Catastrophic cellular events leading to complex chromosomal rearrangements in the germline

Abstract

Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

“…According to our literature search, no other constitutional CCR involving chromosomes 1, 9, and 10 in the same instance has previously been described [e.g., Madan et al, 1997;Nguyen et al, 2015;Fukami et al, 2017]. In fact, CCRs specifically overlapping the breakpoints and entailing the same imbalance for one or the other chromosomes described herein are fairly infrequent (18 cases for chromosome 1, 0 cases for chromosome 9, and 3 cases for chromosome 10; ECARUCA).…”

“…Although the clear overlap between some unspecific features of these syndromes prevents us from accurately defining the preponderancy of one gene imbalance over the other, the brain and cardiac anomalies were probably induced by the 1qter monosomy, whereas the craniofacial and skeletal alterations are likely due to a combination of both imbalances. Since a balanced CCR involving chromosome 10 increases the risk of spontaneous abortions [Tulay et al, 2014;Fukami et al, 2017], the full study of this case allowed improved genetic counseling.…”

“…Constitutional complex chromosomal rearrangements (CCRs) are relatively rare events [e.g., Berend et al, 2002;Scriven et al, 2014] that typically involve 2 or more chromosomes with at least 3 breakpoints and can result in normal or abnormal phenotypes depending on whether they entail imbalances, disrupt coding or regulatory regions, or somehow disturb the euchromatic neighborhood [Fukami et al, 2017]. CCRs often arise through well-known errors in replication or recombination that ultimately lead to the "accumulation" of DNA defects.…”

“…CCRs often arise through well-known errors in replication or recombination that ultimately lead to the "accumulation" of DNA defects. Alternatively, some germline CCRs (mainly nonrecurrent ones) are thought to be caused by a single catastrophic event -termed chromothripsis -during cell division, most likely during spermatogenesis [Kloosterman et al, 2011;Cretu Stancu et al, 2017;Fukami et al, 2017].…”

“…However, in the last decade, a combination of high-resolution platforms and conventional cytogenetics has substantially improved our capability to detect CCRs [e.g., Gu et al, 2013;Fukami et al, 2017]. In this report, an apparent 2-way translocation was reclassified as a 3-way translocation after microarray analysis of the genome of a severely affected toddler revealed the involvement of a new chromosome that was not previously identified by Gbanding in his phenotypically normal mother, i.e., an apparent t(1; 9) translocation turned out to be a t(1; 10; 9) CCR, which is unbalanced in the child and balanced in his mother.…”