Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55902, USA.
Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Manchester Center for Audiology and Deafness, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, UK.
Am J Hum Genet. 2019 Apr 4;104(4):565-577. doi: 10.1016/j.ajhg.2019.02.024.
Structural variation, composed of balanced and unbalanced genomic rearrangements, is an important contributor to human genetic diversity with prominent roles in somatic and congenital disease. At the nucleotide level, structural variants (SVs) have been shown to frequently harbor additional breakpoints and copy-number imbalances, a complexity predicted to emerge wholly as a single-cell division event. Chromothripsis, chromoplexy, and chromoanasynthesis, collectively referred to as chromoanagenesis, are three major mechanisms that explain the occurrence of complex germline and somatic SVs. While chromothripsis and chromoplexy have been shown to be key signatures of cancer, chromoanagenesis has been detected in numerous cases of developmental disease and phenotypically normal individuals. Such observations advocate for a deeper study of the polymorphic and pathogenic properties of complex germline SVs, many of which go undetected by traditional clinical molecular and cytogenetic methods. This review focuses on congenital chromoanagenesis, mechanisms leading to occurrence of these complex rearrangements, and their impact on chromosome organization and genome function. We highlight future applications of routine screening of complex and balanced SVs in the clinic, as these represent a potential and often neglected genetic disease source, a true "iceberg under water."
结构变异由平衡和不平衡的基因组重排组成，是人类遗传多样性的一个重要贡献者，在体细胞核先天疾病中起着重要作用。在核苷酸水平上，结构变异（SVs）经常带有额外的断点和拷贝数失衡，这种复杂性被预测完全是作为一个单细胞分裂事件而出现的。染色体重排、染色体重组和染色体重合，统称为染色体重组，是解释复杂种系和体细胞 SVs 发生的三种主要机制。虽然染色体重排和染色体重组已被证明是癌症的关键特征，但染色体重组在许多发育性疾病和表型正常个体中也有发现。这些观察结果主张对复杂种系 SVs 的多态性和致病性特性进行更深入的研究，其中许多特性是传统的临床分子和细胞遗传学方法无法检测到的。本综述重点介绍先天性染色体重组，导致这些复杂重排发生的机制，以及它们对染色体组织和基因组功能的影响。我们强调了在临床中常规筛查复杂和平衡 SVs 的未来应用，因为这些代表了一个潜在的、经常被忽视的遗传疾病来源，一个真正的“水下冰山”。
