Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis
Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis
复制标题
DOI：
10.1016/j.ajhg.2016.08.022
复制
发表时间：
2016-11-03
影响因子：
9.8
通讯作者：
Morton, Cynthia C.
中科院分区：
文献类型：
--
作者：
Ordulu, Zehra;Kammin, Tammy;Morton, Cynthia C.
在这个激动人心的“下一代细胞遗传学”时代，将基因组测序整合到产前诊断环境中是可能的，并且可以在核苷酸水平上精确描绘平衡的染色体重排。考虑到新生儿染色体重新平衡重排的先天性异常风险增加，对断点的全面解释可以大大提高表型结局的预测，并支持围产期医疗护理。在此，我们提出并评估10个产前受试者的染色体重排平衡的测序结果，相对于调节染色质结构域（拓扑相关结构域[TADS]）的位置。来自所有受试者的基因组材料通过微阵列分析被解释为“正常”，并且它们的重排不会通过无细胞DNA（cfDNA）筛选被检测到。我们的系统方法的结果与妊娠不良结局（5/10）和健康新生儿（3/10）的表型相关。2例妊娠，1例染色体畸变预测为未知临床意义，另1例预测可能为良性，在表型-基因型相关性之前终止（2/10）。我们证明，结构重排的临床解释不应仅限于中断，删除或重复的特定基因，还应纳入人类基因组的调控结构域与关键分支的基因表达控制。如本研究所详述，我们检测和解释结构重排断点的分子方法与其他常用的一级诊断方法（如非侵入性cfDNA筛选和微阵列分析）相比，产生了无与伦比的信息，为产前环境中的表型结果提供了改进的遗传咨询。
In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care. Herein, we present and evaluate sequencing results of balanced chromosomal rearrangements in ten prenatal subjects with respect to the location of regulatory chromatin domains (topologically associated domains [TADS]). The genomic material from all subjects was interpreted to be "normal" by microarray analyses, and their rearrangements would not have been detected by cell-free DNA (cfDNA) screening. The findings of our systematic approach correlate with phenotypes of both pregnancies with untoward outcomes (5/10) and with healthy newborns (3/10). Two pregnancies, one with a chromosomal aberration predicted to be of unknown clinical significance and another one predicted to be likely benign, were terminated prior to phenotype-genotype correlation (2/10). We demonstrate that the clinical interpretation of structural rearrangements should not be limited to interruption, deletion, or duplication of specific genes and should also incorporate regulatory domains of the human genome with critical ramifications for the control of gene expression. As detailed in this study, our molecular approach to both detecting and interpreting the breakpoints of structural rearrangements yields unparalleled information in comparison to other commonly used first-tier diagnostic methods, such as non-invasive cfDNA screening and microarray analysis, to provide improved genetic counseling for phenotypic outcome in the prenatal setting.