The Iceberg under Water: Unexplored Complexity of Chromoanagenesis in Congenital Disorders

Abstract

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.''

Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

“…Chromothripsis results in massive chromosomal reconstruction with or without deletion. The breakpoints are usually consistent with canonical NHEJ [Kloosterman et al, 2011;Stephens et al, 2011;Marcozzi et al, 2018;Zepeda-Mendoza and Morton, 2019]. In addition, the pulverized DNA fragments may also be reassembled via alternative end-joining or via the co-occurrence of NHEJ and alternative end-joining [Kloosterman et al, 2012;Slamova et al, 2018].…”

“…Chromoanasynthesis is characterized by microhomologies around breakpoints. Unlike chromothripsis, chromoanasynthesis is frequently associated with amplifications [Liu et al, 2011a;Marcozzi et al, 2018;Nazaryan-Petersen et al, 2018;Zepeda-Mendoza and Morton, 2019]. Chromoanasynthesis can create multiple CNVs clustered on a single chromosome [Liu et al, 2011a;.…”

“…Chromoplexy is different from chromothripsis in the following ways: (1) it involves multiple chromosomes, (2) it creates fewer breakpoints in 1 chromosome than those created by chromothripsis, and (3) it is implicated primarily in the translocations of somatic cells [Berger et al, 2011;Baca et al, 2013;Marcozzi et al, 2018;Zepeda-Mendoza and Morton, 2019]. However, chromoplexy has several similar characteristics to chromothripsis, such as copynumber-neutral rearrangements with NHEJ-compatible breakpoint structures.…”

Whole‐genome sequencing reveals complex chromosome rearrangement disrupting NIPBL in infant with Cornelia de Lange syndrome

“…Finally, chromoanasynthesis, defined in constitutional mutational studies of patients, results from a chromothripsis‐like pattern with a multitude of break‐join events followed by chromosome reconstitution with resulting multiple CNVs including gains such as locus duplication and triplication events (Liu et al, ). These terms, thought also to reflect the potential underlying rearrangement mechanisms of nonhomologous end joining (NHEJ) versus replicative repair by microhomology‐mediated break‐induced replication (MMBIR) (Maher & Wilson, ; Zhang, Carvalho, & Lupski, ), have been grouped together under the umbrella term chromoanagenesis, or “chromosome rebirth” (Pellestor, ; Zepeda‐Mendoza & Morton, ).…”

Repair and Reconstruction of Telomeric and Subtelomeric Regions and Genesis of New Telomeres: Implications for Chromosome Evolution

“…The mmBIR events probably mediate chromoanasynthesis where a locus has clustered complex structural variations (SVs), especially CNVs in random order, and also has shared microhomology at junctions of the copied segments. [ 106 ] In cancer or congenital diseases, the gene truncation, gene fusion, and gene haploinsufficiency produced by chromoanasynthesis may have an important influence on the resulting phenotypes. In addition, chromoanasynthesis may reconstruct subtelomere or telomeres that are subject to replication stress in normal cells.…”