, Department of Pediatrics, University General Hospital of Patras, Patras, Greece.
Eur J Hum Genet. 2014 Mar;22(3):338-43. doi: 10.1038/ejhg.2013.147. Epub 2013 Jul 17.
Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.
下一代 Mate-Pair 测序（MPS）已经揭示，许多结构复杂的染色体重排（CCRs）与染色体区域的局部破碎（chromothripsis）有关。尽管 MPS 有望确定与许多 CCR 相关的异常表型的分子基础，但报告的 Mate-Pair 测序复杂重排中，没有一个同时用最先进的分子细胞遗传学技术进行了研究。在这里，我们研究了涉及染色体 2、5 和 7 的与全面发育和运动延迟以及严重言语障碍相关的 chromothripsis 相关的 CCR。我们鉴定了三个截断基因：CDH12、DGKB 和 FOXP2，证实了 FOXP2 在严重言语障碍中的作用，以及 CDH12 和/或 DGKB 对全面发育和运动延迟的提示作用。我们的研究证实了 MPS 在接近核苷酸分辨率检测 chromothripsis 中的断点和截断基因的能力。然而，只有将 MPS 数据与传统的 G 带和广泛的荧光原位杂交相结合，我们才能描绘出衍生染色体的精确结构。
